RESUMEN
OBJECTIVES: To quantify the coexistence of inflammatory bowel disease (IBD) and multiple sclerosis (MS) and to characterize the diseases when they coexist. PATIENTS AND METHODS: In this retrospective study of medical records spanning 1950 through 1995, the diagnoses of Crohn disease (CD), ulcerative colitis (UC), and MS were based on review of inpatient and outpatient records by a gastroenterologist and a neurologist. RESULTS: We identified 4 residents of Olmsted County, Minnesota, with IBD (3 UC, 1 CD) who had concurrent, clinically definite MS; all had mild neurologic disease with little disability. These comprised 1% of the IBD and 1.8% of the MS cohort. The CD patient had undergone terminal ileal resection; of the UC patients, 2 had pancolitis, and 1 had proctosigmoiditis. The observed prevalence of MS at onset of IBD was 3.7 times the expected (95% confidence interval, 0.8-10.8). We also reviewed the records of 32 referral patients with both diagnoses. Disability from MS was moderate at median follow-up of 8.5 years. By 15 years, ambulation was impaired in most patients. Neurologic disability was similar between patients with CD and UC. CONCLUSIONS: Concurrence of the 2 diseases was greater than expected. Although MS and IBD may share common predisposing factors, not enough information is available to speculate about possible mechanisms.
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Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/epidemiología , Adolescente , Adulto , Anciano , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/epidemiología , Femenino , Humanos , Incidencia , Masculino , Registros Médicos , Persona de Mediana Edad , Minnesota/epidemiología , Prevalencia , Estudios RetrospectivosAsunto(s)
Enfermedades Autoinmunes/inmunología , Infecciones por Chlamydia/inmunología , Exantema Súbito/inmunología , Mononucleosis Infecciosa/inmunología , Esclerosis Múltiple/inmunología , Encéfalo/inmunología , Chlamydophila pneumoniae/inmunología , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 6/inmunología , HumanosRESUMEN
OBJECTIVE: To report that the syndrome of orthostatic headaches caused by CSF leak can be seen with persistently normal CSF pressures. BACKGROUND: CSF leak or shunt overdrainage is known to cause orthostatic headaches and diffuse pachymeningeal gadolinium enhancement (DPGE), typically associated with unmeasurable or very low CSF pressures. METHODS: Of 40 consecutive patients with orthostatic headaches and DPGE, all had low or unmeasurable CSF pressures, except seven patients who had consistently normal CSF pressures and are thus reported. All had undergone multiple CSF examinations. RESULTS: Two patients had overdraining shunts, and five had documented CSF leaks. One refused treatment, but the other six patients responded to surgical treatment or epidural blood patch with complete resolution of symptoms and related MRI abnormalities. CONCLUSIONS: Some patients with symptomatic CSF leaks may have CSF opening pressures that are consistently within normal limits. In the presence of convincing clinical features and imaging abnormalities, a normal CSF pressure should not discourage the clinician from searching for a source of CSF leak.
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Líquido Cefalorraquídeo/fisiología , Exudados y Transudados/fisiología , Cefalea/líquido cefalorraquídeo , Cefalea/etiología , Adulto , Líquido Cefalorraquídeo/química , Presión del Líquido Cefalorraquídeo , Femenino , Gadolinio , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mielografía , PosturaRESUMEN
We studied patches of CNS myelin in human retina in vivo to determine the pattern of myelination and the local influence of axons. We analysed the position, area and thickness of the nerve-fibre layer in 60 patches of retinal myelin in 47 eyes (in 37 adults and two adolescents). Five patches in four eyes were studied serially over 6-11 years. Nerve-fibre layer thickness was obtained from an atlas of primate retina, and volumes of myelinated tissue were then estimated for each patch. Retinal myelination occurred in three patterns: thick patches contiguous with the optic disc (type I); thin, striated patches detached from the disc (type II); or massive myelination of the posterior pole associated with severe amblyopia (type III). The papillomacular bundle did not myelinate in types I and II and was relatively spared in type III patches, suggesting that migratory oligodendrocyte progenitors are not supported by these axons. The local nerve-fibre layer determined patch size, and quantal myelination was evident with modal peaks of patch volume at 0.16 and 0.64 mm3. Myelination advanced at patch edges when observed over time, consistent with the hypothesis that new oligodendrocytes are produced in adulthood. We propose a theoretical model where patches of retinal myelination are the clonal progeny of a few oligodendrocyte progenitors exhibiting two different behaviours. First, a highly migratory, nonmyelinating progenitor uses larger, phylogenetically older axons as the substrate for movement. Secondly, a more mature progenitor generates myelinating oligodendrocytes well into adult life, but traverses only short distances. Using this data, we can estimate the number of oligodendrocytes in these clones and population doubling-time. This study supports a role for axon-derived signals in the regulation of human oligodendrocyte progenitor behaviour and myelination in vivo.
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Encéfalo/fisiología , Vaina de Mielina/fisiología , Oligodendroglía/fisiología , Retina/fisiología , Células Madre/fisiología , Adolescente , Adulto , Factores de Edad , Encéfalo/citología , Comunicación Celular/fisiología , División Celular/fisiología , Células Clonales/citología , Células Clonales/fisiología , Células Clonales/ultraestructura , Humanos , Fibras Nerviosas/fisiología , Oligodendroglía/citología , Oligodendroglía/ultraestructura , Regeneración/fisiología , Retina/citología , Células Madre/citología , Células Madre/ultraestructuraRESUMEN
Infection of susceptible strains of mice with Daniel's (DA) strains of Theiler's murine encephalomyelitis virus (DAV) results in virus persistence in the central nervous system (CNS) white matter and chronic demyelination similar to that observed in multiple sclerosis. We investigated whether persistence is due to the immune system more efficiently clearing DAV from gray than from white matter of the CNS. Severe combined immunodeficient (SCID) and immunocompetent C.B-17 mice were infected with DAV to determine the kinetics, temporal distribution, and tropism of the virus in CNS. In early disease (6 h to 7 days postinfection), DAV replicated with similar kinetics in the brains and spinal cords of SCID and immunocompetent mice and in gray and white matter. DAV RNA was localized within 48 h in CNS cells of all phenotypes, including neurons, oligodendrocytes, astrocytes, and macrophages/microglia. In late disease (13 to 17 days postinfection), SCID mice became moribund and permitted higher DAV replication in both gray and white matter. In contrast, immunocompetent mice cleared virus from the gray matter but showed replication in the white matter of their brains and spinal cords. Reconstitution of SCID mice with nonimmune splenocytes or anti-DAV antibodies after establishment of infection demonstrated that both cellular and humoral immune responses decreased virus from the gray matter; however, the cellular responses were more effective. SCID mice reconstituted with splenocytes depleted of CD4+ or CD8+ T lymphocytes cleared virus from the gray matter but allowed replication in the white matter. These studies demonstrate that both neurons and glia are infected early following DAV infection but that virus persistence in the white matter is due to preferential clearance of virus from the gray matter by the immune system.
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Sistema Nervioso Central/virología , Enfermedades Desmielinizantes/virología , Poliomielitis/virología , Theilovirus/inmunología , Animales , Anticuerpos Antivirales/inmunología , Astrocitos/virología , Sistema Nervioso Central/anatomía & histología , Enfermedad Crónica , Inmunidad Celular , Subgrupos Linfocitarios/inmunología , Ratones , Ratones Endogámicos , Ratones SCID , Oligodendroglía/virología , ARN Viral/metabolismo , Médula Espinal/virología , Replicación ViralRESUMEN
Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis (Miller et al., 1994; J. Neurosci. 14: 6230-6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3-4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5-2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMkappa antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.
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Anticuerpos Monoclonales/farmacología , Autoanticuerpos/farmacología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/fisiología , Médula Espinal/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Axones/inmunología , Encéfalo/metabolismo , Femenino , Ratones , Ratones Endogámicos , Modelos Biológicos , Vaina de Mielina/inmunología , Oligodendroglía/inmunología , Poliomielitis/metabolismo , Poliomielitis/patología , Médula Espinal/metabolismo , Theilovirus , Distribución TisularRESUMEN
In this article, we assess the roles and the efficacy of immunopharmacologic agents in the treatment of multiple sclerosis (MS) and other demyelinating disease syndromes. The initial clinical manifestations of demyelinating disease, immunotherapeutic goals, efficacy of individual agents, and specific immunopharmacologic recommendations are discussed. MS and other idiopathic demyelinating disease syndromes can be effectively managed with immunotherapy. Exacerbations are treatable, and the frequency and severity of exacerbations can be reduced. Although some agents have a minor effect on progression of disability, current approaches have not proved to have a major influence on treatment of progressive MS. Immunotherapy for inflammatory demyelinating disease necessitates a high degree of clinical certainty about the diagnosis. Because all available therapeutic agents have limitations and significant toxic effects, careful consideration is necessary before use. Treatment should be individualized on the basis of the clinical course of the disease and the degree of patient disability.
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Inmunosupresores/uso terapéutico , Inmunoterapia/métodos , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/terapia , Enfermedad Aguda , Enfermedad Crónica , Diagnóstico Diferencial , Humanos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/inmunología , RecurrenciaRESUMEN
Conditioned medium derived from a rat central nervous system neuronal cell line B104 (B104 CM) was shown previously to contain uncharacterized potent mitogen(s) for oligodendrocyte/type-2 astrocyte (O-2A) progenitor cells. In this study, we demonstrated that B104 cells produce and secrete platelet-derived growth factor (PDGF)-AA homodimer, but not PDGF-B chain. B104 cells did not express other known potent mitogens for O-2A progenitor cells, including fibroblast growth factor-2 and neurotrophin-3. Unexpectedly, B104 cells also expressed transcripts of transforming growth factor-beta1 (TGF-beta1) and -beta2 (TGF-beta2), which are known to regulate O-2A progenitor cell differentiation and proliferation, and secreted exclusively the 25-kDa active forms of TGF-beta1 and TGF-beta2. Neutralization of B104 CM with anti-PDGF-AA antibody decreased proliferation of O-2A progenitor cells, whereas neutralization with anti-TGF-beta antibodies had no effect. The combination of PDGF and TGF-beta on proliferation was not equivalent to the effect of B104 CM, indicating the possibility of an unidentified growth factor. B104 CM maintained a high expression of PDGF-alpha receptor in oligodendrocytes. The observation that both a stimulatory factor (PDGF-AA) and a regulatory factor (TGF-beta) for O-2A progenitor cell proliferation and differentiation are produced from a single neuronal cell line emphasizes the potential critical interaction between neurons and O-2A progenitor cells in myelination and possibly in remyelination.
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Oligodendroglía/metabolismo , Factor de Crecimiento Derivado de Plaquetas/genética , Células Madre/metabolismo , Factor de Crecimiento Transformador beta/genética , Animales , Animales Recién Nacidos , Antimetabolitos/metabolismo , Antimetabolitos/farmacología , Becaplermina , Bromodesoxiuridina/metabolismo , Bromodesoxiuridina/farmacología , División Celular/fisiología , Línea Celular , Sistema Nervioso Central/citología , Dimerización , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Expresión Génica/fisiología , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Neurotrofina 3 , Oligodendroglía/citología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-sis , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Células Madre/citología , Timidina/metabolismo , Timidina/farmacología , Factor de Crecimiento Transformador beta/metabolismo , TritioRESUMEN
Three weeks after an automobile accident, a 35-year-old man experienced left throat and neck pain, numbness of the left face and tongue, dysphagia, left arm pain and weakness, and left miosis. At age 27, he had suffered an aneurysmal subarachnoid hemorrhage. Angiography at that time had also demonstrated a fenestration of the left intracranial vertebral artery. At the time of the second presentation, angiography showed that one of the limbs of the fenestration had become occluded. Although the vast majority of intracranial arterial fenestrations are asymptomatic, occlusion of one of the limbs of a fenestration may be the cause of stroke.
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Arteriopatías Oclusivas/complicaciones , Trastornos Cerebrovasculares/etiología , Heridas y Lesiones/complicaciones , Adulto , Arteriopatías Oclusivas/diagnóstico por imagen , Angiografía Cerebral , Circulación Cerebrovascular/fisiología , Trastornos Cerebrovasculares/fisiopatología , Humanos , MasculinoRESUMEN
Published methods for the isolation of cerebral microvessels primarily yield terminal resistance vessels and capillary networks, not the more proximal, subpial penetrating arterioles desired for certain studies. We report a novel method for isolating microvessels from the cerebral cortex of a single guinea-pig brain that yields large arteriolar complexes that are up to 50% intact. Instead of using homogenization to disperse brain parenchyma, we digested cortical fragments with trypsin, gently dispersed the parenchyma mechanically, and recovered microvascular complexes by sieving. Phase-contrast and electron microscopy showed primary (penetrating) arterioles, secondary arterioles, and capillary networks that frequently were in continuity as intact microvascular units. Culture of microvascular cells was carried out by enzymatic dissociation followed by an overnight incubation in a recovery medium at 4 degrees C before plating onto fibronectin-modified surfaces. Viability of isolated cells was demonstrated by good cell attachment and prompt proliferation that resulted in confluent cultures after 10 days. Confluent secondary cultures demonstrated characteristic features of smooth muscle cells, including a "hill-and-valley" growth pattern and expression of alpha-actin. Less than 1% of cells were endothelial or astrocytic cells by immunocytochemical and morphologic criteria. Ultrastructural studies demonstrated evidence of a synthetic phenotype of smooth muscle cell and absence of a significant number of fibroblasts. This method demonstrates that viable smooth muscle cells from the cerebral parenchymal microvasculature can be isolated in bulk quantities for study in vitro.
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Arteriolas/citología , Corteza Cerebral/irrigación sanguínea , Microcirculación/citología , Músculo Liso Vascular/citología , Actinas/análisis , Animales , Arteriolas/ultraestructura , Membrana Celular/ultraestructura , Núcleo Celular/ultraestructura , Separación Celular/métodos , Células Cultivadas , Retículo Endoplásmico/ultraestructura , Femenino , Proteína Ácida Fibrilar de la Glía/análisis , Cobayas , Inmunohistoquímica , Filamentos Intermedios/ultraestructura , Membrana Dobles de Lípidos , Masculino , Microcirculación/ultraestructura , Microscopía Electrónica , Músculo Liso Vascular/ultraestructuraRESUMEN
During development, myelin-forming oligodendrocytes and type 2 astrocytes are believed to arise from bipotential (O-2A) glial progenitors. Previously we found that conditioned medium (CM) from the B104 rat CNS neuronal cell line promotes growth of neonatal rat O-2A progenitors in serum-free culture conditions with subsequent increases in differentiated progeny. We now report that O-2A progenitors are present in mature rat brains and that this CM promotes the growth, motility, and bipolar morphology of these cells from 30- and 65-day-old rat brains, as shown by quantitative studies using double immunostaining and [3H]thymidine-autoradiography. In addition, the growth-promoting action of B104 CM is not neutralized by antibodies to platelet-derived growth factor, a proposed progenitor mitogen. Subsequent to the proliferation of these O-2A progenitors, increases in oligodendrocytes and type 2 astrocytes occur. These data suggest a novel therapeutic strategy for some demyelinating diseases, e.g., multiple sclerosis, where there is a deficit in oligodendrocytes. Although it has been proposed by others that mature brain O-2A progenitors are less proliferative and thereby incapable of adequately replenishing lost oligodendrocytes in these diseases, we present in vitro evidence for continued response of mature brain O-2A progenitors to this neuronal cell line-derived mitogen.
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Encéfalo/citología , Sistema Nervioso Central/metabolismo , Factores de Crecimiento Nervioso/farmacología , Neuroglía/metabolismo , Células Madre/metabolismo , Animales , Autorradiografía , Línea Celular , Movimiento Celular/fisiología , Células Cultivadas , Sistema Nervioso Central/efectos de los fármacos , Medios de Cultivo , Técnica del Anticuerpo Fluorescente , Masculino , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Fenotipo , Ratas , Ratas EndogámicasRESUMEN
Responses of oligodendrocyte/type 2 astrocyte (O-2A) glial progenitors from neonatal rat brains to different growth factors were studied by a new, serum-free method. Enriched tertiary cultures of O-2A progenitors were produced after 6-7 days in vitro using the growth-promoting factors from the B104 CNS neuronal cell line, heparin, and mechanical separation. These cultures contained about 75-90% A2B5+ cells with less than 10% type 1 astrocytes, and the yield was 4.4 x 10(5) cells/brain. B104 conditioned medium (CM) factors increased both O-2A progenitor number and [3H]thymidine-labeling indices after three days. However, type 1 astrocyte CM was required for continued survival of enriched progenitors beyond 1 day in tertiary culture. Platelet-derived growth factor (PDGF) and glia maturation factor also showed growth-promoting action, but were less effective than B104 CM at tested doses. PDGF-neutralizing antibodies had no effect on progenitor survival or response to B104 CM factors. Thus, type 1 astrocyte-derived PDGF was not required for this response, B104 CM is not likely to contain PDGF, and B104 CM factors act directly on O-2A progenitors. Fibroblast growth factor, transforming growth factor beta, interleukin 2, epidermal growth factor, and triiodothyronine showed no growth-promoting activity; moreover, interleukin 2, epidermal growth factor, transforming growth factor beta, and 0.5% fetal bovine serum inhibited B104 CM action. Enriched progenitors exhibited bipotentiality by slowly differentiating into oligodendrocytes in serum-free medium, whereas culture in 10% fetal bovine serum increased type 2 astrocytes. Thus, this new method selects or produces progenitors which are similar to those from mature brains.
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Astrocitos/citología , Técnicas de Cultivo/métodos , Sustancias de Crecimiento/farmacología , Oligodendroglía/citología , Células Madre/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Factor de Crecimiento Epidérmico/farmacología , Factores de Crecimiento de Fibroblastos/farmacología , Inmunohistoquímica , Interleucina-2/farmacología , Oligodendroglía/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
The growth-promoting activity of conditioned medium (CM) from the B104 CNS neuronal cell line was studied in glial cultures from neonatal rat brain. This CM at 33% (v/v; 8-12 micrograms protein/ml) produced large numbers of oligodendrocytes and multipolar glial progenitors after an 8 to 12-day treatment. At all times studied, cells of the oligodendrocyte/type 2 astrocyte (O-2A) lineage were increased due to CM-treatment, while type 1 astrocytes, microglia, and other cell types were not. Furthermore, we observed a large decrease in the percentage of oligodendrocytes in the O-2A lineage, suggesting a delay in differentiation of the progenitors. By 8 days in vitro (DIV), dose-dependent increases in numbers of galactocerebroside (GalC)-positive cells (oligodendrocytes) and A2B5-positive cells (immature oligodendrocytes and glial progenitors) occurred. In contrast, at 4 DIV only A2B5-positive cells were increased in a dose-dependent manner. The latter cells can differentiate primarily into oligodendrocytes or type 2 astrocytes depending on the culture conditions. Complement lysis studies confirmed that the A2B5-positive, but not the GalC-positive, population at 4 DIV was required for increases in oligodendrocytes to occur by 8 DIV. The [3H]thymidine labeling index of the A2B5-positive population also increased in response to CM in a dose-dependent manner, but the GalC-positive labeling index showed only small increases at 4 DIV and none at later times. Our results suggest that the delayed differentiation coupled with the selective stimulation of the bipotential glial progenitors produces the large increases in numbers of oligodendrocytes observed at 8-12 DIV.
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Sustancias de Crecimiento/farmacología , Neuroglía/citología , Neuronas/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular , Medios de Cultivo , Galactosilceramidas/metabolismo , Sustancias de Crecimiento/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas , Ratas Endogámicas , TimidinaRESUMEN
Recent studies suggest that heterotypic cell-cell interactions influence gliogenesis in the developing rat central nervous system. CNS neuron-derived factors have been hypothesized to exist, and several have been identified and partially characterized which affect the number of oligodendrocytes in vitro. In order to study further the role of neurons in gliogenesis, we have used serum-free culture conditions, the B104 CNS neuronal cell line as a source of soluble factors, and dissociated neonatal rat brain cells as a source of glial cells. We have analyzed the response of the glial cells to serum-free B104 conditioned medium using morphological, immunocytochemical, autoradiographic, and enzymatic methods. Dose-dependent increases in the number of morphologically identified oligodendrocytes occur in response to this conditioned medium. Galactocerebroside (GalC) is a specific marker for oligodendrocytes, and the A2B5 antigen marks bipotential glial progenitor cells and their progeny: immature oligodendrocytes and type 2 astrocytes. In the presence of conditioned medium, the number of cells expressing GalC and/or A2B5 antigen increases over time when measured at 4, 8, and 12 days in vitro. A significantly weaker effect is seen if serum is also present. Since the vast majority of A2B5-positive cells in conditioned medium treated cultures lack glial fibrillary acidic protein (GFA), indicative of type 2 astrocytes, they represent glial progenitors and immature oligodendrocytes. Double immunostaining combined with autoradiography suggests that the latter cell types are the target cells for the oligodendrocyte-promoting activity. In addition, the conditioned medium markedly increases 2',3' cyclic nucleotide 3'-phosphodiesterase (an oligodendrocyte marker) and to a lesser extent enhances glutamine synthetase activity (an astrocyte marker). Type 1 astrocytes are also more morphologically differentiated in this condition, and their percentage is decreased simultaneously. Conditioned medium from other donor neural cells either has no activity or is much less effective than B104 conditioned medium. The active factors are soluble, sensitive to both trypsin and 100 degrees C treatment for 20 min, and appear to be 30-100 kilodaltons by stirred cell ultrafiltration. In summary, we have identified a potent source of growth-stimulating factors that produce increased numbers of glial progenitor cells and oligodendrocytes; the same conditioned medium also appears to inhibit type 1 astrocyte proliferation.