RESUMEN
BACKGROUND: Phosphorylated tau (pTau), total tau (tTau), and ß-amyloid (Aß) are established cerebrospinal fluid (CSF) biomarkers used to help diagnose Alzheimer disease. Preanalytic workups of CSF samples lack harmonization, making interlaboratory comparison of these biomarkers challenging. The Aß adsorbs to sample tubes, yielding underestimated concentrations, and may result in false Alzheimer disease diagnosis. Our primary aim was to compare Aß recovery across multiple polypropylene tubes and to test the stability of tTau, pTau, and Aß in the best performing tube. METHODS: Eight polypropylene tubes were tested using 3 CSF pools with Aß concentrations <500, 500-1000, and >1000 ng/L. All samples were analyzed in duplicate. Tubes were cut open to assess their different infrared adsorption spectra. Freshly drawn CSF from 14 patients was distributed into 4 Sarstedt 5-mL (no. 63.504.027; Sar5CSF) tubes, left at room temperature for up to 7 days, and analyzed for pTau, tTau, and Aß by ELISA. RESULTS: Two Sarstedt 5-mL tubes and a Sarstedt 10-mL (Sar10CSF) tube showed significantly higher Aß recovery at all 3 concentrations compared with the 5 other tubes. The infrared adsorption spectra of Sar10CSF and Sar5CSF tubes were practically identical, unlike the other tubes. No significant loss of pTau, tTau, and Aß was observed in CSF left at room temperature for up to 7 days (P > 0.05). CONCLUSIONS: Recovery of Aß from Sar5CSF tubes is equivalent to Aß recovery from Sar10CSF tubes. Levels of pTau, tTau, and Aß were stable for at least 7 days at room temperature but not at 37 °C.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores , Ensayo de Inmunoadsorción Enzimática , Humanos , Estándares de ReferenciaRESUMEN
OBJECTIVE: To investigate whether a structured medication report at discharge from the hospital could reduce the number of medication discrepancies in primary care. METHOD: The study was performed as an open, randomised controlled study including patients transferred from one hospital in Norway to nursing home or home care. Both groups received epicrisis on discharge. In addition, the intervention group received a structured medication report. After discharge, the medication list in primary care service was compared with the list at discharge and medication discrepancies identified. In addition, these medication lists were retrospectively compared with the lists prior to admission to the hospital and at admission to hospital. A questionnaire on time spent and quality of the medication information was filled in by nurses in primary care. RESULTS: Medication discrepancies were found for 72% (26) of the patients in the intervention group and 76% (42) in the control group (P=0.918). Most common was drugs omitted or committed to the medication lists in primary care service. Typically, the committed drugs in primary care were omitted drugs after admission to the hospital. Nurses used significantly less time (66%) obtaining medication information in the intervention group (P=0.041). CONCLUSIONS: Structured medication report as the only intervention did not reduce the medication discrepancies after discharge from hospital. There is a need for reconciliation at admission to ensure the quality of the medication report. Structured medication report resulted in the nurses spending less time on collecting medication information in primary care service.
RESUMEN
To investigate putative interacting or distinct pathways for hippocampal complex substructure (HCS) atrophy and cognitive affection in early-stage Alzheimer's disease (AD) and cerebrovascular disease (CVD), we recruited healthy controls, patients with mild cognitive impairment (MCI) and poststroke patients. HCSs were segmented, and quantitative white-matter hyperintensity (WMH) load and cerebrospinal fluid (CSF) amyloid-ß concentrations were determined. The WMH load was higher poststroke. All examined HCSs were smaller in amyloid-positive MCI than in controls, and the subicular regions were smaller poststroke. Memory was reduced in amyloid-positive MCI, and psychomotor speed and executive function were reduced in poststroke and amyloid-positive MCI. Size of several HCS correlated with WMH load poststroke and with CSF amyloid-ß concentrations in MCI. In poststroke and amyloid-positive MCI, neuropsychological function correlated with WMH load and hippocampal volume. There are similar patterns of HCS atrophy in CVD and early-stage AD, but different HCS associations with WMH and CSF biomarkers. WMHs add to hippocampal atrophy and the archetypal AD deficit delayed recall. In line with mounting evidence of a mechanistic link between primary AD pathology and CVD, these additive effects suggest interacting pathologic processes.
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Disfunción Cognitiva/patología , Disfunción Cognitiva/psicología , Hipocampo/patología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/psicología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Atrofia , Trastornos Cerebrovasculares/patología , Trastornos Cerebrovasculares/psicología , Función Ejecutiva , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria , Recuerdo Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Desempeño Psicomotor , Tiempo de Reacción , Sustancia Blanca/patología , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND AND PURPOSE: Severe perinatal asphyxia is an important cause of brain injury in the newborn infant. We examined early events after hypoxic ischemia (HI) in the 7-day-old mouse brain by MRI and related them to long-term functional effects and histopathology in the same animals at 4 to 5 weeks of age. METHODS: HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated in vivo by MRI (T2 maps and apparent diffusion coefficient maps) at 3, 6, and 24 hours and 5 days after hypoxia. Locomotion and sensorimotor function were analyzed after 3 weeks. Four weeks after HI, the mice were killed, and cresyl violet-stained brain sections were examined morphologically. RESULTS: A decrease in apparent diffusion coefficient values in cortex on the affected side was found at 3 hours after HI. T2 values were significantly increased after 6 hours and remained so for 5 days. Maximal size of the lesion was attained at 3 to 6 hours after HI and declined thereafter. Animals with MRI-detected lesions had decreased forward locomotion, performed worse than controls in the beam-walking test, and showed a unilateral hypotrophy in the cresyl violet-stained brain sections 4 weeks later. CONCLUSIONS: The temporal progression of the damage after HI in 7-day-old mice differs from that of the adult brain as judged by MRI. The early lesions detected by MRI were related to functional impairments for these mice in near-adult life.
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Isquemia Encefálica/diagnóstico , Corteza Cerebral/patología , Hipoxia-Isquemia Encefálica/diagnóstico , Hipoxia/complicaciones , Imagen por Resonancia Magnética , Factores de Edad , Animales , Animales Recién Nacidos , Conducta Animal , Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Enfermedades de las Arterias Carótidas/complicaciones , Arteria Carótida Común/patología , Arteria Carótida Común/fisiología , Difusión , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hipoxia/fisiopatología , Hipoxia-Isquemia Encefálica/etiología , Hipoxia-Isquemia Encefálica/patología , Locomoción , Ratones , Valor Predictivo de las PruebasRESUMEN
Male Fischer 344 rats aged 3, 6, 12, 18 and 24 months were trained to walk on a narrow beam, then lesioned in the right hindlimb sensorimotor cortex by photothrombosis. Motor performance was measured daily for 60 days using a 7-point rating scale from which deficit scores were calculated. Tissue analysis included lesion volume measurement after Nissl staining. Animals aged 3 and 6 months fully recovered by day 10 and 31, respectively. Animals aged 18 months acquired significant neurological impairment that persisted greater than 60 days. Deficit scores were significantly greater than in groups aged 12, 6 and 3 months. Degenerative morbidity and mortality confounded behavioral study of animals aged 24 months. The duration of neurological impairment after photochemical sensorimotor cortex lesion increased with age. Animals aged 18 months at lesion acquired the greatest chronic impairment. This aged post-acute animal model is clinically relevant to stroke rehabilitation.
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Envejecimiento/fisiología , Modelos Animales de Enfermedad , Desempeño Psicomotor/fisiología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Enfermedad Aguda , Envejecimiento/patología , Animales , Encéfalo/patología , Masculino , Destreza Motora/fisiología , Ratas , Ratas Endogámicas F344RESUMEN
The morphology, time-course and volume of the in vivo uptake of the T1 contrast agent gadolinium (Gd) in the perilymphatic vestibulo-cochlea labyrinth, including the utricle, saccule, semicircular canals and scalae of the guinea pig inner ear were analyzed as Fourier transform signal intensity enhancement levels by 3D MRI at 4.7 T. The uptake of Gd as a function of time in the perilymphatic space of the vestibular labyrinth was shown by ANOVA and PLSD post hoc tests to be significantly less (p < 0.05) than that of the scala tympani of the cochlea 10, 30, 60 and 90 min after i.v. injection. Experimentally induced fistulae resulted in MRI detected morphological and quantitative alterations in Gd concentration in the perilymphatic labyrinthine space. The findings demonstrate that Gd-enhanced 3D MRI of the perilymphatic space may be used to examine the morphology, kinetics and intravenous substance delivery in the in vivo mammalian vestibulo-cochlea labyrinth.
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Oído Interno/metabolismo , Gadolinio DTPA , Imagen por Resonancia Magnética/métodos , Perilinfa/metabolismo , Análisis de Varianza , Animales , Cóclea/metabolismo , Femenino , Fístula/metabolismo , Análisis de Fourier , Gadolinio/metabolismo , Cobayas , Imagenología Tridimensional , Masculino , Factores de Tiempo , Vestíbulo del Laberinto/metabolismoRESUMEN
Precise, non-invasive determination of the aetiology and site of pathology of inner ear disorders is difficult. The aim of this study was to describe an alternative method for inner ear visualization, based on local application of the paramagnetic contrast agent gadolinium. Using a 4.7 T MRI scanner, high contrast images of all four cochlear turns were obtained 3.5 h after placing gadolinium on the round window membrane. Gadolinium cleared from the cochlea within 96 h. Auditory brainstem response measurements performed on a separate group of animals showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea.
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Cóclea/diagnóstico por imagen , Gadolinio , Imagen por Resonancia Magnética/métodos , Estimulación Acústica/métodos , Animales , Audiometría de Respuesta Evocada/métodos , Umbral Auditivo/fisiología , Umbral Auditivo/efectos de la radiación , Mapeo Encefálico/métodos , Tronco Encefálico/fisiología , Tronco Encefálico/efectos de la radiación , Cóclea/anatomía & histología , Gadolinio/farmacocinética , Cobayas , Cintigrafía , Factores de TiempoRESUMEN
In order to find out whether it is possible to visualize experimental endolymphatic hydrops in the cochlea with magnetic resonance imaging (MRI) at 4.7 T, we used 11 guinea pigs. Five normal guinea pigs were used as controls. Early manifestation of endolymphatic hydrops was evaluated in endolymphatic sac (ES)-intact animals (n = 6), and advanced manifestation in ES-damaged animals (n = 5) by means of MRI with gadolinium-diethylenetriaminepentaacetate-bismethylamide (Gd-DTPA-BMA) contrast agent. Hearing was tested with electrocochleography. The surface area of 3 partitions of the cochlea was used to quantify endolymphatic hydrops. The fine structure of the 3 partitions of the cochlea was visualized with MRI in all animals, as Gd-DTPA-BMA appeared mainly in the scala tympani and scala vestibuli. As early as 5 days after endolymphatic sac surgery, endolymphatic hydrops started to appear as visualized by MRI and also verified with histology. Severe damage to the inner ear barrier with Gd-DTPA-BMA leakage into the scala media was detected with MRI in 1 ES-damaged animal that had a 60-dB hearing loss. To conclude, endolymphatic hydrops can be visualized with high-resolution MRI by means of Gd-DTPA-BMA, and it is possible to quantify the extent of endolymphatic hydrops. Damage to the inner ear barrier or possible rupture of membranes can be shown with the assistance of Gd-DTPA-BMA.
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Hidropesía Endolinfática/diagnóstico , Imagen por Resonancia Magnética , Animales , Audiometría de Respuesta Evocada , Cóclea/patología , Medios de Contraste , Hidropesía Endolinfática/patología , Hidropesía Endolinfática/fisiopatología , Femenino , Gadolinio DTPA , Cobayas , MasculinoRESUMEN
OBJECTIVE: To investigate the pharmacokinetics of gadolinium in the perilymphatic fluid spaces of the cochlea in vivo using high-resolution MRI to obtain information concerning perilymph formation. MATERIAL AND METHODS: A Bruker Biospec Avance 47/40 experimental MRI system with a magnetic field strength of 4.7 T was used. Anesthetized pigmented guinea pigs were injected with the contrast agent Gd-diethylenetriaminepentaacetic acid-bismethylamide and placed in the magnet. The signal intensity of Gd in the tissues was used as a biomarker for dynamic changes in the perilymphatic fluid. RESULTS: The most rapid uptake of Gd in the perilymphatic fluid spaces occurred in the lower part of the modiolus, followed by the second turn of the scala tympani. Within the scala tympani, the distribution of Gd in the basal turn was significantly lower than that in the other turns. Destruction of the cochlear aqueduct was followed by an increase in Gd uptake in the perilymph instead of a reduction. CONCLUSIONS: These findings offer further evidence that the pervasive perilymphatic fluid derives from the cochlear blood supply via the cochlear glomeruli, which are in close proximity to the scala tympani within the modiolus, and the capillary in the spiral ligament. Cerebrospinal fluid communicates with perilymph via the cochlear aqueduct but is not the main source of perilymph. These findings are of relevance to the treatment of inner ear diseases, as well as to our understanding of the flow and source of perilymphatic fluid.
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Cóclea/metabolismo , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Perilinfa/metabolismo , Animales , Femenino , Cuarto Ventrículo , Gadolinio DTPA/líquido cefalorraquídeo , Cobayas , Imagen por Resonancia Magnética , MasculinoRESUMEN
Better animal models are needed to aid the development of new medications to alleviate the cognitive deficits associated with schizophrenia. Growing evidence suggests neurodevelopmental insults and disturbances in NMDA receptor (NMDAR) signaling to be involved in the schizophrenia etiology. Acute administration of phencyclidine (PCP) induces schizophrenia-like symptoms in healthy volunteers and exacerbates symptoms in patients with schizophrenia. In this study, pharmacological Magnetic Resonance Imaging (phMRI) was used to evaluate if rats treated with 20mg/kg PCP on postnatal days 7, 9, and 11 (neoPCP), compared to saline (neoVeh), were hypersensitive to acute PCP administration in adulthood (acutePCP). Intravenous administration of 0.5mg/kg acutePCP produced robust and sustained relative cerebral blood volume (rCBV) increase in discrete frontal, neocortical, hippocampal, thalamic, and limbic brain structures in both neoPCP:acutePCP and neoVeh:acutePCP rats compared to acute saline treatment (Vehicle control group). AcutePCP injection significantly increased the rCBV response in the medial prefrontal cortex and nucleus accumbens compared to the Vehicle control group, without distinguishing neoPCP and neoVeh animals. However, at late time points (25-33min post acutePCP injection), neoPCP animals showed significantly higher rCBV values compared to the Vehicle control group, suggesting an altered sensitivity toward NMDAR blockade in adult rats subjected to this neurodevelopmental procedure. In combination with the observed cognitive deficits revealed in this animal model, the present findings indicate that altered NMDAR signaling might underlie the symptomatic changes seen in schizophrenia, adding to the construct and face validity of this model.
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Encéfalo/patología , Antagonistas de Aminoácidos Excitadores/toxicidad , Imagen por Resonancia Magnética , Fenciclidina/toxicidad , Esquizofrenia/inducido químicamente , Esquizofrenia/diagnóstico , Factores de Edad , Animales , Animales Recién Nacidos , Análisis de los Gases de la Sangre , Volumen Sanguíneo/fisiología , Encéfalo/efectos de los fármacos , Mapeo Encefálico , Modelos Animales de Enfermedad , Femenino , Masculino , Análisis Multivariante , Ratas , Esquizofrenia/fisiopatología , Factores de TiempoRESUMEN
We evaluated the transport of Gadolinium-diethylenetriaminepentaacetate-bismethylamide (Gd-DTPA-BMA) through the round window (RW) membrane into the perilymphatic space with 4.7-T MRI in an animal study and 1.5-T MRI in humans. After administration of Gd-DTPA-BMA onto the intact RW membrane of guinea pig, Gd-DTPA-BMA uptake was observed in the basal turn and part of the second turn within 40 min. The scala tympani, scala vestibuli, the fibrous part of the spiral ligament and semicircular canal all showed uptake of Gd-DTPA-BMA. All turns of the cochlea were filled with Gd within 10 min in the perforated RW membrane administration group and within 30 min in the intravenous administration group. In patients who accepted middle ear injection of Gd-DTPA-BMA, uptake was observed within 2 h in the basal turn and semicircular canal. After 12 h the apex did still not show any uptake. Gd-DTPA-BMA is transported from the RW to the semicircular canal, the scala tympani and scala vestibuli without passing the helicotrema.
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Conducto Coclear/anatomía & histología , Gadolinio DTPA , Ligamentos/anatomía & histología , Imagen por Resonancia Magnética/métodos , Rampa Timpánica/anatomía & histología , Animales , Conducto Coclear/metabolismo , Femenino , Gadolinio DTPA/farmacocinética , Cobayas , Inyecciones Intravenosas , Masculino , Perilinfa/metabolismo , Ventana Redonda/metabolismo , Rampa Timpánica/metabolismoRESUMEN
Despite advances in acute treatment of ischemic cerebrovascular events, the most common clinical outcome is disabling neurological impairment. Despite experimental evidence that psychostimulant treatment can positively affect recovery rate after focal brain lesions, beyond rehabilitation therapies there are no currently accepted medical treatments indicated for diminishing neurological impairment after clinically established stroke. To test the effect of amphetamine, task-specific training, limiting motor experience, and their interaction on motor recovery in a postacute animal model of stroke, animals were nonaversively trained in beam walking before a unilateral photochemical sensorimotor cortex lesion and tested for 10 days after lesion. Animals were randomized to groups receiving: a single session of motor training 24 h after lesion; a single injection of amphetamine 2 mg/kg 24 h after lesion; beam-walking experience limited to testing on days 1 and 10 after lesion; and groups that received amphetamine treatment combined with training or combined with limited experience. Motor recovery was maximally enhanced by training, delayed by amphetamine treatment, and most negatively affected by limiting beam-walking experience during the recovery period. These findings support physical training after stroke, indicating that limiting physical activity negatively affects motor recovery and raises questions about the role of stimulant treatment to enhance motor recovery in the postacute phase after stroke.
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Anfetamina/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Actividad Motora/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Anfetamina/efectos adversos , Animales , Estimulantes del Sistema Nervioso Central/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Accidente Cerebrovascular/fisiopatología , Rehabilitación de Accidente Cerebrovascular , Resultado del TratamientoRESUMEN
A photochemical lesion was induced in the right sensory motor cortex of rat brains. We examined at various time points the occurrence of different types of neuronal death with respect to a potential therapeutic window. The lesion appearance was documented by magnetic resonance imaging, and functional recovery was evaluated by behavioral tests showing recovery at 48 hr after lesioning. At 0.5, 1, 3, 6, 12, 24, 48, and 72 hr postlesion, cortical layers IV and V were examined by light and electron microscopy. Ultrastructural changes, which corresponded well to light microscopy findings, were found in both hemispheres. In the lesioned area, the neuropil appeared disorganized at 0.5 hr, and apoptotic and necrotic cell death was found at 0.5-3 hr. After 3 hr, the tissue was disintegrated. On the contralateral side, chromatin clumping appeared at 0.5-3 hr. At 3 hr, ruptured membranes were found, a sign of irreversible cell death. At 6-72 hr, the membranes were intact, and the chromatin was not clumped but heterogeneously distributed. The nuclei contained dispersed nucleoli at 48-72 hr. The morphology correlated well with magnetic resonance images and functional behavior. Our study demonstrates that a photochemical lesion is a useful model for studying morphological changes in injured cells. It results in a permanent infarction within 3 hr. In that the morphology on the contralateral side drastically changed between 3 and 6 hr, the cellular alterations at these time points might represent a break point at which cells either progress toward cell death or recover.
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Corteza Cerebral/patología , Corteza Cerebral/ultraestructura , Neuronas/patología , Neuronas/ultraestructura , Animales , Recuento de Células/métodos , Masculino , Fotoquímica , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
PRIMARY OBJECTIVE: To characterize a necrotic lesion using MRI and motor recovery using behavioural methods. RESEARCH DESIGN: Stroke model based on two steps: (1) development of a lesion using MR-imaging parameters and (2) behavioural recovery. METHODS AND PROCEDURES: Seventy male Sprague-Dawley rats were used. A focal lesion of the right sensorimotor cortex was induced photochemically. MAIN OUTCOMES AND RESULTS: The maximum volume of oedema and the lesion damage was reached by approximately 6 hours. In the lesion area, the apparent diffusion coefficient (ADC) increased from 6 hours, then decreased from 24 hours. All animals spontaneously recovered motor function by day 10, despite the continued presence of the cortical lesion. CONCLUSIONS: The results show that this model mimics a core lesion, as well as the late phase in a human stroke episode. This model might be used for longitudinal study of the basic mechanisms of motor recovery.
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Encéfalo/patología , Imagen por Resonancia Magnética , Modelos Animales , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular/patología , Animales , Conducta Animal , Masculino , Actividad Motora , Ratas , Ratas Sprague-Dawley , TiempoRESUMEN
Dendritic cells (DC) are antigen-presenting cells specialized to regulate immune responses. DC not only control immunity, but also maintain tolerance to self-antigens-two complementary functions that would ensure the integrity of the organism in an environment full of pathogens. Here we report that splenic DC that had been exposed in vitro to IFN-gamma (IFN-gamma-DC) exhibit therapeutic potential on acute experimental allergic encephalomyelitis (EAE) in Lewis rats, and on chronic-relapsing EAE in B6 and SJL/J mice. During incipient EAE [day 5 post-immunization (p.i.) in rats, day 7 p.i. in mice], IFN-gamma-DC were injected s.c. Severity of clinical signs of EAE was dramatically inhibited in animals injected with IFN-gamma-DC, showing normal magnetic resonance imaging (MRI) of the spinal cord and brain. In contrast, the EAE rats receiving PBS or naive DC had severe clinical signs with multiple and extensive MRI lesions in the spinal cord and brain. IFN-gamma-DC triggered an antigen-specific IFN-gamma production, and induced apoptosis of CD4(+) T cells possibly through DC expressing indoleamine 2,3-dioxygenase and/or an IFN-gamma-dependent pathway. As a result, infiltration of macrophages and CD4(+) T cells within the spinal cords was dramatically reduced in animals injected with IFN-gamma-DC as compared to animals injected with PBS or naive DC. This approach may represent a novel possibility of individualized immunotherapy using autologous, in vitro modified DC as a complement to conventional therapy in multiple sclerosis and other diseases with an autoimmune background.