RESUMEN
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
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Restricción Calórica , Monocitos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Adulto , Animales , Antígenos Ly/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Quimiocina CCL2/deficiencia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Femenino , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , PPAR alfa/deficiencia , PPAR alfa/genética , PPAR alfa/metabolismoRESUMEN
Inflammation of the central nervous system (CNS) induces endothelial blood-brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of "chronic neuroinflammatory tolerance" in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.
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Barrera Hematoencefálica/fisiología , Barrera Hematoencefálica/fisiopatología , Uniones Adherentes/patología , Uniones Adherentes/fisiología , Animales , Antígenos CD/genética , Antígenos CD/fisiología , Astrocitos/patología , Astrocitos/fisiología , Cadherinas/genética , Cadherinas/fisiología , Permeabilidad Capilar/genética , Permeabilidad Capilar/fisiología , Claudina-5/genética , Claudina-5/fisiología , Regulación hacia Abajo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Células Endoteliales/patología , Células Endoteliales/fisiología , Femenino , Proteínas Hedgehog/deficiencia , Proteínas Hedgehog/genética , Proteínas Hedgehog/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Neuroglía/patología , Neuroglía/fisiología , Uniones Estrechas/patología , Uniones Estrechas/fisiologíaRESUMEN
Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.
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Sistema Nervioso Central/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Diferenciación Celular , Supervivencia Celular/genética , Cromatina/metabolismo , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factor 6 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Proteínas Proto-Oncogénicas/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Madre/metabolismo , alfa Carioferinas/metabolismoRESUMEN
Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive, often fatal viral infection of the brain without a known treatment. Recently, case reports have demonstrated survival from PML with therapies that improve cell-mediated immunity, including interleukin-7 (IL-7) or the chemokine receptor type 5 (CCR5) antagonist, maraviroc (MVC). We present the first known case of a patient with PML successfully treated with both IL-7 and MVC. A 63-year-old woman presented to our center with a 6-month history of progressive left hemiparesis. Extensive laboratory testing was negative except for a severe CD4 lymphocytopenia (140/µL). Serial brain MRIs done prior to presentation revealed an enlarging, non-enhancing T2-hyperintense lesion in the right fronto-parietal white matter. PML was confirmed through detection of the JC virus by PCR in the cerebrospinal fluid and by brain biopsy, and she was started on mirtazapine and mefloquine. She continued to deteriorate and was then given a course of recombinant IL-7. Though she remained clinically stable after IL-7 treatment and serum JCV PCR decreased from 1000 copies/mL to a nadir of 238 copies/mL, a repeat MRI 3 months later showed lesion enlargement. MVC was then initiated. Now, more than 2 years after initial presentation, she remains stable and serum JCV PCR is undetectable. This case demonstrates successful treatment of PML in a patient with idiopathic CD4 lymphocytopenia and highlights the potential benefits of IL-7 and MVC in the treatment of PML. Treatment with IL-7 and MVC led to clinical stability and improvement in JC virus titers.
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Antagonistas de los Receptores CCR5/uso terapéutico , Interleucina-7/uso terapéutico , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Maraviroc/uso terapéutico , Linfocitopenia-T Idiopática CD4-Positiva/complicaciones , Femenino , Humanos , Leucoencefalopatía Multifocal Progresiva/complicaciones , Leucoencefalopatía Multifocal Progresiva/inmunología , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéuticoRESUMEN
In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.
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Astrocitos/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Timidina Fosforilasa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Barrera Hematoencefálica/fisiopatología , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Desoxirribosa/fisiología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Endotelio Vascular/metabolismo , Humanos , Interleucina-1beta/farmacología , Ratones , Ratones Transgénicos , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Timidina Fosforilasa/antagonistas & inhibidores , Timidina Fosforilasa/farmacología , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/fisiología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex.
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Mapeo Encefálico , Predominio Ocular/genética , Lateralidad Funcional/genética , Proteínas de la Membrana/deficiencia , Proteínas del Tejido Nervioso/deficiencia , Corteza Visual/fisiología , Vías Visuales/fisiología , Potenciales de Acción/fisiología , Análisis de Varianza , Animales , Animales Recién Nacidos , Autorradiografía , Regulación de la Expresión Génica/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Neuronas/fisiología , Estimulación Luminosa , Proteínas Proto-Oncogénicas c-fos/metabolismo , Corteza Visual/citología , Vías Visuales/anatomía & histologíaRESUMEN
BACKGROUND: People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants. The objective of this study is to evaluate humoral and cellular immune responses to a third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays. METHODS: This is an observational study evaluating immunological responses to third COVID-19 vaccine dose in participants treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Groups were compared by one-way ANOVA with Tukey multiple comparisons. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated. Pre-post comparisons were made by Wilcoxon paired t-tests, inter-cohort comparisons by Mann-Whitney t-test. RESULTS: This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P < 0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p < 0.001) and were not significantly "boosted" by a third injection. CONCLUSIONS: Participants on anti-CD20 and S1PR modulator therapies had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , Esfingosina , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , VacunaciónRESUMEN
Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl ) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces and a milder histopathological and clinical course of disease compared with wild-type controls (JAM-Afl/fl ). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte-immune cell signalling as a novel translational target against neuroinflammatory disease.
RESUMEN
BACKGROUND: Prior studies suggest reduced humoral response to COVID-19 vaccination in immunosuppressed populations. Disease modifying therapies (DMTs) for multiple sclerosis (MS) have variable immunomodulatory effects, and limited data are available for all DMTs. We aimed to determine the impact of DMTs on antibody response to COVID-19 vaccination among MS patients. METHODS: Patients with documented COVID-19 vaccination dates and anti-spike antibody results post-vaccination were identified between March-August 2021. Clinical data were retrospectively abstracted from chart review. Deidentified data were analyzed to evaluate antibody response, and multivariable logistic regression analyses were used to identify clinical and demographic predictors of antibody response. Data analysis was completed with SAS Studio, v3.8. RESULTS: A total of 353 individuals had documented COVID-19 vaccine and antibody test dates (58% Pfizer, 38% Moderna, and 4% Johnson & Johnson). Of these 353 patients, 72% developed antibodies, with a mean antibody test interval of 53 days (median 46) post final vaccine dose. 100% of those on no DMT (n = 34), injectables (n = 20), teriflunomide (n = 10), natalizumab (n = 71), and 97.8% of those on fumarates (n = 46/47) had a positive antibody result. One patient on cladribine (n = 1) had a negative antibody result. Of those on sphingosine-1 phosphate (S1P) modulators, 72.4% (n = 21/29) had a positive antibody result. Of those on anti-CD20 therapies, 37.6% (n = 53/141) had a positive antibody result. Multivariate modeling of the total cohort showed anti-CD20 therapy was significantly associated with lower odds of positive antibody response (OR = 0.024, 95% CI 0.01;0.05, p < 0.0001). Among S1P modulators, increased duration of therapy, and not lymphopenia, may be associated with lower odds of positive antibody response. Multivariate modeling of anti-CD20 therapies showed therapy duration < 1 year (OR 8.14, 95% CI 2.896;22.898 p < .0001) and prior COVID-19 infection (OR = 3.95, 95% CI 1.137;13.726, p = .03) were significantly associated with higher odds of a positive antibody response. In patients with recent B-cell data, mean B-cell count was higher in antibody-positive individuals compared to antibody-negative (32.9 vs. 3.9 cells, p = .0056). CONCLUSION: MS DMTs had variable impact on antibody response with mRNA and viral vector COVID-19 vaccines. All patients on no DMT, interferons, glatiramer acetate, teriflunomide, natalizumab, and nearly all on fumarates had positive antibody responses post-vaccine. S1P modulators and anti-CD20 therapies attenuated antibody response post-vaccine. For patients on anti-CD20 therapies, shorter duration of therapy and prior COVID-19 infection predicted positive antibody response. Further studies are needed to determine clinical significance of antibody testing, development of cellular mediated immunity, and benefits of booster vaccinations.
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COVID-19 , Esclerosis Múltiple , Anticuerpos Antivirales , Formación de Anticuerpos , COVID-19/prevención & control , Vacunas contra la COVID-19 , Fumaratos , Humanos , Inmunomodulación , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Estudios RetrospectivosRESUMEN
Importance: People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants. Objective: Evaluate humoral and cellular immune responses to third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays. Design: Observational study evaluating immunological response to third COVID-19 vaccine dose in volunteers treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated. Setting: Mount Sinai Hospital. Participants: People treated with anti-CD20 therapy or S1PR modulators and healthy volunteers. Exposure: Treatment with anti-CD20 therapy, S1PR modulator, or neither. Main outcomes and measures: Serum neutralizing antibodies and ex vivo T cell responses against SARS-CoV-2 antigens. Results: This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P<0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p<0.001) and were not significantly "boosted" by a third injection. Conclusions and Relevance: Participants on immunomodulators had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.
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The mapping of eye-specific, geniculocortical inputs to primary visual cortex (V1) is highly sensitive to the balance of correlated activity between the two eyes during a restricted postnatal critical period for ocular dominance plasticity. This critical period is likely to have amplified expression of genes and proteins that mediate synaptic plasticity. DNA microarray analysis of transcription in mouse V1 before, during, and after the critical period identified 31 genes that were up-regulated and 22 that were down-regulated during the critical period. The highest-ranked up-regulated gene, cardiac troponin C, codes for a neuronal calcium-binding protein that regulates actin binding and whose expression is activity-dependent and relatively selective for layer-4 star pyramidal neurons. The highest-ranked down-regulated gene, synCAM, also has actin-based function. Actin-binding function, G protein signaling, transcription, and myelination are prominently represented in the critical period transcriptome. Monocular deprivation during the critical period reverses the expression of nearly all critical period genes. The profile of regulated genes suggests that synaptic stability is a principle driver of critical period gene expression and that alteration in visual activity drives homeostatic restoration of stability.
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Período Crítico Psicológico , Regulación del Desarrollo de la Expresión Génica , Privación Sensorial/fisiología , Sinapsis/genética , Sinapsis/metabolismo , Corteza Visual/metabolismo , Animales , Predominio Ocular/genética , Regulación hacia Abajo/genética , Perfilación de la Expresión Génica , Potenciales Postsinápticos Inhibidores/genética , Ratones , Vaina de Mielina/genética , Neuronas/citología , Neuronas/metabolismo , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Troponina C/genética , Troponina C/metabolismo , Regulación hacia Arriba/genética , Corteza Visual/crecimiento & desarrolloRESUMEN
OBJECTIVE: Sleep-dependent memory processing occurs in animals including humans, and disturbed sleep negatively affects memory. Sleep disturbance and memory dysfunction are common in multiple sclerosis (MS), but little is known about the contributions of sleep disturbance to memory in MS. We investigated whether subjective sleep disturbance is linked to worse memory in early MS independently of potential confounders. METHODS: Persons with early MS (n = 185; ≤5.0 years diagnosed) and demographically matched healthy controls (n = 50) completed four memory tests to derive a memory composite, and four speeded tests to derive a cognitive efficiency composite. Z-scores were calculated relative to healthy controls. Sleep disturbance was defined by the Insomnia Severity Index score ≥ 10. ANCOVAs examined differences in memory and cognitive efficiency between patients with and without sleep disturbance controlling for potential confounds (e.g., mood, fatigue, disability, T2 lesion volume, gray matter volume). Comparisons were made to healthy controls. RESULTS: Seventy-four (40%) patients reported sleep disturbance. Controlling for all covariates, patients with sleep disturbance had worse memory (z = -0.617; 95% CI: -0.886, -0.348) than patients without disturbance (z = -0.171, -0.425, 0.082, P = .003). Cognitive efficiency did not differ between groups. Relative to healthy controls, memory was worse among patients with sleep disturbance, but not among patients without sleep disturbance. INTERPRETATION: Sleep disturbance contributes to MS memory dysfunction, which may help explain differential risk for memory dysfunction in persons with MS, especially since sleep disturbance is common in MS. Potential mechanisms linking sleep disturbance and memory are discussed, as well as recommendations for further mechanistic and interventional research.
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Disfunción Cognitiva/fisiopatología , Trastornos de la Memoria/fisiopatología , Esclerosis Múltiple/fisiopatología , Trastornos del Sueño-Vigilia/fisiopatología , Adulto , Disfunción Cognitiva/etiología , Femenino , Humanos , Masculino , Trastornos de la Memoria/etiología , Esclerosis Múltiple/complicaciones , Trastornos del Sueño-Vigilia/complicacionesRESUMEN
Primary sensory nuclei of the thalamus process and relay parallel channels of sensory input into the cortex. The developmental processes by which these nuclei acquire distinct functional roles are not well understood. To identify novel groups of genes with a potential role in differentiating two adjacent sensory nuclei, we performed a microarray screen comparing perinatal gene expression in the principal auditory relay nucleus, the medial geniculate nucleus (MGN), and principal visual relay nucleus, the lateral geniculate nucleus (LGN). We discovered and confirmed groups of highly ranked, differentially expressed genes with qRT-PCR and in situ hybridization. A functional role for Zic4, a transcription factor highly enriched in the LGN, was investigated using Zic4-null mice, which were found to have changes in topographic patterning of retinogeniculate projections. Foxp2, a transcriptional repressor expressed strongly in the MGN, was found to be positively regulated by activity in the MGN. These findings identify roles for two differentially expressed genes, Zic4 and Foxp2, in visual and auditory pathway development. Finally, to test whether modality-specific patterns of gene expression are influenced by extrinsic patterns of input, we performed an additional microarray screen comparing the normal MGN to "rewired" MGN, in which normal auditory afferents are ablated and novel retinal inputs innervate the MGN. Data from this screen indicate that rewired MGN acquires some patterns of gene expression that are present in the developing LGN, including an upregulation of Zic4 expression, as well as novel patterns of expression which may represent unique processes of cross-modal plasticity.
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Vías Auditivas/crecimiento & desarrollo , Factores de Transcripción Forkhead/metabolismo , Cuerpos Geniculados/crecimiento & desarrollo , Proteínas de Homeodominio/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Vías Visuales/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Vías Auditivas/anatomía & histología , Vías Auditivas/metabolismo , Factores de Transcripción Forkhead/genética , Expresión Génica , Cuerpos Geniculados/anatomía & histología , Cuerpos Geniculados/metabolismo , Proteínas de Homeodominio/genética , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Represoras/genética , Retina/anatomía & histología , Retina/crecimiento & desarrollo , Retina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tálamo/anatomía & histología , Tálamo/crecimiento & desarrollo , Tálamo/fisiología , Factores de Transcripción/genética , Vías Visuales/anatomía & histología , Vías Visuales/metabolismoRESUMEN
Two key models for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD). Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin expression, implicating parvalbumin-expressing interneurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates molecular pathways related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. Expression of a binding protein of insulin-like growth factor-1 (IGF1) is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Plasticidad Neuronal/fisiología , Transducción de Señal/fisiología , Corteza Visual/citología , Corteza Visual/fisiología , Vías Visuales/fisiología , Animales , Animales Recién Nacidos , Oscuridad , Inmunohistoquímica/métodos , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Privación Sensorial/fisiología , Visión Binocular/fisiología , Visión Monocular/fisiologíaRESUMEN
BACKGROUND: Ethicists have suggested that written consent forms encourage participants in phase 1 cancer trials to expect benefit from the experimental agent and to overlook serious risks. METHODS: To evaluate the written description of direct benefit as well as risk, all consent forms for 1999 phase 1 cancer trials were compiled from 80 percent of the National Cancer Institute-designated cancer centers and from six of eight large pharmaceutical developers of anticancer drugs. In each case, we evaluated the characteristics of the trial, the descriptions of the purpose and procedures of the research, the promise of benefit, the description of risks, and the description of alternatives. RESULTS: Of 272 forms, 268 explicitly mentioned that the trial was research, and 249 stated that the purpose of the trial was testing for safety. Nearly all forms (269) mentioned the right to withdraw from the trial. Almost all forms (260) referred to the experimental agent as "treatment" or "therapy." Only one consent form promised direct benefit to subjects. Most forms (181) mentioned death as a risk, and very few (14) mentioned cure as even a possible benefit. Most (229) stated that there was unknown risk involved and indicated that severe or permanent harms were possible (224). CONCLUSIONS: Consent forms for phase 1 oncology studies almost never promise direct benefit to subjects, rarely mention cure, and usually communicate the seriousness and unpredictability of risk. Although there is room for improvement, the substance of these forms is unlikely to be the primary source of misunderstanding by subjects in phase 1 oncology trials.
Asunto(s)
Ensayos Clínicos Fase I como Asunto/normas , Consentimiento Informado/normas , Oncología Médica/normas , Investigación Biomédica , Ensayos Clínicos Fase I como Asunto/ética , Humanos , Consentimiento Informado/ética , Oncología Médica/ética , National Institutes of Health (U.S.) , Neoplasias/terapia , Medición de Riesgo , Estados UnidosRESUMEN
Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease.
Asunto(s)
Astrocitos/citología , Sistema Nervioso Central/patología , Inflamación , Enfermedades del Sistema Nervioso/patología , Uniones Estrechas , Animales , Barrera Hematoencefálica/patología , Moléculas de Adhesión Celular/metabolismo , Claudina-1/metabolismo , Claudina-4/metabolismo , Técnicas de Cocultivo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esclerosis Múltiple/patología , Receptores de Superficie Celular/metabolismoRESUMEN
The mammalian cortex is organized anatomically into discrete areas, which receive, process, and transmit neural signals along functional pathways. These pathways form a system of complex networks that wire up through development and refine their connections into adulthood. Understanding the processes of cortical-pathway formation, maintenance, and experience-dependent plasticity has been among the major goals of contemporary neurobiology. In this chapter, we will discuss an experimental model used to investigate the role of activity in the patterning of cortical networks during development. This model involves the "rewiring" of visual inputs into the auditory thalamus and subsequent remodeling of the auditory cortex to process visual information. We review the molecular, cellular, and physiological mechanisms of visual "rewiring" and activity-dependent shaping of cortical networks.
Asunto(s)
Corteza Cerebral/fisiología , Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Visión Ocular/fisiología , Corteza Visual/fisiología , Animales , Humanos , Plasticidad Neuronal/genética , Vías Visuales/fisiologíaRESUMEN
Neurological disease has been a central focus in the ongoing ethical debate over the use of invasive placebo controls, especially sham surgery. The risk to research subjects and necessary use of deception involved in these procedures must be balanced against the methodological need to control for bias and the placebo effect. We review a framework formulated for the ethical assessment of sham surgery in the context of research evaluating novel procedures for neurological conditions. Special issues raised include the growing evidence of expectation and conditioning effects in a number of neurological diseases, the escalating scale of risk from different types of invasive placebo interventions, and the increasing use of cross-over designs, which allow a switch from placebo to active intervention without additional procedures.
Asunto(s)
Encefalopatías/cirugía , Ensayos Clínicos como Asunto/ética , Experimentación Humana/ética , Neurocirugia/ética , Placebos , Ética Clínica , HumanosRESUMEN
Ethical, professional, and financial considerations support the highest standards in demonstrating the safety and efficacy of new clinical interventions. Professional and regulatory mechanisms implemented to ensure that medical agents undergo a thorough process of systematic testing are lacking in the case of medical procedures. As a result, many procedures, including surgery, are rapidly introduced into the clinical setting without reliable evaluation of their efficacy. In many cases, a randomized, placebo-controlled procedure trial may be necessary to provide this data. We examine the major ethical objections to placebo-controlled procedure trials, including those involving sham surgery, and provide an ethical framework for assessing whether a placebo procedure is ethical to administer in the context of a clinical trial. A placebo-controlled trial of an invasive procedure can be ethically justified if: 1) there is a valuable, clinically relevant question to be answered by the research, 2) the placebo control is methodologically necessary to test the study hypothesis, 3) the risk of the placebo control itself has been minimized, 4) the risk of a placebo control does not exceed a threshold of acceptable research risk, 5) the risk of the placebo control is justified by valuable knowledge to be gained, and 6) the misleading involved in the administration of a placebo control is adequately disclosed and authorized during the informed consent process.