BackgroundThe immune system of vertebrates has evolved the ability to mount highly elaborate responses to a broad range of pathogen-driven threats. Accordingly, it is quite a challenge to understand how a primitive adaptive immune system that probably lacked much of its present complexity could provide its bearers with significant evolutionary advantage, and therefore, continue to be selected for.ResultsWe have developed a very simple model of the immune system that captures the probabilistic communication between its innate and adaptive components. Probabilistic communication arises specifically from the fact that antigen presenting cells collect and present a range of antigens from which the adaptive immune system must (probabilistically) identify its target. Our results show that although some degree of self-reactivity in the immune repertoire is unavoidable, the system is generally able to correctly target pathogens rather than self-antigens. Particular circumstances that impair correct targeting and that may lead to infection-induced autoimmunity can be predicted within this framework. Notably, the probabilistic immune system exhibits the remarkable ability to detect sudden increases in the abundance of rare self-antigens, which represents a first step towards developing anti-tumoral responses.ConclusionA simple probabilistic model of the communication between the innate and adaptive immune system provides a robust immune response, including targeting tumors, but at the price of being at risk of developing autoimmunity.
The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.
Optic neuritis is an inflammatory optic neuropathy that affects many patients with multiple sclerosis (MS) at some point during their disease course. Differentiation of acute episodes of MS-associated optic neuritis from other autoimmune and inflammatory optic neuropathies is vital for treatment choice and further patient management, but is not always straightforward. Over the past decade, a number of new imaging, laboratory and electrophysiological techniques have entered the clinical arena. To date, however, no consensus guidelines have been devised to specify how and when these techniques can be most rationally applied for the diagnostic work-up of patients with acute optic neuritis. In this article, we review the literature and attempt to formulate a consensus for the investigation of patients with acute optic neuritis, both in standard care and in research with relevance to clinical treatment trials.
Most people in the world (?90%) are infected by the Epstein-Barr virus (EBV), which establishes itself permanently in B cells. Infection by EBV is related to a number of diseases including infectious mononucleosis, multiple sclerosis, and different types of cancer. So far, only seven complete EBV strains have been described, all of them coming from donors presenting EBV-related diseases. To perform a detailed comparative genomic analysis of EBV including, for the first time, EBV strains derived from healthy individuals, we reconstructed EBV sequences infecting lymphoblastoid cell lines (LCLs) from the 1000 Genomes Project. As strain B95-8 was used to transform B cells to obtain LCLs, it is always present, but a specific deletion in its genome sets it apart from natural EBV strains. After studying hundreds of individuals, we determined the presence of natural EBV in at least 10 of them and obtained a set of variants specific to wild-type EBV. By mapping the natural EBV reads into the EBV reference genome (NC007605), we constructed nearly complete wild-type viral genomes from three individuals. Adding them to the five disease-derived EBV genomic sequences available in the literature, we performed an in-depth comparative genomic analysis. We found that latency genes harbor more nucleotide diversity than lytic genes and that six out of nine latency-related genes, as well as other genes involved in viral attachment and entry into host cells, packaging, and the capsid, present the molecular signature of accelerated protein evolution rates, suggesting rapid host-parasite coevolution.
It is currently believed that the incidence rate of optic neuritis (ON) ranges between 0.56 and 5.1 cases per 100,000 person-years. However, since these figures were generated, they have not been updated and there are suggestions that the incidence of ON is on the rise. When designing new therapies and clinical trials for ON, and to improve the management this disease, it is important to have accurate epidemiological data. Thus, we set out to obtain the prevalence and incidence rates of ON in Barcelona (Spain) from 2008 to 2012, by a retrospective evaluation of electronic hospital records at the Hospital Clinic of Barcelona (population of 300,000 in the catchment area) matching the following ICD-9-CM codes as search terms: 377.3-optic neuritis; 377.30-optic neuritis, unspecific; 377.31-optic papillitis; 377.32-retrobulbar neuritis, acute; 377.39-other optic neuritis and "optic neuropathy". Demographic and clinical data were collected from records with a confirmed diagnosis of ON, including cases of idiopathic ON, multiple sclerosis, neuromyelitis optica and CRION. The prevalence of acute ON on 31 December 2012 was 2.75 cases per 100,000 people. The mean annual prevalence of acute ON during the 2008-2012 period was 7.87 cases per 100,000 person-year and the mean annual incidence rate was 5.36 cases per 100,000 person-years. The incidence of ON in Barcelona during 2008-2012 was higher than previously reported. This increase may reflect the evolution of diagnostic criteria, the use of a referral-center approach instead of a population-based approach, increased awareness of demyelinating diseases, latitude-related factors and possibly a true increase in its incidence.
Retrograde trans-synaptic degeneration of retinal ganglion cell layer (GCL) has been proposed as one of the mechanisms contributing to permanent disability after visual pathway damage. We set out to test this mechanism taking advantage of the new methods for imaging the macula with high resolution by optical coherence tomography (OCT) in patients with lesions in the posterior visual pathway. Additionally, we explored the association between thinning of GCL as an imaging marker of visual impairment such as visual field defects.
5'-deoxy-5'-methylthioadenosine (MTA) is an endogenous compound produced through the metabolism of polyamines. The therapeutic potential of MTA has been assayed mainly in liver diseases and, more recently, in animal models of multiple sclerosis. The aim of this study was to determine the neuroprotective effect of this molecule in vitro and to assess whether MTA can cross the blood brain barrier (BBB) in order to also analyze its potential neuroprotective efficacy in vivo.
To assess the association of primary retinal inflammation, namely retinal periphlebitis (RP) and microcystic macular edema, with clinical, brain, and retinal imaging biomarkers of multiple sclerosis (MS) severity.
Multiple Sclerosis (MS) is considered a T-cell-mediated autoimmune disease with a prototypical oscillatory behavior, as evidenced by the presence of clinical relapses. Understanding the dynamics of immune cells governing the course of MS, therefore, has many implications for immunotherapy. Here, we used flow cytometry to analyze the time-dependent behavior of antigen-specific effector (T(eff)) and regulatory (T(reg)) T cells and microglia in mice model of MS, Experimental Autoimmune Encephalomyelitis (EAE), and compared the observations with a mathematical cross-regulation model of T-cell dynamics in autoimmune disease.
Interferon-beta (IFN-beta) activates the immune response through the type I IFN signaling pathway. IFN-beta is important in the response to pathogen infections and is used as a therapy for Multiple Sclerosis. The mechanisms of self-regulation and control of this pathway allow precise and environment-dependent response of the cells in different conditions. Here we analyzed type I IFN signaling in response to IFN-beta in the macrophage cell line RAW 264.7 by RT-PCR, ELISA and xMAP assays. The experimental results were interpreted by means of a theoretical model of the pathway.
Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1?, IL-12 and IL-17, enhanced that of TNF-? and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-? release in microglial cells through a process involving intracellular retention, but induced TNF-? secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL-17 and IFN-? by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro-inflammatory conditions.
The anatomic location of subsequent relapses in early multiple sclerosis (MS) appears to be predicted by the first attack location. We sought to determine if genetic polymorphisms associated with MS susceptibility are associated with attack location.
Patients with early multiple sclerosis (MS) have stereotyped attack severity and recovery. We sought to determine if polymorphisms in MS susceptibility genes are associated with these attack features or with the risk of a second attack.
Relapsing-remitting dynamics are a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). A clinical relapse in MS reflects an acute focal inflammatory event in the central nervous system that affects signal conduction by damaging myelinated axons. Those events are evident in T1-weighted post-contrast magnetic resonance imaging (MRI) as contrast enhancing lesions (CEL). CEL dynamics are considered unpredictable and are characterized by high intra- and inter-patient variability. Here, a population approach (nonlinear mixed-effects models) was applied to analyse of CEL progression, aiming to propose a model that adequately captures CEL dynamics.
Axon injury is a key contributor to the progression of disability in multiple sclerosis (MS). Systemic infections, which frequently precede relapses in MS, have been linked to clinical progression in Alzheimers disease. There is evidence of a role for the innate immune system in MS lesions, as axonal injury is associated with macrophage activation. We hypothesize that systemic inflammation leads to enhanced axonal damage in MS as a consequence of innate immune system activation.
The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens) that are able to trigger the immune system.
Inflammation is the first line of defense against injury and infection and works both by controlling the ongoing pathological processes and by promoting neuroprotection and regeneration. When the inflammatory response is hyper activated, it plays a pivotal role in the pathophysiology of many neurological diseases, as it can also be a source of additional injury to host cells. Since neurons lack the ability to divide and recover poorly from injury, they are extremely vulnerable to auto destructive immune and inflammatory processes, and this side effect is fundamental to the outcome of neurological diseases. Inappropriate immune responses are responsible for diseases such as Multiple Sclerosis (MS), Alzheimers disease (AD) or Parkinsons disease (PD) and for the increased disability after brain trauma or stroke. However, in certain circumstances immune responses in the brain might have a neuroprotective effect, possibly mediated by the release of trophic factors from inflammatory and/or glial cells. The nerve growth factor (NGF) was the first neurotrophin discovered for its stimulatory effect on differentiation, survival, and growth of neurons in peripheral and central nervous system. This factor can protect axons and myelin from inflammatory damage and also can modulate the immune system, reducing the enhanced excitotoxicity during acute inflammatory activation. Therefore, because its neuroprotective activity and immunomodulatory effects, NGF may represent a new therapeutic approach for the treatment of numerous brain disorders.
The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS).
Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter x(c)?, an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system x(c)? in glutamate homeostasis alterations in MS pathology.
We have previously shown that P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates chronic experimental autoimmune encephalomyelitis. Here, we have explored the putative association of functionally relevant single nucleotide polymorphisms of the P2X7 receptor gene with multiple sclerosis. We found that T allele of rs17525809 polymorphism, which yields an Ala-76 to Val change in the extracellular domain, is more frequent in multiple sclerosis patients than in controls. Importantly, P2X7 variants with Val show a gain-of-function consisting in higher calcium permeability, larger electrophysiological responses and higher ethidium uptake, and enhance the effect of the also gain-of-function His-155 to Tyr substitution (rs208294) in the haplotype formed by these two variants. These findings may contribute to define the genetic background predisposing for multiple sclerosis and its pathophysiology.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
The pursuit of personalized medicine requires the development of biomarkers to predict disease course, monitor disease evolution, stratify patient subgroups by disease activity and to predict and monitor response to therapies. Multiple sclerosis (MS) is a common neurological disease in young adults with an unpredictable course that may be associated with significant disability, diminishing the patients quality of life. Currently, disease prognosis is based on clinical information (relapse rate and disability scales) and diagnostic tests (brain MRI or the presence of oligoclonal bands in the cerebrospinal fluid). However, the ability of neurologists to make an accurate prognosis is very limited based on such information, a situation perceived by patients as one of their biggest concerns. Although many recent studies have identified different molecules and imaging techniques associated with the course of MS, in most cases the diagnostic accuracy of such technologies has not been properly assessed. This shortcoming is partly due to the failure to validate such biomarkers, which impedes their application in clinical practice. However, the recent validation of anti-aquaporin-4 antibodies for Devics disease and the development of optic coherent tomography for MS, are examples of the benefits that the development of MS biomarkers can offer. Indeed, it may currently be necessary to redress the bias in research towards clinical validation rather than discovery in order to promote translational research and improve patients quality of life.
The aim of the study was to analyze lexical access strategies in patients with multiple sclerosis (MS) and their changes over time. We studied lexical access strategies during semantic and phonemic verbal fluency tests and also confrontation naming in a 2-year prospective cohort of 45 MS patients and 20 healthy controls. At baseline, switching lexical access strategy (both in semantic and in phonemic verbal fluency tests) and confrontation naming were significantly impaired in MS patients compared with controls. After 2 years follow-up, switching score decreased, and cluster size increased over time in semantic verbal fluency tasks, suggesting a failure in the retrieval of lexical information rather than an impairment of the lexical pool. In conclusion, these findings underline the significant presence of lexical access problems in patients with MS and could point out their key role in the alterations of high-level communications abilities in MS.
Hypointense rims peripherally on T2-weighted MRI (rim lesions) have been associated with gadolinium ring-enhancing lesions in multiple sclerosis (MS) in pathological studies. However, little is known about their frequency, we analyzed clinical significance in a cohort of MS sufferers according to routine clinical practice. Methods: We retrospectively reviewed all available MRI scans performed on our MS patients between 2000 and 2009. A total of 580 MRI scans from 257 patients were analyzed. The presence of rim lesions and ring enhancement was assessed and counted blind. Furthermore, the correlation between both patterns, and with clinical characteristics, was evaluated.
Semantic memory is the subsystem of human memory that stores knowledge of concepts or meanings, as opposed to life-specific experiences. How humans organize semantic information remains poorly understood. In an effort to better understand this issue, we conducted a verbal fluency experiment on 200 participants with the aim of inferring and representing the conceptual storage structure of the natural category of animals as a network. This was done by formulating a statistical framework for co-occurring concepts that aims to infer significant concept-concept associations and represent them as a graph. The resulting network was analyzed and enriched by means of a missing links recovery criterion based on modularity. Both network models were compared to a thresholded co-occurrence approach. They were evaluated using a random subset of verbal fluency tests and comparing the network outcomes (linked pairs are clustering transitions and disconnected pairs are switching transitions) to the outcomes of two expert human raters. Results show that the network models proposed in this study overcome a thresholded co-occurrence approach, and their outcomes are in high agreement with human evaluations. Finally, the interplay between conceptual structure and retrieval mechanisms is discussed.
In the search for a useful parameter to detect and quantify subtle brain abnormalities in infants with intrauterine growth restriction (IUGR), we hypothesised that the analysis of the structural complexity of grey matter (GM) and white matter (WM) using the fractal dimension (FD), a measurement of the topological complexity of an object, could be established as a useful tool for quantitative studies of infant brain morphology. We studied a sample of 18 singleton IUGR premature infants, (12.72 months corrected age (CA), range: 12 months-14 months), 15 preterm infants matched one-to-one for gestational age (GA) at delivery (12.6 months; range: 12 months-14 months), and 15 neonates born at term (12.4 months; range: 11 months-14 months). The neurodevelopmental outcome was assessed in all subjects at 18 months CA according to the Bayley Scale for Infant and Toddler Development - Third edition (BSID-III). For MRI acquisition and processing, the infants were scanned at 12 months CA, in a TIM TRIO 3T scanner, sleeping naturally. Images were pre-processed using the SPM5 toolbox, the GM and WM segmented under the VBM5 toolbox, and the box-counting method was applied for FD calculation of normal and skeletonized segmented images. The results showed a significant decrease of the FD of the brain GM and WM in the IUGR group when compared to the preterm or at-term controls. We also identified a significant linear tendency of both GM and WM FD from IUGR to preterm and term groups. Finally, multiple linear analyses between the FD of the GM or WM and the neurodevelopmental scales showed a significant regression of the language and motor scales with the FD of the GM. In conclusion, a decreased FD of the GM and WM in IUGR infants could be a sensitive indicator for the investigation of structural brain abnormalities in the IUGR population at 12 months of age, which can also be related to functional disorders.
Chemical reaction networks (CRNs) are susceptible to mathematical modelling. The dynamic behavior of CRNs can be investigated by solving the polynomial equations derived from its structure. However, simple CRN give rise to non-linear polynomials that are difficult to resolve. Here we propose a procedure to locate the steady states of CRNs from a formula derived through algebraic geometry methods. We have applied this procedure to define the steady states of a classic CRN that exhibits instability, and to a model of programmed cell death.
The definition of European population genetic substructure and its application to understanding complex phenotypes is becoming increasingly important. In the current study using over 4,000 subjects genotyped for 300,000 single-nucleotide polymorphisms (SNPs), we provide further insight into relationships among European population groups and identify sets of SNP ancestry informative markers (AIMs) for application in genetic studies. In general, the graphical description of these principal components analyses (PCA) of diverse European subjects showed a strong correspondence to the geographical relationships of specific countries or regions of origin. Clearer separation of different ethnic and regional populations was observed when northern and southern European groups were considered separately and the PCA results were influenced by the inclusion or exclusion of different self-identified population groups including Ashkenazi Jewish, Sardinian, and Orcadian ethnic groups. SNP AIM sets were identified that could distinguish the regional and ethnic population groups. Moreover, the studies demonstrated that most allele frequency differences between different European groups could be controlled effectively in analyses using these AIM sets. The European substructure AIMs should be widely applicable to ongoing studies to confirm and delineate specific disease susceptibility candidate regions without the necessity of performing additional genome-wide SNP studies in additional subject sets.
Multiple sclerosis (MS) is a chronic inflammatory, disabling disease of the CNS. A recent study has estimated the annual cost of MS in Europe at euro12.5 billion. There is no definitive cure for the disease. Immunomodulatory therapies, such as IFN-beta and glatiramer acetate, are only partially effective. Various new therapies in the final stages of clinical trials are being developed in the absence of efficacy biomarkers. Hence, there is a pressing need for identification of MS treatment response biomarkers. The focus of the multicenter research initiative United Europeans for the development of pharmacogenomics in MS (UEPHA*MS) is to promote and improve training opportunities in the novel supradisciplinary area of pharmacogenomics, biomarker research and systems biology applied to MS. UEPHA*MS is a Marie Curie Initial Training network funded by the 7th Framework Programme of the European Commission. The main scientific goals of this network are both to enhance our knowledge of the mechanisms determining response outcomes of existing immunomodulatory therapies and to identify novel therapeutic opportunities. UEPHA*MS is composed of 11 internationally recognized research teams from five countries with an assortment of expertise in complementary disciplines. The UEPHA*MS network will provide a coherent and internationally competitive platform for the training of young scientists based on multidisciplinary state-of-the-art laboratory-based and network-wide activities. This network will be instrumental in priming young scientists for Europes collective effort toward improved provision of healthcare based on personalized medicine.
Biomedical research is changing due to the rapid accumulation of experimental data at an unprecedented scale, revealing increasing degrees of complexity of biological processes. Life Sciences are facing a transition from a descriptive to a mechanistic approach that reveals principles of cells, cellular networks, organs, and their interactions across several spatial and temporal scales. There are two conceptual traditions in biological computational-modeling. The bottom-up approach emphasizes complex intracellular molecular models and is well represented within the systems biology community. On the other hand, the physics-inspired top-down modeling strategy identifies and selects features of (presumably) essential relevance to the phenomena of interest and combines available data in models of modest complexity.
Recent advances in molecular biology, neurobiology, genetics, and imaging have demonstrated important insights about the nature of neurological diseases. However, a comprehensive understanding of their pathogenesis is still lacking. Although reductionism has been successful in enumerating and characterizing the components of most living organisms, it has failed to generate knowledge on how these components interact in complex arrangements to allow and sustain two of the most fundamental properties of the organism as a whole: its fitness, also termed its robustness, and its capacity to evolve. Systems biology complements the classic reductionist approaches in the biomedical sciences by enabling integration of available molecular, physiological, and clinical information in the context of a quantitative framework typically used by engineers. Systems biology employs tools developed in physics and mathematics such as nonlinear dynamics, control theory, and modeling of dynamic systems. The main goal of a systems approach to biology is to solve questions related to the complexity of living systems such as the brain, which cannot be reconciled solely with the currently available tools of molecular biology and genomics. As an example of the utility of this systems biological approach, network-based analyses of genes involved in hereditary ataxias have demonstrated a set of pathways related to RNA splicing, a novel pathogenic mechanism for these diseases. Network-based analysis is also challenging the current nosology of neurological diseases. This new knowledge will contribute to the development of patient-specific therapeutic approaches, bringing the paradigm of personalized medicine one step closer to reality.
Attention deficit/hyperactivity disorder (ADHD) is often present in patients with post-streptococcal neuropsychiatric disorders such as Sydenhams chorea and PANDAS, in which anti-basal ganglia antibodies (ABGA) have been frequently found. Our study investigates the hypothesis that pharyngeal group A beta-hemolytic streptococcus (GABHS) infections and serum ABGA are more frequent in children with ADHD non-comorbid (nc-ADHD) with obsessive-compulsive disorder or tics than in controls. We compared 22 children with nc-ADHD (DSM-IV-TR) and 22 healthy controls matched by age, gender and season of sample collection, for the frequency of recent GABHS infection and the presence of ABGA. Eleven out of 22 children (51%) with nc-ADHD showed evidence of GABHS infection compared to three out of 22 (14%) controls (P = 0.007). We found positive ABGA in one ADHD subject (4%) and in one control (4%). This preliminary study indicates that frequency of ABGA in children with nc-ADHD does not differ from that in matched controls, despite the fact that our ADHD patients had had more recent GABHS infections than the controls. This suggests that ABGA do not have a role in the pathogenesis of nc-ADHD.
Working memory relies on information processing by several well-identified gray matter regions. However, the white matter regions and pathways involved in this cognitive process remain unknown. An attractive and underexplored approach to study white matter connectivity in cognitive functions is through the use of non-aprioristic models, which specifically search disrupted white matter pathways. For this purpose, we used voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 54 multiple sclerosis patients with their performance on a verbal working memory task. With this approach, we have identified critical white matter regions involved in verbal working memory in humans. They are located in the cingulum, parieto-frontal pathways and thalamo-cortical projections, with a left-sided predominance, as well as the right cerebellar white matter. Our study provides direct evidence on the white matter pathways subserving verbal working memory in the human brain.
The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Among other applications, FD has been used to identify abnormalities of the human brain in conventional magnetic resonance imaging (MRI), including white matter abnormalities in patients with Multiple Sclerosis (MS). Extensive grey matter (GM) pathology has been recently identified in MS and it appears to be a key factor in long-term disability. The aim of the present work was to assess whether FD measurement of GM in T1 MRI sequences can identify GM abnormalities in patients with MS in the early phase of the disease. A voxel-based morphometry approach optimized for MS was used to obtain the segmented brain, where we later calculated the three-dimensional FD of the GM in MS patients and healthy controls. We found that patients with MS had a significant increase in the FD of the GM compared to controls. Such differences were present even in patients with short disease durations, including patients with first attacks of MS. In addition, the FD of the GM correlated with T1 and T2 lesion load, but not with GM atrophy or disability. The FD abnormalities of the GM here detected differed from the previously published FD of the white matter in MS, suggesting that different pathological processes were taking place in each structure. These results indicate that GM morphology is abnormal in patients with MS and that this alteration appears early in the course of the disease.
Allelic specific gene expression (ASGE) appears to be an important factor in human phenotypic variability and as a consequence, for the development of complex traits and diseases. In order to study ASGE across the human genome, we have performed a study in which genotyping was coupled with an analysis of ASGE by screening 11,500 SNPs using the Mapping 10 K Array to identify differential allelic expression. We found that from the 5,133 SNPs that were suitable for analysis (heterozygous in our sample and expressed in peripheral blood mononuclear cells), 2,934 (57%) SNPs had differential allelic expression. Such SNPs were equally distributed along human chromosomes and biological processes. We validated the presence or absence of ASGE in 18 out 20 SNPs (90%) randomly selected by real time PCR in 48 human subjects. In addition, we observed that SNPs close to -but not included in- segmental duplications had increased levels of ASGE. Finally, we found that transcripts of unknown function or non-coding RNAs, also display ASGE: from a total of 2,308 intronic SNPs, 1510 (65%) SNPs underwent differential allelic expression. In summary, ASGE is a widespread mechanism in the human genome whose regulation seems to be far more complex than expected.
A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.
Multiple Sclerosis (MS) frequently causes injury to the anterior visual pathway (AVP), impairing quality of life due to visual dysfunction. Development of biomarkers in MS is a high priority and both low-contrast visual acuity (LCVA) and time-domain optical coherence tomography (TD-OCT) have been proposed as candidates for this purpose. We sought to assess whether psychophysical assessments of color vision are similarly correlated with structural measures of AVP injury, and therefore augment measures of visual disability in MS.
New "omic" technologies and their application to systems biology approaches offer new opportunities for biomarker discovery in complex disorders, including multiple sclerosis (MS). Recent studies using massive genotyping, DNA arrays, antibody arrays, proteomics, glycomics, and metabolomics from different tissues (blood, cerebrospinal fluid, brain) have identified many molecules associated with MS, defining both susceptibility and functional targets (e.g., biomarkers). Such discoveries involve many different levels in the complex organizational hierarchy of humans (DNA, RNA, protein, etc.), and integrating these datasets into a coherent model with regard to MS pathogenesis would be a significant step forward. Given the dynamic and heterogeneous nature of MS, validating biomarkers is mandatory. To develop accurate markers of disease prognosis or therapeutic response that are clinically useful, combining molecular, clinical, and imaging data is necessary. Such an integrative approach would pave the way towards better patient care and more effective clinical trials that test new therapies, thus bringing the paradigm of personalized medicine in MS one step closer.
Contactin-2 was recently identified as an autoantigen targeted by T-cells and autoantibodies in multiple sclerosis (MS). Here we analyzed the frequency of antibodies to contactin-2 (contactin-2-ab) by a cell-based assay in the serum from 105 MS patients and at least 5 years of follow-up (19 clinically isolated syndromes, 51 relapsing-remitting, 20 secondary-progressive, and 15 primary-progressive). Contactin-2-ab were detected in 4 (7.8%) relapsing-remitting patients. Clinical and magnetic resonance imaging characteristics were not significantly different from the rest of relapsing-remitting patients. In conclusion, contactin-2-ab are identified in a minority of MS patients but their presence is not associated with a particular clinical-radiological profile.
The advance in the achievement of effective therapies for multiple sclerosis (MS), the definition of appropriate therapeutic windows and to establish better diagnostic and prognostic biomarkers have become a challenging task for both researchers and clinicians. Some pitfalls in clinical trials might be related to lack of adequacy of the preclinical studies in MS experimental animal models.
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.