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BACKGROUND: Preoperative anxiety is common in children. It can contribute to negative experiences with anesthetic induction and may cause adverse physiological and psychological effects. Virtual reality (VR) and electronic tablet devices are 2 audiovisual distraction tools that may help to reduce anxiety and enhance the preoperative experience. This study aimed to compare the use of an immersive 3-dimensional (3D) VR to 2-dimensional (2D) video on anxiety in children during induction of general anesthesia. METHODS: Two hundred children (4-13 years) undergoing elective or emergency surgery under general anesthesia were enrolled in this randomized, controlled trial. Participants were randomized to use either the 3D VR goggles (intervention) or 2D video tablet (control) during anesthetic induction. Anxiety, the primary outcome, was measured using the modified Yale Preoperative Anxiety Scale Short Form (mYPAS-SF) at 2 time points: in the preoperative holding area before randomization (T1) and during induction of general anesthesia (T2). The primary outcome was analyzed using a linear regression model, including demographic and other covariates, to investigate any differences in anxiety scores. Secondary outcomes included evaluating compliance during the anesthetic induction (Induction Compliance Checklist), emergence of delirium (Cornell Assessment of Pediatric Delirium), perceived usefulness of the device, and child satisfaction. RESULTS: Participant characteristics were similar between the 3D VR (n = 98) and 2D video (n = 90) groups, with a mean (±standard deviation) age 8. 8 ± 2.8 years. The median (lower quartile, upper quartile) mYPAS-SF scores for the 3D VR group at the preoperative holding area were 22.9 (22.9, 35.4), then 29.2 (24.0, 41.7) during induction. For the 2D Video group, the scores were 27.1 (22.9, 35.4) and then 30.2 (22.9, 41.1). No significant difference was observed in the increase in mYPAS-SF scores between groups (P = .672). Children in the 3D VR group were less likely to be rated as having a perfect induction (P = .039). There was no evidence of a difference between the groups in emergence delirium. Both devices were rated highly for usefulness and patient satisfaction. Children preferred VR, while anesthesiologists and parents felt the 2D was more useful. CONCLUSIONS: This randomized controlled trial demonstrated that preoperative anxiety was equally low and induction compliance high with both 3D VR and 2D video distraction in children with parental presence during anesthetic induction.
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Nuclear inclusion X (NIX), the etiological agent of bacterial gill disease in Pacific razor clams Siliqua patula, was associated with host mortality events in coastal Washington State, USA, during the mid-1980s. Ongoing observations of truncated razor clam size distributions in Kalaloch Beach, Washington, raised concerns that NIX continues to impact populations. We conducted a series of spatial and longitudinal NIX surveillances, examined archived razor clam gill tissue, and used population estimates from stock assessments to test whether (1) the prevalence and intensity of NIX infections is higher at Kalaloch Beach relative to nearby beaches, (2) infected gill tissue has features consistent with historical descriptions of NIX-associated histopathology, and (3) annual clam survival is inversely related to NIX infection prevalence and intensity. NIX prevalence exceeded 85% at all sampled locations, and infection intensity was the highest at Kalaloch Beach by 0.9-2.6 orders of magnitude. Kalaloch Beach clams revealed histopathology consistent with previous NIX epidemics, including enlarged and/or rupturing branchial epithelial cells, branchial necrosis, and high hemocyte densities. Estimated annual survival was 22% at Kalaloch Beach, and ranged between 57 and 99% at other study sites. NIX infection intensity (via quantitative PCR) was not significantly correlated with annual survival; however, annual survival was lowest at Kalaloch Beach, where infection intensities were highest, suggesting that clams can tolerate infections up to a lethal threshold. Collectively these data support the hypothesis that high NIX intensities are associated with host mortality. NIX-associated mortality appears to be more pronounced at Kalaloch Beach relative to other Washington beaches.
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Bivalvos , Cuerpos de Inclusión Intranucleares , Animales , Branquias , Washingtón/epidemiologíaRESUMEN
The objective of the present study was to quantify the accuracy of imputing medium-density single nucleotide polymorphism (SNP) genotypes from lower-density panels (384 to 12,000 SNPs) derived using alternative selection methods to select the most informative SNPs. Four different selection methods were used to select SNPs based on genomic characteristics (i.e., minor allele frequency (MAF) and linkage disequilibrium (LD)) within five sheep breeds (642 Belclare, 645 Charollais, 715 Suffolk, 440 Texel, and 620 Vendeen) separately. Selection methods evaluated included (i) random, (ii) splitting the genome into blocks of equal length and selecting SNPs within block based on MAF and LD patterns, (iii) equidistant location while optimizing MAF, (iv) a combination of MAF, distance from already selected SNPs, and weak LD with the SNP(s) already selected. All animals were genotyped on the Illumina OvineSNP50 Beadchip containing 51,135 SNPs of which 44,040 remained after edits. Within each breed separately, the youngest 100 animals were assumed to represent the validation population; the remaining animals represented the reference population. Imputation was undertaken under three different conditions: (i) SNPs were selected within a given breed and imputed for all breeds individually, (ii) all breeds were collectively used to select SNPs and were included as the reference population, and (iii) the SNPs were selected for each breed separately and imputation was undertaken for all breeds but excluding from the reference population, the breed from which the SNPs were selected. Regardless of SNP selection method, mean animal allele concordance rate improved at a diminishing rate while the variability in mean animal allele concordance rate reduced as the panel density increased. The SNP selection method impacted the accuracy of imputation although the effect reduced as the density of the panel increased. Overall, the most accurate SNP selection method for panels with <9,000 SNPs was that based on MAF and LD pattern within genomic blocks. The mean animal allele concordance rate varied from 0.89 in Texel to 0.97 in Vendeen. Greater imputation accuracy was achieved when SNPs were selected and imputed within each breed individually compared with when SNPs were selected across all breeds and imputed using a multi-breed reference population. In all, results indicate that accurate genotype imputation to medium density is achievable with low-density genotype panels with at least 6,000 SNPs.
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Frecuencia de los Genes , Genómica , Polimorfismo de Nucleótido Simple/genética , Ovinos/genética , Algoritmos , Alelos , Animales , Cruzamiento , Exactitud de los Datos , Genotipo , Desequilibrio de Ligamiento , Análisis de Secuencia por Matrices de Oligonucleótidos/veterinariaRESUMEN
BACKGROUND: The development, monitoring, and reporting of indicator measures that describe standard of care provide the gold standard for assessing quality of care and patient outcomes. Although indicator measures have been reported, little evidence of their use in measuring and benchmarking performance is available. A standard set, defining numerator, denominator, and risk adjustments, will enable global benchmarking of quality of care. OBJECTIVE: To develop a set of indicators to enable assessment and reporting of quality of care for men with localised prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: Candidate indicators were identified from the literature. An international panel was invited to participate in a modified Delphi process. Teleconferences were held before and after each voting round to provide instruction and to review results. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Panellists were asked to rate each proposed indicator on a Likert scale of 1-9 in a two-round iterative process. Calculations required to report on the endorsed indicators were evaluated and modified to reflect the data capture of the Prostate Cancer Outcomes Registry-Australia and New Zealand (PCOR-ANZ). RESULTS AND LIMITATIONS: A total of 97 candidate indicators were identified, of which 12 were endorsed. The set includes indicators covering pre-, intra-, and post-treatment of PCa care, within the limits of the data captured by PCOR-ANZ. CONCLUSIONS: The 12 endorsed quality measures enable international benchmarking on the quality of care of men with localised PCa. Reporting on these indicators enhances safety and efficacy of treatment, reduces variation in care, and can improve patient outcomes. PATIENT SUMMARY: PCa has the highest incidence of all cancers in men. Early diagnosis and relatively high survival rates mean issues of quality of care and best possible health outcomes for patients are important. This paper identifies 12 important measurable quality indicators in PCa care.
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Neoplasias de la Próstata/terapia , Indicadores de Calidad de la Atención de Salud/normas , Calidad de la Atención de Salud/normas , Benchmarking , Atención a la Salud , Técnica Delphi , Humanos , Masculino , Evaluación de Resultado en la Atención de Salud , Evaluación del Resultado de la Atención al Paciente , Neoplasias de la Próstata/epidemiología , Sistema de Registros , Ajuste de Riesgo/métodosRESUMEN
In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).
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Neuroimagen/métodos , Esquizofrenia/diagnóstico por imagen , Adulto , Estudios de Casos y Controles , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Difusión de la Información , Imagen por Resonancia Magnética , Magnetoencefalografía , MasculinoRESUMEN
The development and decline of brain structure and function throughout adulthood is a complex issue, with cognitive aging trajectories influenced by a host of factors including cerebrovascular risk. Neuroimaging studies of age-related cognitive decline typically reveal a linear decrease in gray matter (GM) volume/density in frontal regions across adulthood. However, white matter (WM) tracts mature later than GM, particularly in regions necessary for executive functions and memory. Therefore, it was predicted that a middle-aged group (MC: 35-45 years) would perform best on a verbal working memory task and reveal greater regional WM integrity, compared with both young (YC: 18-25 years) and elder groups (EC: 60+ years). Diffusion tensor imaging (DTI) and magnetoencephalography (MEG) were obtained from 80 healthy participants. Objective measures of cerebrovascular risk and cognition were also obtained. As predicted, MC revealed best verbal working memory accuracy overall indicating some maturation of brain function between YC and MC. However, contrary to the prediction fractional anisotropy values (FA), a measure of WM integrity, were not greater in MC (i.e., there were no significant differences in FA between YC and MC but both groups showed greater FA than EC). An overall multivariate model for MEG ROIs showed greater peak amplitudes for MC and YC, compared with EC. Subclinical cerebrovascular risk factors (systolic blood pressure and blood glucose) were negatively associated with FA in frontal callosal, limbic, and thalamic radiation regions which correlated with executive dysfunction and slower processing speed, suggesting their contribution to age-related cognitive decline. Hum Brain Mapp 38:3472-3490, 2017. © 2017 Wiley Periodicals, Inc.
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Purpose: Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools.Experimental Design: Apoptosis competency of primary tumor samples from patients with stage III colorectal cancer (n = 120) was calculated by APOPTO-CELL from measured protein concentrations of Procaspase-3, Procaspase-9, SMAC, and XIAP. An enriched APOPTO-CELL signature (APOPTO-CELL-PC3) was synthesized to capture apoptosome-independent effects of Caspase-3. Furthermore, a machine learning Random Forest approach was applied to APOPTO-CELL-PC3 and available molecular and clinicopathologic data to identify a further enhanced signature. Association of the signature with prognosis was evaluated in an independent colon adenocarcinoma cohort (TCGA COAD, n = 136).Results: We identified 3 prognostic biomarkers (P = 0.04, P = 0.006, and P = 0.0004 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively) with increasing stratification accuracy for patients with stage III colorectal cancer.The APOPTO-CELL-PC3 signature ranked highest among all features. The prognostic value of the signatures was independently validated in stage III TCGA COAD patients (P = 0.01, P = 0.04, and P = 0.02 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively). The signatures provided further stratification for patients with CMS1-3 molecular subtype.Conclusions: The integration of a systems-biology-based biomarker for apoptosis competency with machine learning approaches is an appealing and innovative strategy toward refined patient stratification. The prognostic value of apoptosis competency is independent of other available clinicopathologic and molecular factors, with tangible potential of being introduced in the clinical management of patients with stage III colorectal cancer. Clin Cancer Res; 23(5); 1200-12. ©2016 AACR.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Pronóstico , Anciano , Apoptosis/genética , Caspasa 3/genética , Caspasa 9/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Modelos Teóricos , Estadificación de Neoplasias , Medicina de Precisión , Medición de Riesgo , Biología de SistemasRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality in the Western world and commonly treated with genotoxic chemotherapy. Stress in the endoplasmic reticulum (ER) was implicated to contribute to chemotherapeutic resistance. Hence, ER stress related protein may be of prognostic or therapeutic significance. METHODS: The expression levels of ER stress proteins calnexin, calreticulin, GRP78 and GRP94 were determined in n = 23 Stage II and III colon cancer fresh frozen tumour and matched normal tissue samples. Data were validated in a cohort of n = 11 rectal cancer patients treated with radiochemotherapy in the neoadjuvant setting. The calnexin gene was silenced using siRNA in HCT116 cells. RESULTS: There were no increased levels of ER stress proteins in tumour compared to matched normal tissue samples in Stage II or III CRC. However, increased calnexin protein levels were predictive of poor clinical outcome in the patient cohort. Data were validated in the rectal cancer cohort treated in the neoadjuvant setting. Calnexin gene-silencing significantly reduced cell survival and increased cancer cell susceptibility to 5FU chemotherapy. CONCLUSION: Increased tumour protein levels of calnexin may be of prognostic significance in CRC, and calnexin may represent a potential target for future therapies.
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Biomarcadores de Tumor/metabolismo , Calnexina/metabolismo , Neoplasias Colorrectales/metabolismo , Retículo Endoplásmico/metabolismo , Terapia Molecular Dirigida , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Clonales , Neoplasias Colorrectales/patología , Retículo Endoplásmico/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fluorouracilo/farmacología , Técnicas de Silenciamiento del Gen , Silenciador del Gen/efectos de los fármacos , Células HCT116 , Humanos , Inmunohistoquímica , Terapia Neoadyuvante , Estadificación de Neoplasias , Pronóstico , Neoplasias del Recto/terapia , Resultado del TratamientoRESUMEN
We examined the health of a control group (18-81years) in our aging study, which is similar to control groups used in other neuroimaging studies. The current study was motivated by our previous results showing that one third of the elder control group had moderate to severe white matter hyperintensities and/or cortical volume loss which correlated with poor performance on memory tasks. Therefore, we predicted that cardiovascular risk factors (e.g., hypertension, high cholesterol) within the control group would account for significant variance on working memory task performance. Fifty-five participants completed 4 verbal and spatial working memory tasks, neuropsychological exams, diffusion tensor imaging (DTI), and blood tests to assess vascular risk. In addition to using a repeated measures ANOVA design, a cluster analysis was applied to the vascular risk measures as a data reduction step to characterize relationships between conjoint risk factors. The cluster groupings were used to predict working memory performance. The results show that higher levels of systolic blood pressure were associated with: 1) poor spatial working memory accuracy; and 2) lower fractional anisotropy (FA) values in multiple brain regions. In contrast, higher levels of total cholesterol corresponded with increased accuracy in verbal working memory. An association between lower FA values and higher cholesterol levels were identified in different brain regions from those associated with systolic blood pressure. The conjoint risk analysis revealed that Risk Cluster Group 3 (the group with the greatest number of risk factors) displayed: 1) the poorest performance on the spatial working memory tasks; 2) the longest reaction times across both spatial and verbal memory tasks; and 3) the lowest FA values across widespread brain regions. Our results confirm that a considerable range of vascular risk factors are present in a typical control group, even in younger individuals, which have robust effects on brain anatomy and function. These results present a new challenge to neuroimaging studies both for defining a cohort from which to characterize 'normative' brain circuitry and for establishing a control group to compare with other clinical populations.
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Envejecimiento/patología , Encéfalo/fisiopatología , Grupos Control , Voluntarios Sanos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Imagen de Difusión Tensora , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Memoria a Corto Plazo/fisiología , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
In this study we employed joint independent component analysis (jICA) to perform a novel multivariate integration of magnetoencephalography (MEG) and diffusion tensor imaging (DTI) data to investigate the link between function and structure. This model-free approach allows one to identify covariation across modalities with different temporal and spatial scales [temporal variation in MEG and spatial variation in fractional anisotropy (FA) maps]. Healthy controls (HC) and patients with schizophrenia (SP) participated in an auditory/visual multisensory integration paradigm to probe cortical connectivity in schizophrenia. To allow direct comparisons across participants and groups, the MEG data were registered to an average head position and regional waveforms were obtained by calculating the local field power of the planar gradiometers. Diffusion tensor images obtained in the same individuals were preprocessed to provide FA maps for each participant. The MEG/FA data were then integrated using the jICA software (http://mialab.mrn.org/software/fit). We identified MEG/FA components that demonstrated significantly different (p<0.05) covariation in MEG/FA data between diagnostic groups (SP vs. HC) and three components that captured the predominant sensory responses in the MEG data. Lower FA values in bilateral posterior parietal regions, which include anterior/posterior association tracts, were associated with reduced MEG amplitude (120-170 ms) of the visual response in occipital sensors in SP relative to HC. Additionally, increased FA in a right medial frontal region was linked with larger amplitude late MEG activity (300-400 ms) in bilateral central channels for SP relative to HC. Step-wise linear regression provided evidence that right temporal, occipital and late central components were significant predictors of reaction time and cognitive performance based on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) cognitive assessment battery. These results point to dysfunction in a posterior visual processing network in schizophrenia, with reduced MEG amplitude, reduced FA and poorer overall performance on the MATRICS. Interestingly, the spatial location of the MEG activity and the associated FA regions are spatially consistent with white matter regions that subserve these brain areas. This novel approach provides evidence for significant pairing between function (neurophysiology) and structure (white matter integrity) and demonstrates that this multivariate, multimodal integration technique is sensitive to group differences in function and structure.
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Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Imagen de Difusión Tensora/métodos , Magnetoencefalografía/métodos , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Adulto , Encéfalo/patología , Encéfalo/fisiopatología , Mapeo Encefálico/métodos , Trastornos del Conocimiento/etiología , Interpretación Estadística de Datos , Femenino , Humanos , Masculino , Análisis de Componente Principal , Reproducibilidad de los Resultados , Esquizofrenia/complicaciones , Sensibilidad y EspecificidadRESUMEN
MEG and EEG measure electrophysiological activity in the brain with exquisite temporal resolution. Because of this unique strength relative to noninvasive hemodynamic-based measures (fMRI, PET), the complementary nature of hemodynamic and electrophysiological techniques is becoming more widely recognized (e.g., Human Connectome Project). However, the available analysis methods for solving the inverse problem for MEG and EEG have not been compared and standardized to the extent that they have for fMRI/PET. A number of factors, including the non-uniqueness of the solution to the inverse problem for MEG/EEG, have led to multiple analysis techniques which have not been tested on consistent datasets, making direct comparisons of techniques challenging (or impossible). Since each of the methods is known to have their own set of strengths and weaknesses, it would be beneficial to quantify them. Toward this end, we are announcing the establishment of a website containing an extensive series of realistic simulated data for testing purposes ( http://cobre.mrn.org/megsim/ ). Here, we present: 1) a brief overview of the basic types of inverse procedures; 2) the rationale and description of the testbed created; and 3) cases emphasizing functional connectivity (e.g., oscillatory activity) suitable for a wide assortment of analyses including independent component analysis (ICA), Granger Causality/Directed transfer function, and single-trial analysis.
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Simulación por Computador , Electroencefalografía/métodos , Electroencefalografía/estadística & datos numéricos , Internet , Magnetoencefalografía/métodos , Magnetoencefalografía/estadística & datos numéricos , Estimulación Acústica , Algoritmos , Animales , Corteza Auditiva/fisiología , Ritmo beta/fisiología , Calibración , Circulación Cerebrovascular/fisiología , Interpretación Estadística de Datos , Bases de Datos Factuales , Lateralidad Funcional/fisiología , Haplorrinos , Humanos , Memoria a Corto Plazo/fisiología , Vías Nerviosas/fisiología , Estimulación Luminosa , Procesamiento de Señales Asistido por Computador , Programas Informáticos , Corteza Somatosensorial/fisiología , Interfaz Usuario-Computador , Percepción Visual/fisiologíaRESUMEN
OBJECTIVE: We describe the systematic approach to incidental findings (IFs) used at the Mind Research Network (MRN) where all MRI scans receive neuroradiologist interpretation and participants are provided results. METHODS: From 2004 to 2011, 8,545 MRI scans were acquired by 45 researchers. As mandated by MRN's external institutional review board, all structural sequences were evaluated by a clinical neuroradiologist who generated a report that included recommendations for referral if indicated. Investigators received a copy of their participants' reports, which were also mailed to participants unless they specifically declined. To better understand the impact of the radiology review process, a financial analysis was completed in addition to a follow-up phone survey to characterize participant perceptions regarding receiving their MRI scan results. RESULTS: The radiologist identified IFs in 34% of the 4,447 participants. Of those with IFs (n = 1,518), the radiologist recommended urgent or immediate referral for 2.5% and routine referral for 17%. For 80.5%, no referral was recommended. Estimated annual cost for this approach including support for the neuroradiologist, medical director, and ancillary staff is approximately $60,000 or $24/scan. The results of the retrospective phone survey showed that 92% of participants appreciated receiving their MRI report, and the majority stated it increased their likelihood of volunteering for future studies. CONCLUSIONS: Addressing IFs in a cost-effective and consistent manner is possible by adopting a policy that provides neuroradiology interpretation and offers participant assistance with clinical follow-up when necessary. Our experience suggests that an ethical, institution-wide approach to IFs can be implemented with minimal investigator burden.
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Encéfalo/patología , Hallazgos Incidentales , Neuroimagen/métodos , Comités de Ética en Investigación , Humanos , Imagen por Resonancia Magnética , Proyectos de Investigación , Estudios RetrospectivosRESUMEN
Many neuroimaging studies of age-related memory decline interpret resultant differences in brain activation patterns in the elderly as reflecting a type of compensatory response or regression to a simpler state of brain organization. Here we review a series of our own studies which lead us to an alternative interpretation, and highlights a couple of potential confounds in the aging literature that may act to increase the variability of results within age groups and across laboratories. From our perspective, level of cognitive functioning achieved by a group of elderly is largely determined by the health of individuals within this group. Individuals with a history of hypertension, for example, are likely to have multiple white matter insults which compromise cognitive functioning, independent of aging processes. The health of the elderly group has not been well-documented in most previous studies and elderly participants are rarely excluded, or placed into a separate group, due to health-related problems. In addition, recent results show that white matter tracts within the frontal and temporal lobes, regions critical for higher cognitive functions, continue to mature well into the 4th decade of life. This suggests that a young age group may not be the best control group for understanding aging effects on the brain since development is ongoing within this age range. Therefore, we have added a middle-age group to our studies in order to better understand normal development across the lifespan as well as effects of pathology on cognitive functioning in the aging brain.
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Envejecimiento/fisiología , Trastornos de la Memoria/fisiopatología , Memoria/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Disfunción Cognitiva/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Hipertensión/fisiopatología , Magnetoencefalografía , Persona de Mediana Edad , Adulto JovenRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a mouse model for multiple sclerosis, where disease is mediated by autoantigen-specific T cells. Although there is evidence linking CD4(+) T cells that secrete IL-17, termed Th17 cells, and IFN-gamma-secreting Th1 cells with the pathogenesis of EAE, the precise contribution of these T cell subtypes or their associated cytokines is still unclear. We have investigated the infiltration of CD4(+) T cells that secrete IFN-gamma, IL-17 or both cytokines into CNS during development of EAE and have examined the role of T cells in microglial activation. Our findings demonstrate that Th17 cells and CD4(+) T cells that produce both IFN-gamma and IL-17, which we have called Th1/Th17 cells, infiltrate the brain prior to the development of clinical symptoms of EAE and that this coincides with activation of CD11b(+) microglia and local production of IL-1beta, TNF-alpha and IL-6 in the CNS. In contrast, significant infiltration of Th1 cells was only detected after the development of clinical disease. Co-culture experiments, using mixed glia and MOG-specific T cells, revealed that T cells that secreted IFN-gamma and IL-17 were potent activators of pro-inflammatory cytokines but T cells that secrete IFN-gamma, but not IL-17, were less effective. In contrast both Th1 and Th1/Th17 cells enhanced MHC-class II and co-stimulatory molecule expression on microglia. Our findings suggest that T cells which secrete IL-17 or IL-17 and IFN-gamma infiltrate the CNS prior to the onset of clinical symptoms of EAE, where they may mediate CNS inflammation, in part, through microglial activation.
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Linfocitos T CD4-Positivos/inmunología , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Microglía/inmunología , Animales , Antígeno CD11b/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Sistema Nervioso Central/citología , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Glicoproteínas , Inyecciones Subcutáneas , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Reacción en Cadena de la Polimerasa , Células TH1/inmunología , Células TH1/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
To explore the effects of commonly encountered pathology on auditory recognition strategies in elderly participants, magnetoencephalographic (MEG) brain activation patterns and performance were examined in 30 elderly [18 controls and 12 elderly with mild cognitive impairment (MCI) or probable Alzheimer's disease (AD)]. It was predicted that participants with known pathology would reveal different networks of brain activation, compared to healthy elderly, which should correlate with poorer performance. Participants heard a list of words representing common objects, twice. After 20 minutes a list of new and old words was presented and participants judged whether each word was heard earlier. MEG responses were analyzed using a semiautomated source modeling procedure. A cluster analysis using all subjects' MEG sources revealed three dominant patterns of activity which correlated with IQ and task performance. The highest performing group revealed activity in premotor, anterior temporal, and superior parietal lobes with little contribution from prefrontal cortex. Performance and brain activation patterns were also compared for individuals with or without abnormalities such as white matter hyperintensities and/or volume reduction evidenced on their MRIs. Memory performance and activation patterns for individuals with white matter hyperintensities resembled the group of MCI/AD patients. These results emphasize the following: (1) general pathology correlates with cognitive decline and (2) full characterization of the health of elderly participants is important in studies of normal aging since random samples from the elderly population are apt to include individuals with subclinical pathology that can affect cognitive performance.
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Envejecimiento , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Trastornos del Conocimiento/fisiopatología , Lenguaje , Adaptación Fisiológica , Anciano , Anciano de 80 o más Años , Percepción Auditiva , Mapeo Encefálico/métodos , Femenino , Humanos , Magnetoencefalografía/métodos , Masculino , Persona de Mediana EdadRESUMEN
Maintenance of the balance between pro- and anti-inflammatory cytokines in the brain, which is affected by the activation state of microglia, is important for maintenance of neuronal function. Evidence has suggested that IL-4 plays an important neuromodulatory role and has the ability to decrease lipopolysaccharide-induced microglial activation and the production of IL-1beta. We have also demonstrated that CD200-CD200R interaction is involved in immune homeostasis in the brain. Here, we investigated the anti-inflammatory role of IL-4 and, using in vitro and in vivo analysis, established that the effect of lipopolysaccharide was more profound in IL-4(-/-), compared with wildtype, mice. Intraperitoneal injection of lipopolysaccharide exerted a greater inhibitory effect on exploratory behaviour in IL-4(-/-), compared with wildtype, mice and this was associated with evidence of microglial activation. We demonstrate that the increase in microglial activation is inversely related to CD200 expression. Furthermore, CD200 was decreased in neurons prepared from IL-4(-/-) mice, whereas stimulation with IL-4 enhanced CD200 expression. Importantly, neurons prepared from wildtype, but not from IL-4(-/-), mice attenuated the lipopolysaccharide-induced increase in pro-inflammatory cytokine production by glia. These findings suggest that the neuromodulatory effect of IL-4, and in particular its capacity to maintain microglia in a quiescent state, may result from its ability to upregulate CD200 expression on neurons.
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Antígenos CD/metabolismo , Inflamación/inmunología , Interleucina-4/inmunología , Neuronas/inmunología , Neuronas/metabolismo , Análisis de Varianza , Animales , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Técnicas de Cocultivo , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Conducta Exploratoria , Técnica del Anticuerpo Fluorescente , Hipocampo/inmunología , Hipocampo/metabolismo , Conducta de Enfermedad , Inflamación/inducido químicamente , Inflamación/genética , Inyecciones Intraperitoneales , Interleucina-4/genética , Lipopolisacáridos/inmunología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroglía/citología , Neuroglía/inmunología , Neuroglía/metabolismo , Neuronas/citología , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Neuronal communication in the brain involves electrochemical currents, which produce magnetic fields. Stimulus-evoked brain responses lead to changes in these fields and can be studied using magneto- and electro-encephalography (MEG/EEG). In this paper we model the spatiotemporal distribution of the magnetic field of a physiologically idealized but anatomically realistic neuron to assess the possibility of using magnetic resonance imaging (MRI) for directly mapping the neuronal currents in the human brain. Our results show that the magnetic field several centimeters from the centre of the neuron is well approximated by a dipole source, but the field close to the neuron is not, a finding particularly important for understanding the possible contrast mechanism underlying the use of MRI to detect and locate these currents. We discuss the importance of the spatiotemporal characteristics of the magnetic field in cortical tissue for evaluating and optimizing an experiment based on this mechanism and establish an upper bound for the expected MRI signal change due to stimulus-induced cortical response. Our simulations show that the expected change of the signal magnitude is 1.6% and its phase shift is 1 degrees . An unexpected finding of this work is that the cortical orientation with respect to the external magnetic field has little effect on the predicted MRI contrast. This encouraging result shows that magnetic resonance contrast directly based on the neuronal currents present in the cortex is theoretically a feasible imaging technique. MRI contrast generation based on neuronal currents depends on the dendritic architecture and we obtained high-resolution optical images of cortical tissue to discuss the spatial structure of the magnetic field in grey matter.
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Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Imagen de Difusión por Resonancia Magnética/métodos , Electroencefalografía/métodos , Corteza Entorrinal/fisiología , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Magnetoencefalografía/métodos , Células Piramidales/fisiología , Procesamiento de Señales Asistido por Computador , Programas Informáticos , Animales , Axones/ultraestructura , Corteza Cerebral/anatomía & histología , Dendritas/fisiología , Dendritas/ultraestructura , Corteza Entorrinal/anatomía & histología , Humanos , Macaca , Potenciales de la Membrana/fisiología , Redes Neurales de la Computación , Neuronas/fisiología , Células Piramidales/ultraestructura , Tractos Piramidales/anatomía & histología , Tractos Piramidales/fisiología , Ratas , Sinapsis/ultraestructura , Transmisión Sináptica/fisiologíaRESUMEN
Cannabis is the most commonly used illegal drug of abuse in Western society. Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana, regulates a variety of neuronal processes including neurotransmitter release and synaptic transmission. An increasing body of evidence suggests that cannabinoids play a key role in the regulation of neuronal viability. In cortical neurons tetrahydrocannabinol has a neurodegenerative effect, the mechanisms of which are poorly understood, but involve the cannabinoid receptor subtype, CB(1). In this study we report that tetrahydrocannabinol (5 muM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB(1) receptor, and the stress-activated protein kinase, c-jun N-terminal kinase, in cultured cortical neurons. Tetrahydrocannabinol increased expression of the p53-transcriptional target, Bax and promoted Bcl phosphorylation. These events were abolished by the p53 inhibitor, pifithrin-alpha (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-alpha. A siRNA knockdown of p53 further verified the role of p53 in tetrahydrocannabinol-induced apoptosis. This study demonstrates a novel cannabinoid signalling pathway involving p53 that culminates in neuronal apoptosis.
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Dronabinol/farmacología , Alucinógenos/farmacología , Receptor Cannabinoide CB1/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Fragmentación del ADN/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neuronas/efectos de los fármacos , Fosforilación , Ratas , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/efectos de los fármacos , Proteína bcl-X/metabolismoRESUMEN
OBJECTIVE: Hemiparesis due to damage by stroke in primary motor cortex (MI) or its underlying projections presents a problem for functional neuroimaging technologies that attempt to evaluate the neurophysiological basis for restoration of motor function. Traditional assessments of MI function require patients to move their fingers, hands, or limbs, which can be either impossible or markedly compromised after stroke. We recently demonstrated in normal subjects that magnetoencephalography (MEG), a non-invasive neuromagnetic functional imaging technique, detects neuronal response elicited by electrical median nerve stimulation in MI, as well as primary somatosensory cortex (SI). In the present study, we used the MEG response from median nerve stimulation to investigate the recovery of primary motor and somatosensory in acute ischemic stroke patients. METHODS: Twelve patients with unilateral ischemic strokes that affected sensorimotor functions of their hand were studied in the acute stage (4.4+/-1.2 days, mean+/-SD) and during a 1-month follow-up (38.6+/-5.6 days, except for one patient's follow-up done 6 month after stroke). RESULTS: Among the multiple cortical sources localized after median nerve stimulation, one source localized to SI and another localized to the vicinity of MI. Changes in the source strengths of the first component post-stimulus of MI and SI correlated with the extent of recovery of sensorimotor functions as determined by neurological exams. CONCLUSIONS: This study provides a novel way of indirectly assessing MI function using MEG during the acute stroke phase, when many patients often cannot perform motor tasks due to paralysis.