RESUMO
Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.
Assuntos
Aquaporinas/genética , Edema Encefálico/terapia , Deleção de Genes , Acidente Vascular Cerebral/terapia , Intoxicação por Água/complicações , Animais , Aquaporina 4 , Encéfalo/irrigação sanguínea , Encéfalo/ultraestrutura , Edema Encefálico/etiologia , Terapia Genética , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Acidente Vascular Cerebral/complicaçõesRESUMO
Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.
RESUMO
BACKGROUND AND PURPOSE: Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment. MATERIALS AND METHODS: We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment. RESULTS: Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression. CONCLUSIONS: This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.
Assuntos
Biomarcadores , Doenças do Sistema Nervoso/diagnóstico por imagem , Traumatismos da Medula Espinal/diagnóstico por imagem , Adulto , Idoso , Vértebras Cervicais/lesões , Estudos de Coortes , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Adulto JovemRESUMO
Aquaporins are intrinsic membrane proteins involved in water transport in fluid-transporting tissues. In the brain, aquaporin-4 (AQP4) is expressed widely by glial cells, but its function is unclear. Extensive basic and clinical studies indicate that osmolarity affects seizure susceptibility, and in our previous studies we found that AQP4 -/- mice have an elevated seizure threshold in response to the chemoconvulsant pentylenetetrazol. In this study, we examined the seizure phenotype of AQP4 -/- mice in greater detail using in vivo electroencephalographic recording. AQP4 -/- mice were found to have dramatically longer stimulation-evoked seizures following hippocampal stimulation as well as a higher seizure threshold. These results implicate AQP4 in water and potassium regulation associated with neuronal activity and seizures.
Assuntos
Aquaporina 4/metabolismo , Hipocampo/fisiopatologia , Convulsões/diagnóstico , Convulsões/fisiopatologia , Desequilíbrio Hidroeletrolítico/diagnóstico , Desequilíbrio Hidroeletrolítico/fisiopatologia , Animais , Aquaporina 4/genética , Células Cultivadas , Eletroencefalografia , Camundongos , Camundongos Transgênicos , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes and remains without a treatment of proven benefit. Despite several existing outcome prediction models for ICH, there is no standard clinical grading scale for ICH analogous to those for traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke. METHODS: Records of all patients with acute ICH presenting to the University of California, San Francisco during 1997-1998 were reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the ICH Score) was developed with weighting of independent predictors based on strength of association. RESULTS: Factors independently associated with 30-day mortality were Glasgow Coma Scale score (P<0.001), age >/=80 years (P=0.001), infratentorial origin of ICH (P=0.03), ICH volume (P=0.047), and presence of intraventricular hemorrhage (P=0.052). The ICH Score was the sum of individual points assigned as follows: GCS score 3 to 4 (=2 points), 5 to 12 (=1), 13 to 15 (=0); age >/=80 years yes (=1), no (=0); infratentorial origin yes (=1), no (=0); ICH volume >/=30 cm(3) (=1), <30 cm(3) (=0); and intraventricular hemorrhage yes (=1), no (=0). All 26 patients with an ICH Score of 0 survived, and all 6 patients with an ICH Score of 5 died. Thirty-day mortality increased steadily with ICH Score (P<0.005). CONCLUSIONS: The ICH Score is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH Score could improve standardization of clinical treatment protocols and clinical research studies in ICH.
Assuntos
Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/mortalidade , Índice de Gravidade de Doença , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Glicemia , California/epidemiologia , Hemorragia Cerebral/epidemiologia , Estudos de Coortes , Gerenciamento Clínico , Feminino , Escala de Coma de Glasgow , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Taxa de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
Paraneoplastic encephalomyelitis/paraneoplastic sensory neuronopathy (PEM/PSN) associated with small cell lung cancer is characterized by high serum and CSF titers of anti-neuronal (anti-Hu) antibodies and by intrathecal synthesis of anti-Hu IgG. A pathologic role for the anti-Hu antibodies in PEM/PSN is further suggested by reported intraneuronal accumulation of the antibodies in the nervous system of PEM/PSN patients at autopsy. We immunized SJL/J mice, Lewis rats, and Hartley guinea pigs with purified recombinant HuD fusion protein. In spite of high-titer anti-HuD antibodies, neurologic and pathologic examination of the animals was normal. Apparent uptake of purified IgG by neurons in the brain proved to be artifactual.
Assuntos
Encefalomielite/imunologia , Proteínas do Tecido Nervoso , Síndromes Paraneoplásicas/imunologia , Proteínas de Ligação a RNA/imunologia , Animais , Anticorpos/administração & dosagem , Formação de Anticorpos , Sequência de Bases , Encéfalo/patologia , Proteínas ELAV , Proteína Semelhante a ELAV 4 , Encefalomielite/patologia , Cobaias , Humanos , Imunização , Imuno-Histoquímica , Camundongos , Dados de Sequência Molecular , Síndromes Paraneoplásicas/patologia , Proteínas de Ligação a RNA/administração & dosagem , RatosRESUMO
HuD is one of a family of neural antigens recognised by the sera of patients with antibody-associated paraneoplastic encephalomyelitis. Localised exclusively to neurons, these proteins are among the earliest markers of the developing nervous system. Sequence analysis suggests that HuD is an RNA-binding protein. Hu protein levels were determined for the three cell types characterising human neuroblastoma cell lines: sympathoadrenal neuroblasts (N), substrate-adherent Schwann/glial/melanoblastic precursors (S) and stem cells (I) which can give rise to both N and S cells. Western blot analysis showed similar levels of protein in three N-type cell lines; S cells have no detectable Hu protein. Northern blot analysis indicated that N cells express all three Hu genes, HuD, HuC and Hel-N1. N cells, mostly from MYCN-amplified cell lines, have consistently higher steady-state levels of MYCN mRNA than S cell counterparts. Nuclear run-on and mRNA half-life experiments revealed no differences in transcription rate or mRNA stability between N and S cells from the LA-N-1 cell line, implicating differences in post-transcriptional regulation. HuD is postulated to be instrumental in splicing/processing and/or stabilisation of mRNAs involved in cell growth and neuronal differentiation. As determined by gel-mobility shift assays, HuD fusion protein binds to the 3'UTR of human MYCN mRNA. Analysis of HuD deletion mutants has demonstrated that the first and second RNA-recognition motifs (RRMs) are required for binding. Whether HuD regulates MYCN expression and thereby influences tumour aggressiveness is of major interest.
Assuntos
Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso , Neuroblastoma/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sítios de Ligação , Northern Blotting , Proteínas ELAV , Proteína Semelhante a ELAV 4 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Neuroblastoma/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Deleção de Sequência , Células Tumorais CultivadasRESUMO
Aquaporins (AQPs) are membrane proteins involved in water transport in many fluid-transporting tissues. Aquaporins AQP1, AQP4, and AQP9 have been identified in brain and hypothesized to participate in brain water homeostasis. Here we use reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry to describe the expression and immunolocalization of AQPs in adult mouse spinal cord. AQP4 was expressed in glial cells, predominantly in gray matter, and in astrocytic end-feet surrounding capillaries in spinal cord white matter. AQP9 expression extensively co-localized with glial fibrillary acidic protein-immunoreactive astrocytes, located predominantly in the white matter. AQP5 was detected by RT-PCR but not by immunohistochemical analysis. Interestingly, AQP8 was detected primarily in ependymal cells lining the fluid-filled central canal. The aquaporin expression pattern in spinal cord suggests involvement in water homeostasis and diseases associated with abnormal water fluxes such as spinal cord injury and syringomyelia.
Assuntos
Aquaporinas/genética , Aquaporinas/metabolismo , Medula Espinal/metabolismo , Animais , Animais não Endogâmicos , Aquaporina 1 , Aquaporina 4 , Aquaporina 5 , Canais Iônicos/genética , Canais Iônicos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Água/metabolismoRESUMO
Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.
Assuntos
Aquaporinas/genética , Edema Encefálico/fisiopatologia , Sistema Nervoso Central/fisiologia , Equilíbrio Hidroeletrolítico/genética , Água/metabolismo , Animais , Aquaporina 4 , Edema Encefálico/genética , Permeabilidade da Membrana Celular/genética , Sistema Nervoso Central/fisiopatologia , Predisposição Genética para Doença/genética , Camundongos , Camundongos Knockout , Fenótipo , Transdução de Sinais/genéticaRESUMO
Despite their diverse histological types, most brain tumours cause brain oedema, which is a significant cause of patient morbidity and mortality. Brain tumour oedema occurs when plasma-like fluid enters the brain extracellular space through impaired capillary endothelial tight junctions in tumours. Under-expression of the tight junction proteins occludin, claudin-1 and claudin-5 are key molecular abnormalities responsible for the increased permeability of tumour endothelial tight junctions. Recent evidence suggests that the membrane water channel protein aquaporin-4 (AQP4) also plays a role in brain tumour oedema. AQP4-deficient mice show remarkably altered brain water balance after various insults, including brain tumour implantation. AQP4 expression is strongly upregulated around malignant human brain tumours in association with reduced extracellular volume, which may restrict the flow of extracellular fluid from the tumour bed into the brain parenchyma. Elimination of excess fluid leaking into brain parenchyma requires passage across three AQP4-rich barriers: a) the glia limitans externa, b) the glia limitans interna/ependyma, and c) the blood-brain barrier. Modulation of the expression and/or function of endothelial tight junction proteins and aquaporins may provide novel therapeutic options for reducing brain tumour oedema.
Assuntos
Barreira Hematoencefálica/fisiopatologia , Edema Encefálico/fisiopatologia , Neoplasias Encefálicas/fisiopatologia , Células Endoteliais/metabolismo , Animais , Aquaporinas/genética , Aquaporinas/metabolismo , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Neoplasias Encefálicas/complicações , Permeabilidade da Membrana Celular/genética , Claudina-1 , Células Endoteliais/ultraestrutura , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Junções Íntimas/genética , Junções Íntimas/metabolismo , Junções Íntimas/ultraestruturaRESUMO
OBJECTIVE: To describe the normal relationships between brain tissue oxygen tension (PbrO2) and physiological parameters of systemic blood pressure and CO2 concentrations. METHODS: Licox Clark-type oxygen probes (GMS mbH, Kiel, Germany) were inserted in the frontal white matter of 12 swine maintained under general anesthesia with a 1.0 fraction of inspired oxygen (FiO2). In seven swine, alterations in end-tidal carbon dioxide (ET-CO2) concentration (range, 13-72 mm Hg) were induced via hyperventilation or instillation of CO2 into the ventilation circuit. In nine swine, mean arterial pressure (MAP) (range, 33-200 mm Hg) was altered; phenylephrine was used to induce hypertension, and a nitroprusside-esmolol combination or systemic hemorrhage was used for hypotension. Quantitative cerebral blood flow (CBF) was measured in two animals by using a thermal diffusion probe. RESULTS: Mean baseline PbrO2 was 41.9 +/- 11.3 mm Hg. PbrO2 varied linearly with changes in ET-CO2, ranging from 20 to 60 mm Hg (r2 = 0.70). The minimum PbrO2 with hypocarbia was 5.9 mm Hg, and the maximum PbrO2 with hypercarbia was 132.4 mm Hg. PbrO2 varied with MAP in a sigmoid fashion suggestive of pressure autoregulation between 60 and 150 mm Hg (r2 = 0.72). The minimum PbrO2 with hypotension was 1.4 mm Hg, and the maximum PbrO2 with hypertension was 97.2 mm Hg. In addition, CBF correlated linearly with PbrO2 during CO2 reactivity testing (r2 = 0.84). CONCLUSION: In the uninjured brain, PbrO2 exhibits CO2 reactivity and pressure autoregulation. The relationship of PbrO2 with ET-CO2 and MAP appears to be similar to those historically established for CBF with ET-CO2 and MAP. This suggests that, under normal conditions, PbrO2 is strongly influenced by factors that regulate CBF.
Assuntos
Pressão Sanguínea/fisiologia , Encéfalo/metabolismo , Dióxido de Carbono/metabolismo , Homeostase/fisiologia , Oxigênio/metabolismo , Animais , Dióxido de Carbono/sangue , Hipertensão/metabolismo , Hipotensão/metabolismo , Masculino , Pressão Parcial , Suínos , Volume de Ventilação PulmonarRESUMO
The authors report on a series of patients who underwent lumbar drainage of cerebrospinal fluid (CSF) for treatment of posterior fossa pseudomeningoceles and who subsequently developed an acute posterior fossa syndrome. These patients were found to have similar radiological findings demonstrating acute mass effect secondary to movement of CSF from the pseudomeningocele into the cerebellar parenchyma. Discontinuation of lumbar drainage resulted in symptomatic and radiological improvement in all patients. From these cases the authors infer that not all pseudomeningoceles communicate directly with the subarachnoid space. A readily recognizable appearance on magnetic resonance imaging that is useful in diagnosing this reversible complication of treatment for posterior fossa pseudomeningocele is also illustrated.
Assuntos
Doenças Cerebelares/cirurgia , Derivações do Líquido Cefalorraquidiano , Cistos/cirurgia , Meningocele/cirurgia , Complicações Pós-Operatórias/cirurgia , Doença Aguda , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/fisiopatologia , Fossa Craniana Posterior/cirurgia , Cistos/diagnóstico , Cistos/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Meningocele/diagnóstico , Meningocele/fisiopatologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/fisiopatologia , Reoperação , Punção EspinalRESUMO
The authors investigated the effects of a nontoxic differentiation inducer, phenylacetate (PA), on neuroectodermal tumor-derived cell lines. Treatment of medulloblastoma (Daoy and D283 MED) and glioma (U-251MG, C6, and RG2) cell lines resulted in a dose-dependent decline in DNA synthesis and cell proliferation, associated with accumulation in the G0/G1 phase of the cell cycle. Phenylacetate decreased transforming growth factor (TGF)-beta 2 production by medulloblastoma Daoy cells. Neutralizing antibodies against either TGF beta 2 or TGF beta 1 failed to block the growth arrest observed. This suggests that, unlike other differentiation agents, such as retinoic acid, the effect of PA on medulloblastoma proliferation is not mediated by a TGF beta pathway. In addition to cytostasis, PA induced marked morphological changes in U-251MG and C6 glioma cells associated with increased abundance of glial fibrillary acidic protein-positive processes. Although the morphology of PA-treated medulloblastoma cells was not significantly altered, the D283 MED cells exhibited increased expression of neurofilament proteins and Hu antigen, indicative of differentiation along a neuronal pathway. The effects of PA on the medulloblastoma cell lines were compared to its effects on the human neuroblastoma cell line BE(2)C, which is capable of a bidirectional differentiation toward a neuronal or a glial/schwann cell pathway. In BE(2)C cells, PA induced differentiation toward a schwann/glial cell-like phenotype, suggesting that the choice of differentiation pathway is cell type and agent specific. These in vitro antiproliferative and differentiation inducing effects of PA suggest that this agent warrants further evaluation as a potential therapeutic modality for the treatment of medulloblastoma and malignant glioma in humans.
Assuntos
Astrocitoma/patologia , Meduloblastoma/patologia , Proteínas do Tecido Nervoso , Fenilacetatos/farmacologia , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , DNA de Neoplasias/biossíntese , DNA de Neoplasias/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas ELAV , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas de Neurofilamentos/efeitos dos fármacos , Proteínas de Neurofilamentos/genética , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fenótipo , Fenilacetatos/administração & dosagem , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Ratos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/efeitos dos fármacosRESUMO
Aquaporin-1 (AQP1) is a water channel that is strongly expressed at the ventricular-facing surface of choroid plexus epithelium. Using wildtype and AQP1 null mice, we developed novel methods to compare the water permeability in isolated choroid plexus, and cerebrospinal fluid (CSF) production in living mice. Osmotically-induced water transport was rapid in freshly isolated choroid plexus from wildtype mice as measured by a spatial-filtering optical method, and reduced by 5-fold by AQP1 deletion. CSF production, an isosmolar fluid secretion process, was measured by a dye dilution method involving fluid collections using a second microneedle introduced into the cisterna magna. CSF production in wildtype mice was (in microl/min) 0.37 +/- 0.04 microl/min (control), 0.16 +/- 0.03 microl/min (acetazolamide-treated) and 1.14 +/- 0.15 microl/min (forskolin-treated), and reduced by up to 25% in AQP1 null mice. The impaired CSF production in AQP1 null mice provides direct functional evidence for the involvement of AQP1 in CSF formation.
Assuntos
Aquaporinas/genética , Líquido Cefalorraquidiano/metabolismo , Deleção de Genes , Água/metabolismo , Animais , Aquaporina 1 , Plexo Corióideo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Osmose , PermeabilidadeRESUMO
Aquaporins are membrane proteins involved in water transport in many fluid-transporting tissues. The objective of this study was to investigate the expression of aquaporins in malignant glial tumors associated with cerebral edema. Eighteen human glial tumors were obtained from the UCSF Neurosurgery Tissue Bank. Aquaporin-1 (AQP1) expression was evaluated via Western blot and immunohistochemistry. Intense upregulation of AQP1 expression was found in all glioblastomas. The robust expression of aquaporins in glioblastomas suggests a pathologic role for these membrane water channels, and raises the possibility that selective AQP inhibition might offer a new therapeutic option for tumor-associated cerebral edema.
Assuntos
Aquaporinas/metabolismo , Edema Encefálico/etiologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/metabolismo , Glioma/complicações , Glioma/metabolismo , Aquaporina 1 , Aquaporinas/antagonistas & inibidores , Astrócitos/metabolismo , Astrócitos/patologia , Antígenos de Grupos Sanguíneos , Western Blotting , Edema Encefálico/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioblastoma/complicações , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioma/patologia , Humanos , Imuno-HistoquímicaRESUMO
BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) may be a useful index of microstructural changes implicated in diffuse axonal injury (DAI) linked to persistent postconcussive symptoms, especially in mild traumatic brain injury (TBI), for which conventional MR imaging techniques may lack sensitivity. We hypothesized that for mild TBI, DTI measures of DAI would correlate with impairments in reaction time, whereas the number of focal lesions on conventional 3T MR imaging would not. MATERIALS AND METHODS: Thirty-four adult patients with mild TBI with persistent symptoms were assessed for DAI by quantifying traumatic microhemorrhages detected on a conventional set of T2*-weighted gradient-echo images and by DTI measures of fractional anisotropy (FA) within a set of a priori regions of interest. FA values 2.5 SDs below the region average, based on a group of 26 healthy control adults, were coded as exhibiting DAI. RESULTS: DTI measures revealed several predominant regions of damage including the anterior corona radiata (41% of the patients), uncinate fasciculus (29%), genu of the corpus callosum (21%), inferior longitudinal fasciculus (21%), and cingulum bundle (18%). The number of damaged white matter structures as quantified by DTI was significantly correlated with mean reaction time on a simple cognitive task (r = 0.49, P = .012). In contradistinction, the number of traumatic microhemorrhages was uncorrelated with reaction time (r = -0.08, P = .71). CONCLUSION: Microstructural white matter lesions detected by DTI correlate with persistent cognitive deficits in mild TBI, even in populations in which conventional measures do not. DTI measures may thus contribute additional diagnostic information related to DAI.
Assuntos
Concussão Encefálica/patologia , Lesões Encefálicas/patologia , Transtornos Cognitivos/diagnóstico , Imagem de Difusão por Ressonância Magnética/métodos , Fibras Nervosas Mielinizadas/patologia , Tempo de Reação , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estatística como Assunto , SíndromeRESUMO
Aquaporin-type water channels are expressed widely in mammalian tissues, particularly in the kidney, lung, eye and gastrointestinal tract. To define the role of aquaporins in organ physiology, we have generated and analysed transgenic mice lacking aquaporins (AQP) 1, 3, 4 and 5. Multiple phenotype abnormalities were found in the null mice. For example, in kidney, deletion of AQP1 or AQP3 produced marked polyuria whereas AQP4 deletion produced only a mild concentrating defect. Deletion of AQP5, the apical membrane water channel in the salivary gland, caused defective saliva production. Deletion of AQP1 or AQP5, water channels in lung endothelia and epithelia, resulted in a 90% decrease in airspace-capillary water permeability. In the brain, deletion of AQP4 conferred marked protection from brain swelling induced by acute water intoxication and ischaemic stroke. The general paradigm that has emerged from these phenotype studies is that aquaporins facilitate rapid near-isosmolar transepithelial fluid absorption/secretion, as well as rapid vectorial water movement driven by osmotic gradients. However, we have found many examples in which the tissue-specific expression of an aquaporin is not associated with any apparent phenotypic abnormality. The physiological data on aquaporin null mice suggest the utility of aquaporin blockers and aquaporin gene replacement in selected human diseases.
Assuntos
Aquaporinas/genética , Aquaporinas/metabolismo , Rim/química , Rim/metabolismo , Água/metabolismo , Animais , Camundongos , Camundongos Knockout , FenótipoRESUMO
HuD, a human neuronal RNA-binding protein, was the first identified member of a family of antigens that also includes HuC and Hel-N1 (Hu antigens). The serum of all patients with anti-Hu-associated paraneoplastic encephalomyelitis and sensory neuronopathy react with HuD and Hel-N1, but the reactivity with HuC is unknown. In the current study we examined (1) the reactivity of anti-Hu sera with HuD, HuC, and Hel-N1; (2) the expression of HuD, HuC, and Hel-N1 messenger RNA in small-cell lung cancer of patients with and those without paraneoplastic encephalomyelitis/sensory neuronopathy; (3) the correlation between anti-Hu serum reactivity with these three Hu antigens and the type of neurological symptoms; and (4) the major immunogenic sites of HuD. Our findings indicate that all anti-Hu sera react with HuD, HuC, and Hel-N1. However, only HuD is expressed in the small-cell lung cancer tumors, indicating that among the three Hu antigens, HuD appears to play a central role in triggering the anti-Hu immune response. No differences were identified regarding the reactivity of the anti-Hu antibodies with HuD, HuC, and Hel-N1 and the spectrum of neurological symptoms presented by the patients. Study of the major immunogenic sites of HuD resulted in the identification of two major immunodominant regions with at least two distinct epitopes recognized by the serum of all patients with anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy.
Assuntos
Anticorpos/imunologia , Epitopos/imunologia , Expressão Gênica/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas de Ligação a RNA/imunologia , Adolescente , Idoso , Sequência de Bases , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/imunologia , Proteínas ELAV , Proteína Semelhante a ELAV 4 , Encefalomielite/genética , Encefalomielite/imunologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Síndromes Paraneoplásicas/genética , Síndromes Paraneoplásicas/imunologia , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/imunologia , RNA Neoplásico/genética , RNA Neoplásico/imunologia , Deleção de Sequência , Células Tumorais CultivadasRESUMO
OBJECTIVES: Prophylactic hyperventilation of patients with head injuries worsens outcome, presumably by exacerbating tissue hypoxia. Oxygen tension in brain tissue (PbrO2) provides a direct measurement of cerebral metabolic substrate delivery and varies with changing end-tidal carbon dioxide tension (ETCO2) and mean arterial pressure. However, the effects of hyperventilation and hypoventilation on PbrO2 during hemorrhagic shock are not known. The aim of this study was to examine the effects of alteration in ventilation on PbrO2 in hemorrhaged swine. METHODS: Clark-type polarographic probes were inserted into the brain tissue of seven swine to measure PbrO2 directly. To examine the effects of alterations in ventilation on hemorrhage-induced hypotension, swine were hemorrhaged to 50% estimated blood volume and PbrO2 was monitored during hyperventilation (RR = 30) and hypoventilation (RR = 4). RESULTS: After the 50% hemorrhage, PbrO2 declined rapidly from 39.8 +/- 4.6 mm Hg to 11.4 +/- 2.2 mm Hg. Hyperventilation resulted in a further 56% mean decrease in PbrO2. Hypoventilation produced a 166% mean increase in PbrO2. These changes were significant (p = 0.001) for absolute and percentage differences from baseline. CONCLUSION: During hemorrhage, alterations in ventilation significantly changed PbrO2: hyperventilation increased brain-tissue hypoxia whereas hypoventilation alleviated it. This finding suggests that hyperventilation has deleterious effects on brain oxygenation in patients with hemorrhagic shock and those with head trauma. Conversely, hypoventilation with resultant hypercapnia may actually help resolve hemorrhagic shock-induced cerebral hypoxia.
Assuntos
Encéfalo/metabolismo , Hiperventilação/metabolismo , Hipoventilação/metabolismo , Oxigenoterapia/efeitos adversos , Ressuscitação/métodos , Choque Hemorrágico/terapia , Animais , Hemodinâmica , Hiperventilação/complicações , Hipóxia Encefálica/etiologia , Pressão Intracraniana , Masculino , Polarografia , Ressuscitação/efeitos adversos , Choque Hemorrágico/complicações , Choque Hemorrágico/metabolismo , SuínosRESUMO
OBJECTIVES: Recently developed polarographic microelectrodes permit continuous, reliable monitoring of oxygen tension in brain tissue (PbrO2). The aim of this study was to investigate the feasibility and utility of directly monitoring PbrO2 in cerebral tissue during changes in oxygenation or ventilation and during hemorrhagic shock and resuscitation. We also sought to develop a model in which treatment protocols could be evaluated using PbrO2 as an end point. METHODS: Licox Clark-type polarographic probes were inserted in the brain tissue of 16 swine to monitor PbrO2. In eight swine, changes in PbrO2 were observed over a range of fractional concentrations of inspired O2 (FiO2) as well as during periods of hyperventilation and hypoventilation. In eight other swine, PbrO2 was monitored during a graded hemorrhage of up to 70% estimated blood volume and during the resuscitation period. RESULTS: When FiO2 was elevated to 100%, PbrO2 increased from a baseline of 15+/-2 mm Hg to 36+/-11 mm Hg. Hyperventilation while breathing 100% oxygen resulted in a 40% decrease in PbrO2 (p < 0.05), whereas hypoventilation increased PbrO2 to 88 mm Hg (p < 0.01). A graded hemorrhage to 50% estimated blood volume significantly reduced PbrO2, mean arterial pressure, and intracranial pressure (p < 0.01). Continued hemorrhage to 70% estimated blood volume resulted in a PbrO2 of 2.9+/-1.5 mm Hg. After resuscitation, PbrO2 was significantly elevated, reaching 65+/-13 mm Hg (p < 0.01), whereas mean arterial pressure and cerebral perfusion pressure simply returned to baseline. CONCLUSION: Directly measured PbrO2 was highly responsive to changes in FiO2, ventilatory rate, and blood volume in this experimental model. In particular, hypoventilation significantly increased PbrO2, whereas hyperventilation had the opposite effect. The postresuscitation increase in PbrO2 may reflect changes in both O2 delivery and O2 metabolism. These experiments set the stage for future investigations of a variety of resuscitation protocols in both normal and injured brain.