RESUMEN
Stromatolites composed of apatite occur in post-Lomagundi-Jatuli successions (late Palaeoproterozoic) and suggest the emergence of novel types of biomineralization at that time. The microscopic and nanoscopic petrology of organic matter in stromatolitic phosphorites might provide insights into the suite of diagenetic processes that formed these types of stromatolites. Correlated geochemical micro-analyses of the organic matter could also yield molecular, elemental and isotopic compositions and thus insights into the role of specific micro-organisms among these communities. Here, we report on the occurrence of nanoscopic disseminated organic matter in the Palaeoproterozoic stromatolitic phosphorite from the Aravalli Supergroup of north-west India. Organic petrography by micro-Raman and Transmission Electron Microscopy demonstrates syngeneity of the organic matter. Total organic carbon contents of these stromatolitic phosphorite columns are between 0.05 and 3.0 wt% and have a large range of δ(13) Corg values with an average of -18.5 (1σ = 4.5). δ(15) N values of decarbonated rock powders are between -1.2 and +2.7. These isotopic compositions point to the important role of biological N2 -fixation and CO2 -fixation by the pentose phosphate pathway consistent with a population of cyanobacteria. Microscopic spheroidal grains of apatite (MSGA) occur in association with calcite microspar in microbial mats from stromatolite columns and with chert in the core of diagenetic apatite rosettes. Organic matter extracted from the stromatolitic phosphorites contains a range of molecular functional group (e.g. carboxylic acid, alcohol, and aliphatic hydrocarbons) as well as nitrile and nitro groups as determined from C- and N-XANES spectra. The presence of organic nitrogen was independently confirmed by a CN(-) peak detected by ToF-SIMS. Nanoscale petrography and geochemistry allow for a refinement of the formation model for the accretion and phototrophic growth of stromatolites. The original microbial biomass is inferred to have been dominated by cyanobacteria, which might be an important contributor of organic matter in shallow-marine phosphorites.
Asunto(s)
Cianobacterias/química , Fósiles , Minerales/análisis , Compuestos Orgánicos/análisis , Fosfatos/análisis , Ciclo del Carbono , Isótopos de Carbono/análisis , India , Microscopía Electrónica de Transmisión , Fijación del Nitrógeno , Isótopos de Nitrógeno/análisis , Vía de Pentosa Fosfato , Espectrometría RamanRESUMEN
We combine small-angle x-ray scattering (SAXS) and wide-angle x-ray scattering (WAXS) with aerodynamic levitation techniques to study in situ phase transitions in the liquid state under contactless conditions. At very high temperatures, yttria-alumina melts show a first-order transition, previously inferred from phase separation in quenched glasses. We show how the transition coincides with a narrow and reversible maximum in SAXS indicative of liquid unmixing on the nanoscale, combined with an abrupt realignment in WAXS features related to reversible shifts in polyhedral packing on the atomic scale. We also observed a rotary action in the suspended supercooled drop driven by repetitive transitions (a polyamorphic rotor) from which the reversible changes in molar volume (1.2 +/- 0.2 cubic centimeters) and entropy (19 +/- 4 joules mole(-1) kelvin(-1)) can be estimated.
RESUMEN
We present work on the creation of a ceramic materials database which contains data gleaned from literature data sets as well as new data obtained from combinatorial experiments on the London University Search Instrument. At the time of this writing, the database contains data related to two main groups of materials, mainly in the perovskite family. Permittivity measurements of electroceramic materials are the first area of interest, while ion diffusion measurements of oxygen ion conductors are the second. The nature of the database design does not restrict the type of measurements which can be stored; as the available data increase, the database may become a generic, publicly available ceramic materials resource.
Asunto(s)
Cerámica/química , Bases de Datos Factuales , Conductividad Eléctrica , Iones , Londres , OxígenoRESUMEN
The authors have studied the structural evolution of the fragile glass-forming liquid CaAl2O4 during supercooling from the stable liquid phase to the cold glass below Tg. The evolution is characterized by a sharpening of the first diffraction peak and a shortening of the average nearest-neighbor bond length around 1.25Tg, indicating an increase in the degree of both intermediate-range and short-range orders occurring close to the dynamical crossover temperature. The cooling curve developed a kink at this temperature, indicating a simultaneous change in thermodynamic properties.
RESUMEN
INTRODUCTION: The incidence of neurological injury following carotid angioplasty and stenting is of great interest to those advocating it as an alternative to endarterectomy in the management of critical carotid stenosis. A significant inter-observer variation exists in determining the presence or absence of a neurological deficit following the procedure objective imaging would be advantageous. In this study, we sought to assess diffusion weighted MRI as a diagnostic tool in evaluating the incidence of neurological injury following carotid angioplasty and stenting (CAS). PATIENTS AND METHODS: The first 110 cases of CAS in our unit were included in this series. The procedure was abandoned in three patients. Patients underwent intracranial and extracranial MR angiography, together with diffusion-weighted MRI (DWI) prior to and following CAS and had a formal neurological assessment in the intensive care unit after the procedure. RESULTS: One hundred and ten Procedures were attempted in 98 patients. Twenty-eight percent were asymptomatic. Following CAS, 7.2% of patients had a positive neurological exam (two major strokes with one fatality) and 21% had positive DWI scans, equating to a sensitivity of 86% and a specificity of 85% for DWI in detecting cerebral infarction following CAS. The positive predictive value of the test was 0.3 and negative predictive value 0.99. The major stroke and death rate was 1.8%. While the use of a cerebral protection device appeared to significantly reduce the incidence of cerebral infarction (5% vs. 25%, p = 0.031) this may be a reflection of the learning curve encountered during the study. CONCLUSION: The incidence of subclinical DWI detected neurological injury was significantly higher than clinical neurological deficit following CAS. Conventional methods of neurological assessment of patients undergoing CAS may be too crude to detect subtle changes and more sensitive tests of cerebral function are required to establish whether these subclinical lesions are relevant.
Asunto(s)
Arteria Carótida Interna , Estenosis Carotídea/terapia , Infarto Cerebral/diagnóstico , Imagen de Difusión por Resonancia Magnética , Complicaciones Posoperatorias/diagnóstico , Anciano , Anciano de 80 o más Años , Angioplastia de Balón , Encéfalo/patología , Arteria Carótida Interna/patología , Estenosis Carotídea/patología , Infarto Cerebral/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Examen Neurológico , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , StentsRESUMEN
OBJECTIVE: To investigate changes in cognitive function following carotid endarterectomy (CEA). DESIGN: Prospective study with controls. METHODS: CEA patients (n=159) were compared to a urology surgery control group (n=20). In CEA patients cerebrovascular reserve (CVR) was measured preoperatively. During surgery emboli and blood flow velocity in the middle cerebral artery were measured by transcranial Doppler (TCD) and cerebral oxygen saturation (CsO2) by near infrared spectroscopy. Cognitive function was measured preoperatively and at 5 days and 8 weeks postoperatively using a standardised computer battery of tests. RESULTS: Only 8% of patients had normal CVR bilaterally. The median number of emboli during CEA was 12 (range 0-181). On carotid clamping, TCD velocity fell a median of 41% and cerebral oxygen saturation by 5%. Attention deteriorated compared to controls 5 days following CEA (p=0.003) and this deterioration was related to the rise in TCD velocity on declamping (r=-0.3, p=0.002). Median attention reaction times improved significantly by 8 weeks (p=0.001) especially in patients' with severely impaired CVR before surgery (p=0.02). CONCLUSIONS: Attention improved at 2 months following CEA in patients with impaired CVR. CEA may offer more than reduced stroke risk to patients with impaired CVR.
Asunto(s)
Estenosis Carotídea/fisiopatología , Estenosis Carotídea/cirugía , Circulación Cerebrovascular , Cognición , Endarterectomía Carotidea , Anciano , Atención , Velocidad del Flujo Sanguíneo , Estenosis Carotídea/psicología , Femenino , Humanos , Masculino , Memoria , Persona de Mediana Edad , Arteria Cerebral Media/diagnóstico por imagen , Oxígeno/sangre , Estudios Prospectivos , Tiempo de Reacción , Ultrasonografía Doppler TranscranealAsunto(s)
Implantación de Prótesis Vascular/métodos , Angiopatías Diabéticas/cirugía , Isquemia/cirugía , Pierna/irrigación sanguínea , Arteria Radial/cirugía , Anciano , Prótesis Vascular , Femenino , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Grado de Desobstrucción VascularRESUMEN
OBJECTIVES: we investigated whether carotid sinus nerve infiltration with lignocaine reduced blood pressure lability during the first 24h following carotid endarterectomy (CEA). DESIGN: prospective randomised double-blind controlled trial. MATERIALS: eighty patients undergoing CEA for significant symptomatic stenosis of the internal carotid artery. METHODS: after initial dissection, 5 ml of 1% lignocaine or normal saline placebo according to randomisation was infiltrated around the carotid sinus nerve. Blood pressure was measured by intra-arterial cannula during surgery and for four hours afterwards every 15 min, then manually, hourly for 18 h. RESULTS: patients having excision of the carotid sinus nerve were grouped separately for analysis: 29 patients had lignocaine, 33 placebo and 17 excision (one early death with incomplete data was excluded). Mean systolic, diastolic and pulse pressures did not differ significantly between the three groups before carotid sinus nerve infiltration. After infiltration, those patients who had carotid sinus nerve excision, had significantly higher systolic [mean (SD)=155 (16)mmHg] and diastolic [75 (9)mmHg] pressures than those receiving LA [systolic=136 (15)mmHg, diastolic=65 (10)mmHg] or placebo [systolic=136 (19)mmHg, diastolic=65 (9)mmHg], (p<0.005 ANOVA). Nerve excision also resulted in wider variability of blood pressure as defined by the mean of individual standard deviations (systolic=25 mmHg, diastolic=13 mmHg) compared to LA (systolic=19 mmHg, diastolic=12 mmHg) or placebo (systolic=18 mmHg, diastolic=10 mmHg) (p<0.05 ANOVA). Normotensive patients had significantly lower mean diastolic pressures (p<0.001 ANOVA) and variability (p<0.05) if they received lignocaine although this did not influence pulse pressure. CONCLUSIONS: lignocaine injection of the carotid sinus nerve has no benefit in those patients with existing treated hypertension and only marginal effects in normotensives. It is more important to preserve the carotid sinus nerve if possible.
Asunto(s)
Anestesia Local , Anestésicos Locales/farmacología , Presión Sanguínea/efectos de los fármacos , Arteria Carótida Interna/inervación , Arteria Carótida Interna/cirugía , Seno Carotídeo/efectos de los fármacos , Seno Carotídeo/inervación , Estenosis Carotídea/cirugía , Endarterectomía Carotidea , Lidocaína/farmacología , Bloqueo Nervioso , Anciano , Anciano de 80 o más Años , Arteria Carótida Interna/efectos de los fármacos , Seno Carotídeo/cirugía , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
PURPOSE: This trial compares stapled anopexy with open hemorrhoidectomy in patients with prolapsing (Grade 3) hemorrhoids. Particular attention was paid to changes in anorectal physiology, nature of tissue resected, quality-of-life assessments, and cost implications of the treatments studied. METHODS: An initial pilot study was followed by a randomized, controlled trial in a District General Hospital in the United Kingdom. All patients had Grade 3 hemorrhoids. Nineteen patients were studied in the pilot study, with 99 patients in the randomized, controlled trial. All patients in the pilot study and 59 in the randomized, controlled trial underwent stapled anopexy. Thirty patients in the randomized, controlled trial underwent open hemorrhoidectomy. Of the 59 patients in the stapled group, 32 were treated with the Ethicon PPH stapling device, and 27 received stapling with a reusable Autosuture stapling device. The following variables were measured: demographic details, quality of life (Medical Outcomes Study Short Form 36 and directed questions), anorectal manometry, and histology. RESULTS: There was no difference in the case mix within or between the groups. The stapled anopexy groups showed a significant reduction in operative time (P < 0.001) and blood loss (P < 0.001) compared with open hemorrhoidectomy. Open hemorrhoidectomy resulted in significantly greater usage of protective pads postoperatively (P < 0.001) and longer rehabilitation (P < 0.006). CONCLUSIONS: Stapled anopexy is an effective alternative treatment for prolapsing hemorrhoids that allows reduced operative time and shorter rehabilitation. It does not appear to affect continence or overall quality of life.
Asunto(s)
Hemorroides/cirugía , Calidad de Vida , Grapado Quirúrgico/métodos , Adulto , Anciano , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Costos Directos de Servicios , Hemorroides/patología , Humanos , Tiempo de Internación , Manometría , Persona de Mediana Edad , Proyectos Piloto , Complicaciones Posoperatorias , Grapado Quirúrgico/economía , Técnicas de SuturaRESUMEN
OBJECTIVES: Cerebral microembolisation still occurs during cardiopulmonary bypass and may cause both stroke and postoperative cognitive impairment. We investigated the frequency of cerebral embolisation during coronary artery bypass surgery with modern cardiopulmonary bypass and related these to ascending aortic atherosclerosis. METHODS: Transcranial Doppler monitoring for cerebral embolisation to both middle cerebral arteries was performed in 65 patients undergoing coronary artery surgery with non-pulsatile alpha-stat hypothermic bypass. Epicardial ultrasound imaging of ascending aortic atherosclerosis was performed in 14 patients. RESULTS: Thirty patients (56.9%) had more than 200 emboli entering the middle cerebral artery territories during surgery; most at the start of bypass and during defibrillation. Readjustment of aortic clamps and aortic cannulation also caused a large number of emboli which were probably particulate. Aortic disease was mild (mean plaque thickness 1 mm, interquartile range 0.9-1.2 mm) and did not relate to the number of cerebral emboli produced by aortic manipulation. CONCLUSIONS: Cerebral embolisation remains common during coronary surgery despite advances in filter and bypass pump technology. Aortic manipulation and clamping was associated with emboli but epicardial ultrasound imaging was of little help in its prediction.
Asunto(s)
Puente Cardiopulmonar/efectos adversos , Embolia Intracraneal/etiología , Adulto , Anciano , Enfermedades de la Aorta , Puente de Arteria Coronaria , Femenino , Humanos , Embolia Intracraneal/diagnóstico por imagen , Complicaciones Intraoperatorias , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Ultrasonografía Doppler TranscranealRESUMEN
OBJECTIVE AND DESIGN: We have evaluated the effects of the broad-spectrum cysteine protease inhibitor E64 on allergic lung inflammation in the mouse ovalbumin model of human asthma. We have also characterised membrane-associated cathepsin enzyme activity on a range of cell types. MATERIALS: Balb/C mice, E64 and CA074, various cell lines. TREATMENT: E64 was administered by subcutaneous minipump into ovalbumin-sensitised mice prior to intranasal ovalbumin challenge. The effect of E64 on ovalbumin-induced inflammation in vivo and ovalbumin-specific T cell proliferation in vitro and ex vivo was examined. Membrane-associated cathepsin activity on various cell types was measured. RESULTS: E64 treatment (0.36-0.48 mg/day) led to a significant reduction in eosinophil numbers and lung weights in the mouse model. Histological examination of lungs confirmed the anti-inflammatory effect. E64 greatly reduced ovalbumin-specific T cell numbers in the lymph nodes draining the lung following intranasal challenge whilst an accumulation of these T cells was found in the 'priming' lymph nodes. An analysis of various cells involved in lymphocyte priming and migration revealed that monocytes, dendritic cells and endothelial cells express high levels of membrane-associated cathepsin B activity. CONCLUSIONS: Since E64 is not cell permeable and does not inhibit antigen-induced T cell proliferation in vitro or in vivo, the data indicate that membrane-associated cysteine proteases, possibly cathepsin B, may regulate T lymphocyte migration in vivo.
Asunto(s)
Alérgenos/farmacología , Inhibidores de Cisteína Proteinasa/uso terapéutico , Neumonía/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Animales , Catepsina B/metabolismo , División Celular/efectos de los fármacos , Línea Celular , Membrana Celular/metabolismo , Movimiento Celular/efectos de los fármacos , Espacio Extracelular/metabolismo , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Leucina/análogos & derivados , Leucina/uso terapéutico , Pulmón/enzimología , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Neumonía/inmunología , Neumonía/patologíaRESUMEN
OBJECTIVES: Cognitive deficits occur in up to 80% of patients after cardiac surgery. We investigated the influence of cerebral perfusion and embolization during cardiopulmonary bypass on cognitive function and recovery. METHODS: Cerebrovascular reactivity was measured in 70 patients before coronary operations in which nonpulsatile bypass was used. Throughout the operations, middle cerebral artery flow velocity and embolization were recorded by transcranial Doppler and regional oxygen saturation was recorded by near-infrared spectroscopy. Cognitive function was measured by a computerized battery of tests before the operation and 1 week, 2 months, and 6 months after surgery. Elderly patients undergoing urologic surgery served as controls. RESULTS: Cerebrovascular reactivity was impaired preoperatively in 49 patients. Median (interquartile range) regional cerebral oxygen saturation fell during bypass by 10% (6%-15%), indicating increased oxygen extraction, whereas mean middle cerebral flow velocity increased significantly by a median of 6 cm/s (both P <.0001, Wilcoxon), suggesting increased arterial tone. More than 200 emboli were detected in 40 patients, mainly on aortic clamping and release, when bypass was initiated, and during defibrillation. Cognitive function deteriorated more in patients having cardiopulmonary bypass than in control patients having urologic operations but recovered in most tests by 2 months. Measures of cerebral perfusion (poor cerebrovascular reactivity, low arterial pressures, and flow velocity in the middle cerebral artery) predicted poor attention at 1 week (r = 0.3, P <.01, Spearman). Emboli were associated with memory loss (r = 0.3, P <.02, Spearman). CONCLUSIONS: Cognitive deficits were common after cardiopulmonary bypass. Occult cerebrovascular disease was more severe than expected and predisposed to attention difficulties, whereas emboli caused memory deficits. We believe this to be the first report of differing cognitive effects from emboli and hypoperfusion.
Asunto(s)
Puente Cardiopulmonar/efectos adversos , Trastornos del Conocimiento/etiología , Puente de Arteria Coronaria/efectos adversos , Embolia Intracraneal/etiología , Trastornos de la Memoria/etiología , Anciano , Anciano de 80 o más Años , Puente Cardiopulmonar/métodos , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Puente de Arteria Coronaria/métodos , Enfermedad Coronaria/cirugía , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Embolia Intracraneal/diagnóstico por imagen , Embolia Intracraneal/epidemiología , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/epidemiología , Persona de Mediana Edad , Examen Neurológico , Periodo Posoperatorio , Cuidados Preoperatorios , Probabilidad , Valores de Referencia , Factores de Riesgo , Resultado del Tratamiento , Ultrasonografía DopplerRESUMEN
PURPOSE: In the presence of carotid occlusion, the external carotid artery (ECA) becomes an important source of cerebral blood flow, especially if the circle of Willis is incomplete. The contribution of the ECA to hemispheric blood flow in patients with severe ipsilateral carotid stenosis has never been previously investigated. METHODS: One hundred eight patients were monitored during sequential cross-clamping of the external (ECA) and then ipsilateral internal carotid artery (ICA) during carotid endarterectomy using transcranial Doppler sonography (TCD) (Neuroguard CDS, Los Angeles, Calif), to measure middle cerebral artery blood flow velocity, and near-infrared spectroscopy, to measure regional cerebral oxygen saturation (CsO(2)) (Invos 3100A; Somanetics, Troy, Mich). RESULTS: On the ipsilateral ECA cross-clamp, the median fall in CsO(2) was 3% (interquartile range, 1%-4%; P <.0001). On addition of the ICA cross-clamp there was a further fall of 3% and a total fall of 6% (3%-9%; P <.0001). The median percentage fall in middle cerebral artery blood flow velocity on ECA clamping was 12% (4%-24%; P <.0001); on ICA clamping it was 48% (25%-74%; P <.0001). Falls in TCD on ECA clamping were greater with increasing severity of ipsilateral ICA stenosis. The correlation between CsO(2) and TCD on external clamping, although less strong than that on internal clamping, was statistically significant r = 0.32; P =.01; Spearman rank correlation). CONCLUSIONS: The falls in TCD and CsO(2) were of a similar order of magnitude and must therefore reflect a fall in cerebral perfusion. The ipsilateral ECA contributes significantly to intracranial blood flow and oxygen saturation in severe carotid stenosis.
Asunto(s)
Arteria Carótida Externa/fisiología , Circulación Cerebrovascular/fisiología , Anciano , Velocidad del Flujo Sanguíneo/fisiología , Arteria Carótida Externa/diagnóstico por imagen , Circulación Colateral/fisiología , Endarterectomía Carotidea , Femenino , Humanos , Masculino , Monitoreo Intraoperatorio , Oxígeno/metabolismo , Ultrasonografía Doppler TranscranealRESUMEN
Lesion-induced inflammatory responses in both brain and spinal cord have recently become a topic of active investigation. Using C57BL/6J mice, we compared the tissue reaction in these two central nervous system (CNS) compartments with mechanical lesions of similar size involving both grey and white matter. This evaluation included the quantitative assessment of neutrophils, lymphocytes and activated macrophages/microglia, as well as astrocyte activation, upregulation of vascular cell adhesion molecules (ICAM-1, VCAM-1, PECAM) and the extent of blood-brain barrier (BBB) breakdown. Time points analysed post-lesioning included 1, 2, 4 and 7 days (as well as 10 and 14 days for the BBB). We found clear evidence that the acute inflammatory response to traumatic injury is significantly greater in the spinal cord than in the cerebral cortex. The numbers of both neutrophils and macrophages recruited to the lesion site were significantly higher in the spinal cord than in the brain, and the recruitment of these cells into the surrounding parenchyma was also more widespread in the cord. The area of BBB breakdown was substantially larger in the spinal cord and vascular damage persisted for a longer period. In the brain, as in spinal cord, the area to which neutrophils were recruited correlated well with the area of BBB breakdown. It will be of interest to determine the extent to which the infiltration of inflammatory cells contributes, either directly or indirectly, to the vascular permeability and secondary tissue damage or, conversely, to local tissue repair in the brain and the spinal cord.
Asunto(s)
Reacción de Fase Aguda/inmunología , Encéfalo/inmunología , Encefalitis/inmunología , Mielitis/inmunología , Médula Espinal/inmunología , Animales , Astrocitos/química , Astrocitos/fisiología , Barrera Hematoencefálica/fisiología , Encéfalo/irrigación sanguínea , Encéfalo/citología , Endotelio/citología , Femenino , Proteína Ácida Fibrilar de la Glía/análisis , Peroxidasa de Rábano Silvestre/farmacocinética , Molécula 1 de Adhesión Intercelular/análisis , Recuento de Linfocitos , Linfocitos/citología , Linfocitos/inmunología , Macrófagos/química , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/química , Microglía/fisiología , Neutrófilos/inmunología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Médula Espinal/irrigación sanguínea , Médula Espinal/citología , Molécula 1 de Adhesión Celular Vascular/análisisRESUMEN
Different compartments in the central nervous system mount distinct inflammatory responses. The meninges and choroid plexus respond to pro-inflammatory stimuli in a manner reminiscent of a peripheral inflammatory response, whereas the brain parenchyma is refractory. Trauma-induced lesions in brain and in spinal cord are associated with leukocyte infiltration, blood-brain barrier (BBB) breakdown, and secondary tissue destruction. Unexpectedly, these phenomena are generally more pronounced in the parenchyma of the spinal cord than in the parenchyma of the brain. To investigate whether these differences between brain and spinal cord can be attributed, at least in part, to differing sensitivities to proinflammatory cytokines, we stereotactically injected recombinant rat (rr) TNFalpha or rrIL-1beta into the striatum or the spinal cord of Wistar rats. In the brain, the injection of rrTNFalpha failed to evoke BBB breakdown or leukocyte recruitment, whereas in the spinal cord injection of TNFalpha resulted in marked BBB breakdown and leukocyte recruitment. Similarly, the injection of rrIL-1beta into the brain parenchyma failed to induce BBB breakdown and gave rise to only minimal neutrophil recruitment, whereas the injection of rrIL-1beta into the spinal cord induced significant BBB breakdown and recruitment of neutrophils and lymphocytes. Thus, using a minimally invasive injection technique, equivalent in both circumstances, we have shown that there are marked differences in the inflammatory response between the brain parenchyma and spinal cord parenchyma. This observation has important implications for the treatment of spinal cord injuries.
Asunto(s)
Encefalopatías/inducido químicamente , Inflamación/inducido químicamente , Interleucina-1/farmacología , Enfermedades de la Médula Espinal/inducido químicamente , Factor de Necrosis Tumoral alfa/farmacología , Enfermedad Aguda , Animales , Permeabilidad Capilar/efectos de los fármacos , Recuento de Leucocitos/efectos de los fármacos , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacología , Técnicas EstereotáxicasRESUMEN
Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1-5]. Rodent models have demonstrated a 'window of susceptibility' in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6-7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys-X-Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1beta. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1beta-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility.
Asunto(s)
Barrera Hematoencefálica , Encéfalo/fisiopatología , Quimiocinas CXC/fisiología , Inflamación/fisiopatología , Péptidos y Proteínas de Señalización Intercelular , Neutrófilos/fisiología , Adulto , Envejecimiento , Animales , Encéfalo/inmunología , Encéfalo/fisiología , Quimiocina CXCL1 , Quimiocina CXCL2 , Factores Quimiotácticos/farmacología , Factores Quimiotácticos/fisiología , Niño , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Sustancias de Crecimiento/farmacología , Sustancias de Crecimiento/fisiología , Peroxidasa de Rábano Silvestre/farmacocinética , Humanos , Inflamación/inmunología , Interleucina-1/farmacología , Ratones , Monocinas/farmacología , Monocinas/fisiología , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacologíaRESUMEN
In an experimentally-induced DTH model of MS, we examined mRNA and protein expression of a range of MMPs and of TNFalpha to establish the contribution that individual MMPs might make to the pathogenesis. In control rat brain, mRNA for all of the MMPs examined was detectable. However, by immunohistochemistry, only MMP-2 could be detected. In the DTH lesions, significant increases in the level of mRNA expression were observed for MMP-7, MMP-8, MMP-12, and TNFalpha. Where expression of MMP mRNA was increased, there was a corresponding increase in protein expression detected by immunohistochemistry. To determine whether the upregulated MMPs could invoke destructive events in the CNS, highly purified activated MMP-7, MMP-8, and MMP-9 were stereotaxically injected into the brain parenchyma. All provoked recruitment of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss of myelin staining. In conclusion, specific MMPs are upregulated in DTH lesions; for the most part, measurement of mRNA was a predictor of increased protein expression. From our injections of MMPs, it is clear that the upregulated MMPs in the DTH lesions could participate in the disruption of the BBB, leukocyte recruitment, and tissue damage.