RIG-I contributes to the innate immune response after cerebral ischemia

BACKGROUND: Focal cerebral ischemia induces an inflammatory response that when exacerbated contributes to deleterious outcomes. The molecular basis regarding the regulation of the innate immune response after focal cerebral ischemia remains poorly understood. METHODS: In this study we examined the expression of retinoic acid-inducible gene (RIG)-like receptor-I (RIG-I) and its involvement in regulating inflammation after ischemia in the brain of rats subjected to middle cerebral artery occlusion (MCAO). In addition, we studied the regulation of RIG-I after oxygen glucose deprivation (OGD) in astrocytes in culture. RESULTS: In this study we show that in the hippocampus of rats, RIG-I and IFN-α are elevated after MCAO. Consistent with these results was an increased in RIG-I and IFN-α after OGD in astrocytes in culture. These data are consistent with immunohistochemical analysis of hippocampal sections, indicating that in GFAP-positive cells there was an increase in RIG-I after MCAO. In addition, in this study we have identified n-propyl gallate as an inhibitor of IFN-α signaling in astrocytes. CONCLUSION: Our findings suggest a role for RIG-I in contributing to the innate immune response after focal cerebral ischemia

Context-sensitive autoassociative memories as expert systems in medical diagnosis

BACKGROUND: The complexity of our contemporary medical practice has impelled the development of different decision-support aids based on artificial intelligence and neural networks. Distributed associative memories are neural network models that fit perfectly well to the vision of cognition emerging from current neurosciences. METHODS: We present the context-dependent autoassociative memory model. The sets of diseases and symptoms are mapped onto a pair of basis of orthogonal vectors. A matrix memory stores the associations between the signs and symptoms, and their corresponding diseases. A minimal numerical example is presented to show how to instruct the memory and how the system works. In order to provide a quick appreciation of the validity of the model and its potential clinical relevance we implemented an application with real data. A memory was trained with published data of neonates with suspected late-onset sepsis in a neonatal intensive care unit (NICU). A set of personal clinical observations was used as a test set to evaluate the capacity of the model to discriminate between septic and non-septic neonates on the basis of clinical and laboratory findings. RESULTS: We show here that matrix memory models with associations modulated by context can perform automatic medical diagnosis. The sequential availability of new information over time makes the system progress in a narrowing process that reduces the range of diagnostic possibilities. At each step the system provides a probabilistic map of the different possible diagnoses to that moment. The system can incorporate the clinical experience, building in that way a representative database of historical data that captures geo-demographical differences between patient populations. The trained model succeeds in diagnosing late-onset sepsis within the test set of infants in the NICU: sensitivity 100%; specificity 80%; percentage of true positives 91%; percentage of true negatives 100%; accuracy (true positives plus true negatives over the totality of patients) 93,3%; and Cohen's kappa index 0,84. CONCLUSION: Context-dependent associative memories can operate as medical expert systems. The model is presented in a simple and tutorial way to encourage straightforward implementations by medical groups. An application with real data, presented as a primary evaluation of the validity and potentiality of the model in medical diagnosis, shows that the model is a highly promising alternative in the development of accuracy diagnostic tools

Sex and the city: Differences in disease- and disability-free life years, and active community participation of elderly men and women in 7 cities in Latin America and the Caribbean

<p>Abstract</p> <p>Background</p> <p>The world's population is ageing, and four of the top 10 most rapidly ageing developing nations are from the region of Latin America and the Caribbean (LAC).</p> <p>Although an ageing population heralds likely increases in chronic disease, disability-related dependence, and economic burden, the societal contribution of the chronically ill or those with disability is not often measured.</p> <p>Methods</p> <p>We calculated country-specific prevalences of 'disability' (difficulty with at least one activity of daily living), 'disease' and 'co-morbidity' (presence of at least one, and at least two, of seven chronic diseases/conditions, respectively), and 'active community engagement' (using five levels of community participation, from less than weekly community contact to voluntary or paid work) in seven LAC cities. We estimated remaining life expectancy (LE) with and without disability, disease and co-morbidity, and investigated age, sex, and regional variations in disability-free LE. Finally, we modeled the association of disease, co-morbidity and disability with active community participation using an ordinal regression model, adjusted for depression.</p> <p>Results</p> <p>Overall, 77% of the LAC elderly had at least one chronic disease/condition, 44% had co-morbidity and 19% had a disability. The proportion of disability-free LE declined between the youngest (60–64 years) and the eldest (90 years and over) age-groups for both men (from 85% to 55%) and women (from 75% to 45%). Disease-free and co-morbidity-free LE, however, remained at approximately 30% and 62%, respectively, for men (20% and 48% for women), until 80–84 years of age, then increased. Only Bridgetown's participants had statistically significantly longer disability-free LE than the regional average (IRR = 1.08; 95%CI 1.05–1.10; p < 0.001). Only Santiago's participants had disability-free LE which was shorter than the regional average (IRR = 0.94; 95%CI 0.92–0.97; p < 0.001). There was 75% active community participation overall, with more women than men involved in active help (49% vs 32%, respectively) and more men involved in voluntary/paid work (46% vs 25%, respectively). There was either no, or borderline significance in the association between having one or more diseases/conditions and active community engagement for both sexes. These associations were limited by depression (odds ratio [OR] reduced by 15–17% for men, and by 8–11% for women), and only remained statistically significant in men. However, disability remained statistically significantly associated with less community engagement after adjusting for depression (OR = 0.58, 95%CI 0.49–0.69, p < 0.001 for women and OR = 0.50, 95%CI 0.47–0.65, p < 0.001 for men).</p> <p>Conclusion</p> <p>There is an increasing burden of disease and disability with older age across the LAC region. As these nations cope with resulting social and economic demands, governments and civic societies must continue to develop and maintain opportunities for community participation by this increasingly frail, but actively engaged group.</p

Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression

Early-onset major depressive disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not optimally effective. Biological markers of early-onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early-onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. We carried out unbiased analyses of this combined set of 26 candidate blood transcriptomic markers in a sample of 15–19-year-old subjects with MDD (N=14) and subjects with no disorder (ND, N=14). A panel of 11 blood markers differentiated participants with early-onset MDD from the ND group. Additionally, a separate but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Four transcripts, discovered from the chronic stress animal model, correlated with maltreatment scores in youths. These pilot data suggest that our approach can lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies

Mesenchymal Stem Cells Induce T-Cell Tolerance and Protect the Preterm Brain after Global Hypoxia-Ischemia

Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE

Neuron-glial Interactions

Although lagging behind classical computational neuroscience, theoretical and computational approaches are beginning to emerge to characterize different aspects of neuron-glial interactions. This chapter aims to provide essential knowledge on neuron-glial interactions in the mammalian brain, leveraging on computational studies that focus on structure (anatomy) and function (physiology) of such interactions in the healthy brain. Although our understanding of the need of neuron-glial interactions in the brain is still at its infancy, being mostly based on predictions that await for experimental validation, simple general modeling arguments borrowed from control theory are introduced to support the importance of including such interactions in traditional neuron-based modeling paradigms.Junior Leader Fellowship Program by “la Caixa” Banking Foundation (LCF/BQ/LI18/11630006

From influence to impact: the multifunctional land-use in Mediterranean prehistory emerging from palynology of archaeological sites (8.0-2.8 ka BP)

Archaeobotany is used to discover details on local land uses in prehistoric settlements developed during the middle and beginning of late Holocene. Six archaeological sites from four countries (Spain, Italy, Greece, and Turkey) have pollen and charcoal records showing clear signs of the agrarian systems that had developed in the Mediterranean basin during different cultural phases, from pre-Neolithic to Recent Bronze Age. A selected list of pollen taxa and sums, including cultivated trees, other woody species, crops and annual or perennial synanthropic plants are analysed for land use reconstructions. In general, cultivation has a lower image in palynology than forestry, and past land uses became visible when oakwoods were affected by human activities. On-site palynology allows us to recognise the first influence of humans even before it can be recognised in off-site sequences, and off-site sequences can allow us to determine the area of influence of a site. Neolithic and Bronze Age archaeological sites show similar land use dynamics implying oak exploitation, causing local deforestation, and cultivation of cereal fields in the area or around the site. Although a substantial difference makes the Neolithic influence quite distant from the Bronze Age impact, mixed systems of land exploitation emerged everywhere. Multiple land use activities exist (multifunctional landscapes) at the same time within the area of influence of a site. Since the Neolithic, people have adopted a diffuse pattern of land use involving a combination of diverse activities, using trees\u2013crops\u2013domesticated animals. The most recurrent combination included wood exploitation, field cultivation and animal breeding. The lesson from the past is that the multifunctional land use, combining sylvo-pastoral and crop farming mixed systems, has been widely adopted for millennia, being more sustainable than the monoculture and a promising way to develop our economy