RESUMEN
OSP/claudin-11 and PLP are both tetraspan proteins concentrated in CNS myelin. It has been proposed that they have a structural role in myelin formation and maintenance due to their localization and concentration in membrane sheaths. This hypothesis is not supported by the fact that both OSP/claudin-11- and PLP-null mice have relatively normal-appearing myelin and mild neurological deficits. Since both OSP/claudin-11 and PLP are abundant in myelin and have similar structures, the mild phenotypes of the knockout mice are likely due to compensatory mechanisms. Here we show that when both OSP/claudin-11 and PLP genes are knocked out, mice had severe neurological deficits, markedly abnormal myelin compaction, and smaller axon diameters. Interestingly, when either of these genes was knocked out, the expression of the other protein was increased. These data demonstrate that OSP/claudin-11 and PLP have essential structural functions in maintaining normal compact myelin and there is redundancy in their functions.
Asunto(s)
Sistema Nervioso Central/anomalías , Proteína Proteolipídica de la Mielina/genética , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas/metabolismo , Proteínas del Tejido Nervioso/genética , Malformaciones del Sistema Nervioso/metabolismo , Adaptación Fisiológica/fisiología , Animales , Axones/metabolismo , Axones/patología , Axones/ultraestructura , Membrana Celular/metabolismo , Membrana Celular/patología , Membrana Celular/ultraestructura , Tamaño de la Célula , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Claudinas , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Trastornos del Movimiento/genética , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/fisiopatología , Vaina de Mielina/patología , Vaina de Mielina/ultraestructura , Fibras Nerviosas Mielínicas/patología , Fibras Nerviosas Mielínicas/ultraestructura , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Regulación hacia Arriba/fisiologíaRESUMEN
We performed 118 consecutive DBS cases from November 1999 to June 2002. Intraoperatively there were 10 cases studied with fluoroscopy, 73 with 0.2 Tesla (T) MRI and 35 with 1.5 T MRI. Ten electrodes were secured by Medtronic caps, 25 by methyl methacrylate with titanium miniplates, and 82 by Navigus caps. The 3-dimensional displacement between the planned target and actual electrode position (3DD) was determined by fusing the postoperative MRI with the preoperative imaging. The 3DD for using Medtronic caps, methyl methacrylate with miniplates, and Navigus caps were 4.80 +/- 3.16, 2.64 +/- 1.26 and 2.23 +/- 1.15 mm (mean +/- SD), respectively. Navigus caps had statistically significant accuracy (P = 0.03) in holding the electrode when compared with Medtronic caps, and it facilitated electrode revision. The fixation devices significantly affect the final vertical position of the electrode. The 3DD for fluoroscopy, 0.2 T and 1.5 T MRI cases were 4.80 +/- 3.16, 2.31 +/- 1.21 and 2.34 +/- 1.14 mm (mean +/- SD), respectively. No statistically significant difference (P = 0.91) in 3DD was demonstrated between 0.2 T and 1.5 T MRI cases. The presence of intraoperative 1.5 T MRI allowed near real-time electrode position confirmation and early detection of hemorrhagic complications. Satisfactory microelectrode recording was feasible in low-field 0.2 T and high-field 1.5 T MRI environments. Further studies on performing DBS in real-time intraoperative MRI are warranted.
Asunto(s)
Estimulación Encefálica Profunda , Diencéfalo/cirugía , Fluoroscopía , Globo Pálido/cirugía , Imagen por Resonancia Magnética , Neuronavegación/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Diencéfalo/diagnóstico por imagen , Diencéfalo/patología , Electrodos Implantados , Femenino , Globo Pálido/diagnóstico por imagen , Globo Pálido/patología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Multiple sclerosis (MS) is characterized by demyelination of the CNS with associated neurological deficits. Remyelination can occur but is often incomplete. The process of myelin repair requires the proliferation and migration of oligodendrocyte progenitor cells (OPC) into the lesion from the neighboring areas. OPC migration is altered by several factors, including antibodies that bind to OPC surface proteins. We have previously reported elevated anti-OSP/claudin-11 antibodies in the cerebrospinal fluid (CSF) of MS patients and that anti-OSP/claudin-11 antibodies generated in rabbits can inhibit OPC migration. In the study presented here, we investigated the effect of CSF IgG from MS patients and controls on OPC migration in culture. Rat OPC cultured with CSF from MS patients tended to migrate more than those cultured with control CSF, but this did not reach statistical significance. To determine whether the IgG fraction in the CSF influenced migration, we removed it using protein-A sepharose. A dramatic decrease in OPC migration was found in both MS (45 +/- 24 vs.16 +/- 9) and control (40 +/- 19 vs. 22 +/- 13) samples after IgG was removed (P <.05). Anti-OSP/claudin-11 antibody concentration did not significantly correlate with OPC migration. These data demonstrate that CSF IgG promotes OPC migration. Identification of the specific IgG fraction responsible for this effect could lead to novel therapies to promote recovery in MS.
Asunto(s)
Movimiento Celular/inmunología , Inmunoglobulina G/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Oligodendroglía/citología , Células Madre/citología , Adulto , Animales , Femenino , Humanos , Inmunoglobulina G/fisiología , Masculino , Persona de Mediana Edad , Oligodendroglía/inmunología , Ratas , Células Madre/inmunologíaRESUMEN
Oligodendrocyte-specific protein (OSP) is concentrated in CNS myelin and is a potential autoantigen in the development of multiple sclerosis (MS). We performed proliferation assays with lymphocytes from MS patients and normal controls. OSP peptide-induced proliferation was common in relapsing-remitting MS and controls samples but was less pronounced in samples from secondary progressive MS subjects. These data demonstrate that OSP-reactive T cells are part of the normal immune repertoire and therefore have the potential to contribute to the pathogenesis of MS. Given the lack of specificity to MS, OSP-reactive T-cells are unlikely to be solely responsible for the disease process.
Asunto(s)
Autoantígenos/farmacología , División Celular/efectos de los fármacos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Proteínas del Tejido Nervioso/farmacología , Linfocitos T/efectos de los fármacos , Adulto , Anciano , Autoantígenos/inmunología , Autoantígenos/metabolismo , Bioensayo , División Celular/inmunología , Claudinas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Proteínas del Tejido Nervioso/inmunología , Proteínas del Tejido Nervioso/metabolismo , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Concerns with access and costs in the Medicaid program often lead policy makers to consider alternatives. These include subsidizing poor persons' purchases of health insurance in private markets or integrating Medicaid beneficiaries into commercial managed care systems. As policy makers consider such alternatives, a persistent question is, apart from the disabled within Medicaid, do younger Medicaid enrollees represent a different insurance risk than people of similar age and sex within private insurance pools? We use 1994 data from Georgia, Mississippi, and California to assess relative payment levels, resource use/costs, and risk-adjusted utilization of fee-for-service (FFS) Medicaid enrollees versus privately insured people. When resources are valued at private prices, the use by Medicaid enrollees represents a higher cost. After risk adjustment, Medicaid enrollee resource use appears higher than expected for the privately insured only for outpatient facility visits in the southern states and for inpatient days by pregnant women in California Medi-Cal. Indeed, we find evidence that Medicaid enrollees are underserved relative to their health needs. Given the higher dollar value of their resource usage, apparently obtained under FFS at discounted provider rates, and the lack of evidence on significant overuse relative to need, their integration into private provider systems appears challenging.
Asunto(s)
Planes de Aranceles por Servicios/estadística & datos numéricos , Gastos en Salud/estadística & datos numéricos , Seguro de Salud/estadística & datos numéricos , Medicaid/estadística & datos numéricos , Adolescente , Adulto , California , Niño , Preescolar , Planes de Aranceles por Servicios/economía , Georgia , Gastos en Salud/clasificación , Recursos en Salud/estadística & datos numéricos , Investigación sobre Servicios de Salud , Humanos , Lactante , Recién Nacido , Seguro de Salud/economía , Programas Controlados de Atención en Salud/economía , Programas Controlados de Atención en Salud/estadística & datos numéricos , Medicaid/economía , Persona de Mediana Edad , Mississippi , Método de Control de Pagos , Ajuste de RiesgoRESUMEN
Oligodendrocyte-specific protein (OSP)/claudin-11 is a major component of central nervous system myelin and forms tight junctions (TJs) within myelin sheaths. TJs are essential for forming a paracellular barrier and have been implicated in the regulation of growth and differentiation via signal transduction pathways. We have identified an OSP/claudin-11-associated protein (OAP)1, using a yeast two-hybrid screen. OAP-1 is a novel member of the tetraspanin superfamily, and it is widely expressed in several cell types, including oligodendrocytes. OAP-1, OSP/claudin-11, and beta1 integrin form a complex as indicated by coimmunoprecipitation and confocal immunocytochemistry. Overexpression of OSP/claudin-11 or OAP-1 induced proliferation in an oligodendrocyte cell line. Anti-OAP-1, anti-OSP/claudin-11, and anti-beta1 integrin antibodies inhibited migration of primary oligodendrocytes, and migration was impaired in OSP/claudin-11-deficient primary oligodendrocytes. These data suggest a role for OSP/claudin-11, OAP-1, and beta1 integrin complex in regulating proliferation and migration of oligodendrocytes, a process essential for normal myelination and repair.
Asunto(s)
División Celular/fisiología , Movimiento Celular/fisiología , Integrina beta1/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos/inmunología , Anticuerpos/metabolismo , Northern Blotting , Encéfalo/citología , Encéfalo/metabolismo , Línea Celular , Claudinas , Fibronectinas/metabolismo , Hibridación in Situ , Sustancias Macromoleculares , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Microscopía Fluorescente , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Oligodendroglía/química , Oligodendroglía/citología , Oligodendroglía/ultraestructura , Alineación de Secuencia , Tetraspaninas , Uniones Estrechas/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
OBJECT: Several investigators have described the motor benefits derived from performing unilateral stereotactic pallidotomy for the treatment of Parkinson disease (PD), but little is known about the efficacy and complication rates of bilateral procedures. The goal of this study was to assess both these factors in 12 patients. METHODS: Eleven patients with medically intractable PD underwent staged bilateral pallidotomy and one patient underwent a simultaneous bilateral procedure. Unilateral pallidotomy resulted in an improvement in the patients' Unified Parkinson Disease Rating Scale (UPDRS) total scores and motor subscores, Hoehn and Yahr stages, and Schwab and England Activities of Daily Living scores. There were no complications. The second procedures were performed 5 to 25 months after the first, and nearly complete 3-month follow-up data are available for eight of these patients. Staged bilateral pallidotomy did result in further improvements in some symptoms, but the patients proved to be less responsive to levodopa. In contrast to outcomes of the initial unilateral pallidotomy, there were significant complications. One patient suffered an acute stroke, two patients suffered delayed infarctions of the internal capsule, four patients had mild-to-moderate worsening of speech and increased drooling, and one patient complained of worsening memory. CONCLUSIONS: Bilateral pallidotomy results in modest benefits but is associated with an increased risk of complications.
Asunto(s)
Lateralidad Funcional , Globo Pálido/cirugía , Procedimientos Neuroquirúrgicos/métodos , Enfermedad de Parkinson/cirugía , Adulto , Anciano , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Satisfacción del Paciente , Complicaciones Posoperatorias , Resultado del TratamientoRESUMEN
During the past few years, significant advances have been made in elucidating the mechanisms by which point mutations and altered gene dosages in tetraspan genes cause neurological disease. In addition, several new myelin tetraspans have been identified that are involved in adhesion, molecular trafficking, growth regulation, and migration of oligodendrocytes and Schwann cells.
Asunto(s)
Vaina de Mielina/fisiología , Proteínas del Tejido Nervioso/fisiología , Animales , Humanos , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteolípidos/química , Proteolípidos/metabolismoRESUMEN
Oligodendrocyte-specific protein (OSP/claudin-11) is a major component of CNS myelin and has been recently added to the claudin family of tight junction proteins. In this study, the developmental expression of OSP/claudin-11 was determined using in situ hybridization, immunohistochemistry (IH), and Western blot analysis. OSP/claudin-11 mRNA was expressed in a bimodal fashion. During prenatal development, OSP/claudin-11 mRNA was abundant in developing meninges, in areas adjacent to cartilage, and in mesoderm. In postnatal animals, OSP/claudin-11 was expressed primarily in developing oligodendrocytes and to a lesser extent, in testes. Double-labeled IH using O2-A progenitor cells revealed that OSP/claudin-11 expression occurs from the early progenitor stage and continues in mature oligodendrocytes. Electron microscopic IH localized OSP/claudin-11 to laminar myelin in the adult CNS. Western blot analysis of OSP/claudin-11 in developing brain revealed the expression of two separate transcripts that were developmentally regulated. These data demonstrate that OSP/claudin-11 expression is highly regulated during development and, therefore, may play an important role in growth and differentiation of oligodendrocytes and other cells outside the CNS.
Asunto(s)
Química Encefálica/fisiología , Encéfalo/crecimiento & desarrollo , Proteínas de la Membrana/biosíntesis , Proteínas del Tejido Nervioso , Animales , Western Blotting , Encéfalo/citología , Diferenciación Celular , Claudinas , Femenino , Inmunohistoquímica , Hibridación in Situ , Masculino , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Embarazo , Ratas , Células Madre/fisiología , Testículo/crecimiento & desarrollo , Testículo/inervación , Testículo/metabolismoRESUMEN
Oligodendrocyte-specific protein (OSP/claudin-11) is a four transmembrane protein concentrated in central nervous system myelin. Recent evidence has emerged suggesting that OSP/claudin-11 is involved in membrane interactions at tight junctions and with the extracellular matrix. OSP/claudin-11 seems to modulate proliferation and migration of oligodendrocytes presumably through these interactions. Furthermore, evidence is presented implicating OSP/claudin-11 as an autoantigen in the development of autoimmune demyelinating disease.
Asunto(s)
Membrana Celular/metabolismo , Enfermedades Autoinmunes Desmielinizantes SNC/fisiopatología , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Animales , ClaudinasRESUMEN
Identification of the genes that are differentially expressed in brain tumor cells but not in normal brain cells is important for understanding the molecular basis of these neurological cancers and for defining possible targets for therapeutic intervention. In an effort to discover potentially antigenic proteins that may be involved in the malignant transformation and progression of human glioblastomas, a novel antibody-based approach was developed to identify and isolate gene products that are expressed in brain tumors versus normal brain tissue. Using this method, whereby tumor-specific antibodies were isolated and used to screen a glioblastoma cDNA expression library, 28 gene products were identified. Nine of these clones had homology to known gene products, and 19 were novel. The expression of these genes in multiple different human gliomas was then evaluated by cDNA microarray hybridization. One of the isolated clones had consistently higher levels of expression (3-30-fold) in brain tumors compared with normal brain. Northern blot analysis and in situ hybridization confirmed this differential overexpression. cDNA sequence analysis revealed that this gene was identical to a relatively new class of growth regulators known as granulins, which have tertiary structures resembling the epidermal growth factor-like proteins. The 2.1-kb granulin mRNA was expressed predominantly in glial tumors, with lower levels in spleen, kidney, and testes, whereas expression was not detected in non-tumor brain tissues. Functional assays using [3H]thymidine incorporation indicated that granulin may be a glial mitogen, as addition of synthetic granulin peptide to primary rat astrocytes and three different early-passage human glioblastoma cultures increased cell proliferation in vitro, whereas increasing concentrations of granulin antibody inhibited cell growth in a dose-dependent manner. The differential expression pattern, tissue distribution, and implication of this glioma-associated molecule in growth regulation suggest a potentially important role for granulin in the pathogenesis and/or malignant progression of primary brain neoplasms.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/genética , Glioma/genética , Técnicas de Inmunoadsorción , Péptidos y Proteínas de Señalización Intercelular , Proteínas Virales/análisis , Proteínas Virales/genética , Animales , ADN Complementario/análisis , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Biblioteca de Genes , Humanos , Progranulinas , RatasRESUMEN
This study examines the correspondence between medical records and Medicaid claims to determine whether claims are a valid source of data for monitoring quality of asthma care. A total of 460 claims for care encounters were matched to medical records of the encounters. While most of the diagnoses and procedures recorded on the claims were documented in medical records, claims failed to identify 29% of encounters with asthma diagnoses and 45% of nebulization procedures administered during encounters. About 30% of documented asthma prescriptions were not associated with filed claims, and about 30% of filed claims for asthma medication were not documented in medical records.
Asunto(s)
Asma/terapia , Manejo de la Enfermedad , Formulario de Reclamación de Seguro/normas , Registros Médicos/normas , Garantía de la Calidad de Atención de Salud/métodos , Adolescente , Niño , Preescolar , Documentación/normas , Investigación sobre Servicios de Salud/métodos , Humanos , Medicaid/estadística & datos numéricosRESUMEN
Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine. A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed. To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acid-eluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway.
Asunto(s)
Neoplasias Encefálicas/terapia , Células Dendríticas/inmunología , Glioblastoma/terapia , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoterapia Adoptiva/métodos , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Células Dendríticas/trasplante , Resultado Fatal , Femenino , Glioblastoma/inmunología , Glioblastoma/patología , Humanos , Imagen por Resonancia Magnética , Persona de Mediana EdadRESUMEN
Oligodendrocyte-specific protein (OSP)/claudin-11 is a recently identified transmembrane protein found in CNS myelin and testis with unknown function. Herein we demonstrate that Osp null mice exhibit both neurological and reproductive deficits: CNS nerve conduction is slowed, hindlimb weakness is conspicuous, and males are sterile. Freeze fracture reveals that tight junction intramembranous strands are absent in CNS myelin and between Sertoli cells of mutant mice. Our results demonstrate that OSP is the mediator of parallel-array tight junction strands and distinguishes this protein from other intrinsic membrane proteins in tight junctions. These novel results provide direct evidence of the pivotal role of the claudin family in generating the paracellular physical barrier of tight junctions necessary for spermatogenesis and normal CNS function.
Asunto(s)
Encéfalo/metabolismo , Proteínas de la Membrana/metabolismo , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células de Sertoli/metabolismo , Uniones Estrechas/metabolismo , Animales , Encéfalo/citología , Claudinas , Técnica de Fractura por Congelación , Regulación del Desarrollo de la Expresión Génica , Haplorrinos , Miembro Posterior/crecimiento & desarrollo , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Microscopía Confocal , Microscopía Electrónica , Proteínas del Tejido Nervioso/genética , Oligodendroglía/citología , Oligodendroglía/metabolismo , Ratas , Células de Sertoli/ultraestructura , Testículo/patología , Uniones Estrechas/ultraestructuraRESUMEN
The objective of this workshop was to provide recommendations on several issues involving pallidotomy for patients with medically intractable Parkinson disease to physicians, patients, and other health care providers. An international consortium of experts in neurology, neurosurgery, and neurophysiology who had extensive experience with pallidotomy were invited to the workshop. Participants were sent background materials from the scientific literature for review-based participant recommendations. A proposed agenda was circulated to all participants before the workshop, and the final agenda was based on their recommendations. Topics were introduced at the workshop by members of the organizing committee, followed by extensive group discussion. A draft of a consensus statement, based on the previous day's discussion, was circulated and further modifications were made. The final statement was agreed on by all members. The conclusions of the participants were: (1) Pallidotomy should be performed only at centers that have a team of physicians with substantial expertise and experience in the field. (2) Patients with disabling idiopathic Parkinson disease, without dementia, and who have exhausted medical therapy should be considered for pallidotomy. (3) All patients should be examined by means of standardized rating scales both preoperatively and postoperatively to ensure quality of care at each center. (4) Symptoms that respond best to pallidotomy include medication-induced dyskinesias, rigidity, and tremor, while balance, gait disorders, and hypophonia are generally less responsive to surgery. Benefits of pallidotomy appear to be long lasting. (5) Each institution's complication rate should be discussed before surgery.
Asunto(s)
Globo Pálido/cirugía , Procedimientos Neuroquirúrgicos/normas , Enfermedad de Parkinson Secundaria/cirugía , Técnicas Estereotáxicas , Consejo , Humanos , Procedimientos Neuroquirúrgicos/métodos , Educación del Paciente como Asunto , Selección de PacienteRESUMEN
OBJECTIVE: To determine the antibody response to oligodendrocyte-specific protein (OSP) in patients with MS. BACKGROUND: OSP is a recently identified CNS-specific myelin protein that is abundant and therefore a candidate autoantigen in MS. METHODS: The presence of anti-OSP antibodies was determined using Western blot analysis, peptide blots, and ELISA in patients with MS and in other neurologic and normal control subjects. RESULTS: Using Western blot analysis, seven patients with relapsing-remitting MS (RRMS) were found to contain anti-OSP antibodies in their CSF that were not present in control subjects. Peptide mapping determined that the antibody response was directed to a seven aa peptide (OSP 114-120), which has 71% homology with several common pathogenic proteins. Using OSP 114-120 as antigen, ELISAs were performed on CSF from 85 MS and 51 control patients. Eighty percent of the samples from RRMS patients followed at the University of California at Los Angeles had an ELISA reading above 0.55 optical density units, whereas all 20 control CSF samples had values less than 0.55 U. Similar results were found in specimens from an outside research bank. ELISAs performed on CSF using homologous viral peptides as antigen showed a close correlation with anti-OSP 114-120 ELISA readings, and in some, the readings were higher than those using OSP peptides. CONCLUSIONS: There is a specific humoral response directed against a region of OSP in RRMS patients that cross-reacts with several common viral peptides. This suggests a possible role for molecular mimicry in the development of MS.
Asunto(s)
Autoanticuerpos/líquido cefalorraquídeo , Linfocitos B/inmunología , Esclerosis Múltiple/inmunología , Proteínas del Tejido Nervioso/inmunología , Adulto , Anciano , Secuencia de Aminoácidos , Formación de Anticuerpos , Encéfalo/patología , Claudinas , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/patología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Mapeo Peptídico , Proteínas Recombinantes/inmunología , Valores de Referencia , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.
Asunto(s)
Antígenos de Neoplasias/uso terapéutico , Trasplante de Médula Ósea , Neoplasias Encefálicas/terapia , Células Dendríticas/trasplante , Glioma/terapia , Animales , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Femenino , Glioma/inmunología , Glioma/patología , Ratas , Ratas Endogámicas F344 , Análisis de Supervivencia , Linfocitos T Citotóxicos/fisiologíaRESUMEN
Oligodendrocyte-specific protein (OSP) is a recently isolated and cloned, 207-aa, hydrophobic, four-transmembrane protein found in CNS myelin. It represents approximately 7% of total myelin protein. The OSP cDNA sequence has no significant homology with previously reported genes, but the predicted protein structure suggests that OSP is a CNS homologue of peripheral myelin protein-22. We previously reported the presence of anti-OSP Abs in the cerebrospinal fluid of relapsing-remitting multiple sclerosis (MS) patients, but not control patient groups. In this study, we tested the ability of a panel of 20-mer peptides with 10-aa overlaps, representing the sequence of murine OSP, to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS. SJL mice challenged with murine OSP peptides 52-71, 82-101, 102-121, 142-161, 182-201, and 192-207 exhibited clinical EAE. OSP:52-71 elicited severe relapsing-remitting EAE in some individuals. All other encephalitogenic peptides elicited, at most, a loss of tail tonicity from which the mice most often completely recovered. Mononuclear cell infiltrates and focal demyelination characteristic of EAE were evident. T cell proliferative responses were seen with all encephalitogenic peptides except 142-161 and 182-201. OSP peptides 72-91 and 132-151 did not cause clinical EAE, but did elicit robust proliferative responses. B10.PL and PL/J mice challenged with the same OSP peptide doses as SJL mice did not exhibit clinical EAE. These results in the SJL EAE model, together with the results from MS patient clinical samples, make OSP a promising candidate for autoantigenic involvement in MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Proteínas del Tejido Nervioso/inmunología , Oligodendroglía/inmunología , Fragmentos de Péptidos/inmunología , Secuencia de Aminoácidos , Animales , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/patología , Epítopos de Linfocito T/inmunología , Femenino , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/química , Solubilidad , Especificidad de la Especie , Linfocitos T/inmunologíaRESUMEN
OBJECTIVE: To evaluate the effects of ventroposterior pallidotomy on motor disability and on behavior and cognition in patients with medically intractable idiopathic Parkinson disease. DESIGN: Detailed motor testing both while receiving and discontinuing levodopa medication, posturography, and neurocognitive and behavioral assessments were performed before and 3 to 6 months after unilateral ventroposterior pallidotomy. SETTING: University-based movement disorder program. PATIENTS: Thirty-two patients without dementia with medically refractory idiopathic Parkinson disease were studied. MAIN OUTCOME MEASURES: Motor function and disability were measured using the Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, and the Schwab and England Activities of Daily Living Scale. Dynamic balance was measured by sway (amplitude and velocity) using the Chattecx Balance System. Detailed cognitive and behavioral assessments were also performed both before and after surgery. RESULTS: Eighty-three percent of patients experienced improvement of their total Unified Parkinson's Disease Rating Scale score at 3 to 6 months after surgery. Significant improvements were also seen in the contralateral Unified Parkinson's Disease Rating Scale motor subscore (78%) as well as in the contralateral Unified Parkinson's Disease Rating Scale total score both during the on and off period (78% and 79%, respectively). The Hoehn and Yahr stage, Schwab and England Activities of Daily Living Scale score, and dynamic balance when standing on foam also improved following unilateral pallidotomy in many patients. Cognitive performance remained relatively unchanged following surgery with the exception of category fluency, which exhibited a modest decline (P < .04). A significant improvement in depression was found on the Beck Depression Inventory. CONCLUSIONS: Ventroposterior pallidotomy significantly improves motor performance and daily level of function in Parkinson disease. Cognition and behavior are not adversely affected in patients without dementia, and a cognitive screening battery is proposed.
Asunto(s)
Cognición , Globo Pálido/cirugía , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Desempeño Psicomotor , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/cirugía , PosturaRESUMEN
OBJECTIVE: To assess the relationship between clinical, demographic, and site-of-care factors and the use of tocolysis and corticosteroid therapy in the treatment of premature labor. DATA SOURCE: Secondary clinical and demographic data collected for the five-center March of Dimes Prematurity Prevention clinical trial, 1983-1986. STUDY DESIGN: We used logistic regression analysis in assessing the clinical, patient, and care site factors associated with the use of tocolysis and corticosteroid therapy during episodes of premature labor occurring to women enrolled in the trial. The two interventions were not subject to control in the trial, but were provided according to customary practice at the care site. DATA EXTRACTION: A total of 4,625 episodes of labor occurring before 37 weeks gestation were identified from either preterm labor or preterm delivery records recorded for the 33,792 women enrolled in the trial. PRINCIPAL FINDINGS: The use of tocolysis, an intervention that attempts to control premature labor contractions and that was widely used in high-risk obstetrics, varied almost exclusively by clinical factors. The use of corticosteroid therapy, a little used but effective intervention that reduces respiratory complications in premature infants, varied significantly by site of care and was used less frequently across sites and clinical conditions for minority group patients. CONCLUSION: This study confirms the premise that practice variation on the basis of nonclinical factors occurs more commonly for interventions where there is more uncertainty about clinical indications and effectiveness. The study also identifies another area of clinical care in which the use of aggressive and relatively uncertain interventions is provided less frequently to minority group patients.