RESUMEN
Two cases of high-grade glioma comprising sheets of oligodendroglial cells multifocally disrupted by regions of remarkable neuronal differentiation are described. These tumours morphologically resemble 'oligodendroglioma with ganglioglioma-like maturation', a rare tumour of man, but appear to be phenotypically more aggressive. Neuronal markers (synaptophysin, neuron-specific enolase and ßIII-tubulin) effectively highlight neuronal elements within these tumours and could potentially help to further investigate the prevalence and biological significance of neuronal differentiation in canine oligodendroglioma.
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Neoplasias Encefálicas/veterinaria , Enfermedades de los Perros/patología , Oligodendroglioma/veterinaria , Fosfopiruvato Hidratasa/metabolismo , Sinaptofisina/metabolismo , Tubulina (Proteína)/metabolismo , Animales , Biomarcadores/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Diferenciación Celular , Enfermedades de los Perros/metabolismo , Perros , Histocitoquímica , Masculino , Neuronas/metabolismo , Neuronas/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Oligodendroglioma/metabolismo , Oligodendroglioma/patologíaRESUMEN
BACKGROUND AND PURPOSE: Atherosclerotic plaque composition and structure contribute to the risk of plaque rupture and embolization. Virtual histology by intravascular ultrasonography and high-resolution MR imaging are new imaging modalities that have been used to characterize plaque morphology and composition in peripheral arteries. MATERIALS AND METHODS: The objectives of this study were 1) to determine the correlation between virtual histology-intravascular ultrasonography and histopathologic analysis (reference standard) and 2) to explore the comparative results of 7T MR imaging (versus histopathologic analysis), both to be performed in vitro by use of intracranial arterial segments with atherosclerotic plaques. Thirty sets of postmortem samples of intracranial circulation were prepared for the study. These samples included the middle cerebral artery (n = 20), basilar artery (n = 8), and anterior cerebral artery (n = 2). Virtual histology-intravascular ultrasonography and 7T MR imaging were performed in 34 and 10 points of interest, respectively. The formalin-fixed arteries underwent tissue processing and hematoxylin-eosin staining. The plaques were independently categorized according to revised Stary classification after review of plaque morphology and characteristics obtained from 3 modalities. The proportion of fibrous, fibrofatty, attenuated calcium, and necrotic components in the plaques were determined in histology slides and compared with virtual histology-intravascular ultrasonography and MR imaging. RESULTS: Of 34 points of interest in the vessels, 32 had atherosclerotic plaques under direct visualization. Plaques were visualized in gray-scale intravascular ultrasonography as increased wall thickness, outer wall irregularity, and protrusion. The positive predictive value of virtual histology-intravascular ultrasonography for identifying fibroatheroma was 80%. Overall, virtual histology-intravascular ultrasonography accurately diagnosed the type of the plaque in 25 of 34 samples, and κ agreement was 0.58 (moderate agreement). The sensitivity and specificity of virtual histology-intravascular ultrasonography readings for fibroatheroma were 78.9% and 73.3%, respectively. The overall sensitivity and specificity for virtual histology-intravascular ultrasonography were 73.5% and 96.6%, respectively. Plaques were identified in 7T MR imaging as increased wall thickness, luminal stenosis, or outer wall protrusion. The positive predictive value of 7T MR imaging for detecting fibrous and attenuated calcium deposits was 88% and 93%, respectively. CONCLUSIONS: This in vitro study demonstrated that virtual histology-intravascular ultrasonography and high-resolution MR imaging are reliable imaging tools to detect atherosclerotic plaques within the intracranial arterial wall, though both imaging modalities have some limitations in accurate characterization of the plaque components. Further clinical studies are needed to determine the clinical utility of plaque morphology and composition assessment by noninvasive tests.
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Arterias Cerebrales/diagnóstico por imagen , Arterias Cerebrales/patología , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/patología , Imagen por Resonancia Magnética/métodos , Ultrasonografía Intervencional/métodos , Interfaz Usuario-Computador , Humanos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadAsunto(s)
Neurilemoma/diagnóstico , Neoplasias Torácicas/diagnóstico , Vértebras Torácicas/cirugía , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Mielitis Transversa/diagnóstico , Mielitis Transversa/cirugía , Neurilemoma/cirugía , Compresión de la Médula Espinal/diagnóstico , Compresión de la Médula Espinal/cirugía , Neoplasias Torácicas/cirugíaRESUMEN
OBJECTIVE: To provide clinical data on a cohort of 6 patients with massive expansion (>200 CAG repeats) of spinocerebellar ataxia type 2 (SCA2) and investigate possible pathways of pathogenesis using bioinformatics analysis of ATXN2 networks. METHODS: We present data on 6 patients with massive expansion of SCA2 who presented in infancy with variable combinations of hypotonia, global developmental delay, infantile spasms, and retinitis pigmentosa. ATXN2 is known to interact with a network of synaptic proteins. To investigate pathways of pathogenesis, we performed bioinformatics analysis on ATXN2 combined with known genes associated with infantile spasms, retinitis pigmentosa, and synaptic function. RESULTS: All patients had a progressive encephalopathy with autonomic dysfunction, 4 had retinitis pigmentosa, and 3 had infantile spasms. The bioinformatics analysis led to several interesting findings. First, an interaction between ATXN2 and SYNJ1 may account for the development of retinitis pigmentosa. Second, dysfunction of postsynaptic vesicle endocytosis may be important in children with this progressive encephalopathy. Infantile spasms may be associated with interactions between ATXN2 and the postsynaptic structural proteins MAGI2 and SPTAN1. CONCLUSIONS: Severe phenotype in children with massive expansion of SCA2 may be due to a functional deficit in protein networks in the postsynapse, specifically involving vesicle endocytosis.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/genética , Retinitis Pigmentosa/genética , Espasmos Infantiles/genética , Expansión de Repetición de Trinucleótido/genética , Ataxinas , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Preescolar , Resultado Fatal , Femenino , Humanos , Lactante , Masculino , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Fenotipo , Densidad Postsináptica/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/metabolismo , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/metabolismoRESUMEN
Lymphomatoid granulomatosis (LA) is a rare angiocentric lymphoreticular proliferative disease that primarily involves the lungs but may also involve extrapulmonary sites including the central nervous system, skin, and kidneys. It is rare for this condition to affect children, and presentation as a cerebellar mass is unusual. In this report, we describe a 10-year-old girl with biopsy-proved cerebellar LA.
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Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/patología , Granulomatosis Linfomatoide/diagnóstico por imagen , Granulomatosis Linfomatoide/patología , Adolescente , Femenino , Humanos , RadiografíaRESUMEN
A 20-year-old patient, who received a bone marrow transplant in order to treat metachromatic leukodystrophy (MLD), succumbed to cytomegalovirus (CMV) encephalitis. After CMV viremia developed, the patient received ganciclovir, but he was switched to foscarnet when ganciclovir resistance was suspected. Foscarnet was discontinued because of concern about its potential central nervous system toxicity. Autopsy samples of brain and cerebrospinal fluid contained CMV DNA with a UL97 mutation (M460V) known to confer ganciclovir resistance. No foscarnet resistance mutations were found.
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Antivirales/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Infecciones por Citomegalovirus/tratamiento farmacológico , Encefalitis Viral/tratamiento farmacológico , Ganciclovir/uso terapéutico , Adulto , Citomegalovirus/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/patología , Farmacorresistencia Viral , Encefalitis Viral/etiología , Encefalitis Viral/patología , Foscarnet/uso terapéutico , Humanos , Leucodistrofia Metacromática/terapia , MasculinoRESUMEN
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles contained proteins from the somatodendritic membrane, including mGluR1, GluRDelta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examination of PKCgamma revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKCgamma localization at the Purkinje cell dendritic membrane and decreased detection of PKCgamma by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic membrane trafficking and loss of proteins including PKCgamma, are a part of the neuronal dysfunction in SCA1 transgenic mice.
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Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/fisiología , Proteínas Nucleares/fisiología , Células de Purkinje/metabolismo , Animales , Ataxina-1 , Ataxinas , Cisteína Endopeptidasas/metabolismo , Citoplasma/metabolismo , Citoplasma/ultraestructura , Dendritas/metabolismo , Membranas Intracelulares/metabolismo , Isoenzimas/metabolismo , Ratones , Ratones Transgénicos/genética , Complejos Multienzimáticos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Complejo de la Endopetidasa Proteasomal , Proteína Quinasa C/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Distribución Tisular , Ubiquitinas/metabolismoRESUMEN
OBJECTIVE AND IMPORTANCE: Venous obstruction has been postulated as a cause of increased intracranial pressure, but it has been documented rarely. We present a case of obstruction of the torcula by a slow-growing epidermoid. The tumor caused increased intracranial pressure, which was relieved when it was excised. In addition, the torcular epidermoid is associated with a bifid straight sinus. CLINICAL PRESENTATION: A 35-year-old man presented with a headache and a lump on the back of the head. Physical examination revealed a firm, bony lesion approximately 4 x 4 cm in size. Lumbar puncture demonstrated an intraspinal pressure of 39 cm H2O. Neuroradiological studies revealed an epidermoid that compressed and almost completely occluded the torcula. INTERVENTION: After the tumor was resected, the intraspinal pressure decreased to 19 cm H2O and remained stable 6 months later. CONCLUSION: Pure venous obstruction causes increased intracranial pressure. Removal of the obstruction relieves the intracranial hypertension. In addition, computed tomographic venography is a safe and easy method of documenting torcular anatomy, and it was useful in the follow-up of this patient. Computed tomographic venography can demonstrate a double straight sinus, which is a congenital variant that may be associated with the epidermoid.
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Quiste Epidérmico/cirugía , Hipertensión Intracraneal/cirugía , Hueso Occipital/cirugía , Diagnóstico Diferencial , Quiste Epidérmico/complicaciones , Humanos , Hipertensión Intracraneal/etiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Hueso Occipital/patologíaRESUMEN
We evaluate the impact of extent of surgery (EOS) on survival of patients with supratentorial nonpilocytic low-grade gliomas (LGG) treated with postoperative radiation therapy (PORT). Sixty-five patients with pathologically confirmed supratentorial nonpilocytic LGG (36 astrocytomas and 29 oligodendrogliomas) were treated with PORT after different extents of surgery: 12 gross total resections (GTR), 27 minimal or subtotal resections (MR/SR), and 26 biopsies (B). EOS was confirmed with postoperative imaging. The median radiation dose delivered was 5,940 cGy (range, 4,950-6,620 cGy). One of 12 patients (8%) in the GTR group and 12 of 53 patients (23%) in the less than GTR group demonstrated contrast enhancement. The median follow-up was 61 months (range 5-194 month). The 10-year overall survival (OS) was 82.5% and 32% for the GTR and the less than GTR groups, respectively (P = 0.0008). The corresponding 10-year disease-specific survival (DSS) was 90% and 41.4%%, respectively (P = 0.001). Multivariate analysis showed that only contrast enhancement and EOS were predictors for OS and DSS. Our data suggest that EOS correlates with OS and DSS in patients who have PORT. GTR should be the goal if technically achievable without causing significant morbidity, and its combination with PORT is compatible with long-term survival.
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Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Glioma/radioterapia , Glioma/cirugía , Adulto , Neoplasias Encefálicas/mortalidad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta en la Radiación , Femenino , Glioma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Spinocerebellar ataxia type 1 (SCA1) is one of a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene. One of the major cell types affected by the gene (ataxin-1) mutation in SCA1 is the cerebellar Purkinje cell. Targeted expression of mutant ataxin-1 in Purkinje cells of transgenic mice produces an ataxic phenotype with pathological similarities to the human disease. Other transgenic experiments using altered forms of mutant ataxin-1 have shown that nuclear localization of the mutant protein is necessary for pathogenesis and that nuclear aggregates of ubiquitinated mutant protein, while a feature of SCA1 and other polyglutamine diseases, are not a requirement for pathogenesis in transgenic models of SCA1. Present and future generations of transgenic mouse models of SCA1 will be valuable tools to further address mechanisms of pathogenesis in polyglutamine-related disorders.
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Modelos Animales de Enfermedad , Enfermedades Neurodegenerativas/patología , Péptidos/genética , Ataxias Espinocerebelosas/patología , Animales , Ataxina-1 , Ataxinas , Encéfalo/patología , Núcleo Celular/metabolismo , Núcleo Celular/patología , Núcleo Celular/ultraestructura , Cerebelo/patología , Cerebelo/ultraestructura , Nervios Craneales/patología , Humanos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Atrofias Olivopontocerebelosas/patología , Células de Purkinje/patología , Células de Purkinje/ultraestructura , Médula Espinal/patología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/metabolismo , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
PURPOSE: To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy. METHODS AND MATERIALS: Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35 %) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. RESULTS: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p<0.05). CONCLUSION: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.
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Astrocitoma/cirugía , Neoplasias Encefálicas/cirugía , Recurrencia Local de Neoplasia/cirugía , Oligodendroglioma/cirugía , Radiocirugia/métodos , Adolescente , Adulto , Anciano , Astrocitoma/mortalidad , Encéfalo/patología , Encéfalo/efectos de la radiación , Neoplasias Encefálicas/mortalidad , Femenino , Glioblastoma/mortalidad , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Necrosis , Recurrencia Local de Neoplasia/mortalidad , Oligodendroglioma/mortalidad , Traumatismos por Radiación/patología , Radiocirugia/efectos adversos , Dosificación Radioterapéutica , Estudios Retrospectivos , Análisis de Supervivencia , Insuficiencia del TratamientoRESUMEN
The prostaglandin synthesizing enzyme cyclooxygenase-2 (COX-2) is up-regulated in the brain of rodents during cerebral ischemia and contributes to ischemic brain injury. This study sought to determine whether COX-2 is also up-regulated in the human brain in the acute stages of cerebral ischemic infarction. Paraffin-embedded sections from patients who died 1-2 days following infarction in the middle cerebral artery territory were processed for COX-2 immunohistochemistry. COX-2 immunoreactivity was observed in infiltrating neutrophils, in vascular cells and in neurons located at the border of the infarct. The data suggest that COX-2 up-regulation is also relevant to cerebral ischemia in humans and raise the possibility that COX-2 reaction products participate in the mechanisms of ischemic injury also in the human brain.
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Isquemia Encefálica/enzimología , Encéfalo/enzimología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/irrigación sanguínea , Arterias Cerebrales/enzimología , Infarto Cerebral/enzimología , Infarto Cerebral/patología , Ciclooxigenasa 2 , Femenino , Humanos , Inmunohistoquímica , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Neuronas/enzimología , Neuronas/patología , Neutrófilos/enzimologíaRESUMEN
The inducible or "immunological" isoform of nitric oxide synthase (iNOS) is induced in many cell types by inflammatory stimuli and synthesizes toxic amounts of NO. In rodent models of focal cerebral ischemia, iNOS is expressed in neutrophils invading the injured brain and in local blood vessels. Studies with iNOS inhibitors and iNOS null mice indicate that NO produced by iNOS contributes to ischemic brain injury. In the present study, we sought to determine whether iNOS is also expressed in the human brain after ischemic stroke. Studies were conducted using immunohistochemistry on autopsy brains with neuropathological evidence of acute cerebral infarction. iNOS immunoreactivity was observed in neutrophils infiltrating the ischemic brain and in blood vessels within the ischemic territory. iNOS-positive cells also were immunoreactive for nitrotyrosine, reflecting protein nitration by NO-derived peroxynitrite and nitrites. iNOS or nitrotyrosine immunoreactivity was not detected outside the region of the infarct. These observations provide evidence that iNOS is expressed in the human brain after ischemic infarction and support the hypothesis that iNOS inhibitors may be useful in the treatment of ischemic stroke in humans.
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Infarto Cerebral/enzimología , Óxido Nítrico Sintasa/biosíntesis , Anciano , Anciano de 80 o más Años , Vasos Sanguíneos/enzimología , Eosinófilos/enzimología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Necrosis , Neuronas/patología , Neutrófilos/enzimología , Óxido Nítrico Sintasa de Tipo IIRESUMEN
Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.
Asunto(s)
Ataxia/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Animales , Ataxia/inducido químicamente , Ataxina-1 , Ataxinas , Células COS , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Enfermedades Neurodegenerativas/etiología , Señales de Localización Nuclear/genética , Señales de Localización Nuclear/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Péptidos , Células de Purkinje/metabolismoRESUMEN
Transgenic targeting of SV40 large T antigen (Tag) expression to murine cerebellar Purkinje cells induces these normally postmitotic neurons to undergo DNA synthesis and apoptosis. It has been proposed that these effects of Tag are due to the binding of Tag to pRb, which leads to the release and activation of the transcription factor E2F. Here it is reported that E2F and CDC2, the protein product of a gene regulated by E2F, were detectable in the Purkinje cell nuclei of Tag expressing transgenic animals. To directly test whether E2F-1 is part of the mechanism of Tag-induced Purkinje cell degeneration, transgenic mice that overexpress E2F-1 specifically in cerebellar Purkinje cells were generated. Although E2F-1 itself did not affect Purkinje cells, it did accelerate Tag-induced ataxia and Purkinje cell loss, suggesting that E2F-1 can contribute to the mechanism of Tag-induced Purkinje cell degeneration.
Asunto(s)
Antígenos Transformadores de Poliomavirus/genética , Proteínas Portadoras , Moléculas de Adhesión Celular Neuronal , Proteínas de Ciclo Celular , Degeneración Nerviosa/metabolismo , Células de Purkinje/fisiología , Factores de Transcripción/fisiología , Animales , Antígenos Transformadores de Poliomavirus/metabolismo , Northern Blotting , Proteína Quinasa CDC2/genética , Contactina 2 , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/fisiología , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Expresión Génica/fisiología , Glicoproteínas de Membrana/genética , Ratones , Ratones Transgénicos , Células de Purkinje/química , ARN Mensajero/metabolismo , Proteína 1 de Unión a Retinoblastoma , Factor de Transcripción DP1 , Factores de Transcripción/análisisRESUMEN
We used transgenic mice with Purkinje cell dysfunction (PO3 line) to study the role of these neurons in the increase in cerebellar blood flow (BFcrb) produced by stimulation of the cerebellar parallel fibers (PF). Mice (age 8-10 wk) were anesthetized (halothane) and artificially ventilated. Arterial pressure and end-tidal CO2 were monitored continuously. Arterial blood gases were measured. The PF were stimulated electrically (100 microA, 30 Hz; 40 s), and the increases in BFcrb were monitored by a laser-Doppler flow probe. First, we characterized the increases in BFcrb and the field potentials produced by PF stimulation in normal mice. PF stimulation evoked the typical field potentials and increased BFcrb by 60 +/- 4% (100 microA, 30 Hz; n = 10). The increases in BFcrb were attenuated by the broad-spectrum glutamate receptor antagonist kynurenate (-84 +/- 3%; P < 0.05 analysis of variance; n = 5), by the DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (-62 +/- 6%; P < 0.05; n = 5), and by the nitric oxide synthase inhibitor N omega-nitro-L-arginine (-46 +/- 7%; P < 0.05; n = 5). In PO3 transgenic mice, the increases in BFcrb produced by PF stimulation were reduced (P < 0.001) at every stimulus intensity and frequency tested (residual increase at 100 microA, 30 Hz: 19 +/- 2%; n = 6). The field potentials evoked by PF stimulation also were abnormal in that they lacked the late negative wave (n = 6), a finding consistent with lack of depolarization of Purkinje cells. The residual flow response in the transgenics was abolished by N omega-nitro-L-arginine (n = 5; P > 0.05). Ultrastructural studies showed that the density of PF-Purkinje cell synapses is reduced in PO3 mice, whereas the morphology of molecular layer interneurons (stellate cells) is normal. The findings suggest that Purkinje cells are responsible for a sizable component of the flow response whereas molecular layer interneurons mediate the remainder of the response. The study provides evidence that mouse mutants with spontaneous or genetically engineered cerebellar abnormalities could be useful to study the cellular and molecular correlates of functional hyperemia in the central nervous system.
Asunto(s)
Cerebelo/irrigación sanguínea , Cerebelo/fisiología , Células de Purkinje/fisiología , Sinapsis/fisiología , Potenciales de Acción , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Cerebelo/ultraestructura , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Quinurénico/farmacología , Flujometría por Láser-Doppler , Ratones , Ratones Transgénicos , Microscopía Electrónica , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Células de Purkinje/ultraestructura , Quinoxalinas/farmacología , Receptores AMPA/antagonistas & inhibidoresRESUMEN
In this study we evaluate prognostic factors that predict local-regional control and survival following stereotactic radiosurgery (SRS) in patients with brain metastasis and establish guidelines for patient selection. Our evaluation is based on 73 patients with brain metastasis treated with SRS at the University of Minnesota between March 1991 and November 1995. The ability of stereotactic radiosurgery to improve local control in patients with brain metastases is confirmed in our study in which only 6 of 62 patients failed locally after SRS, with an actuarial local progression-free survival of 80% at 2 years. Variables that predicted worse prognosis were larger tumor size (p = 0.05) for local progression-free survival and multiplicity of metastasis (p = 0.03) and infratentorial location of metastases (p = 0.006) for regional progression-free survival. Absence of extracranial disease, KPS > or = 70, and single intracranial metastasis were significant predictors of longer survival. Patients who fulfill all three criteria will survive longer after SRS (MS = 17.7 months) and will most likely benefit from the increase local control in the brain achieved by SRS. Survival in patients who do not meet any of these criteria is very poor (MS = 1.5 months), and these patients are less likely to benefit from this treatment. Careful selection of patients for SRS is warranted.
Asunto(s)
Neoplasias Encefálicas/cirugía , Selección de Paciente , Radiocirugia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Complicaciones Posoperatorias/mortalidad , Pronóstico , Estudios Retrospectivos , Técnicas Estereotáxicas , Análisis de Supervivencia , Insuficiencia del TratamientoRESUMEN
Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the alpha1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.
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Edad de Inicio , Potenciales Evocados Visuales , Degeneración Nerviosa , Nistagmo Patológico/fisiopatología , Células de Purkinje , Degeneraciones Espinocerebelosas/patología , Degeneraciones Espinocerebelosas/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Movimientos Oculares , Femenino , Ligamiento Genético , Humanos , Escala de Lod , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nistagmo Patológico/patología , Linaje , Fenotipo , Degeneraciones Espinocerebelosas/complicaciones , Degeneraciones Espinocerebelosas/genéticaRESUMEN
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract. Work presented here describes the behavioral and neuropathological course seen in mutant SCA1 transgenic mice. Behavioral tests indicate that at 5 weeks of age mutant mice have an impaired performance on the rotating rod in the absence of deficits in balance and coordination. In contrast, these mutant SCA1 mice have an increased initial exploratory behavior. Thus, expression of the mutant SCA1 allele within cerebellar Purkinje cells has divergent effects on the motor behavior of juvenile animals: a compromise of rotating rod performance and a simultaneous enhancement of initial exploratory activity. With age, these animals develop incoordination with concomitant progressive Purkinje neuron dendritic and somatic atrophy but relatively little cell loss. Therefore, the eventual development of ataxia caused by the expression of a mutant SCA1 allele is not the result of cell death per se, but the result of cellular dysfunction and morphological alterations that occur before neuronal demise.
Asunto(s)
Conducta Animal/fisiología , Cerebelo/fisiopatología , Ratones Transgénicos/genética , Actividad Motora/fisiología , Células de Purkinje/fisiología , Degeneraciones Espinocerebelosas/genética , Alelos , Animales , Recuento de Células , Cerebelo/patología , Ratones , Mutación , Sistema Nervioso/fisiopatología , Células de Purkinje/patología , Degeneraciones Espinocerebelosas/patología , Degeneraciones Espinocerebelosas/fisiopatologíaRESUMEN
Expansions of CAG trinucleotide repeats encoding glutamine have been found to be the causative mutations of seven human neurodegenerative diseases. Similarities in the clinical, genetic, and molecular features of these disorders suggest they share a common mechanism of pathogenesis. Recent progress in the generation and characterization of transgenic mice expressing the genes containing expanded repeats associated with spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD/SCA3), and Huntington's disease (HD) is beginning to provide insight into the underlying mechanisms of these neurodegenerative disorders.