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Graph theory has provided a key mathematical framework to analyse the architecture of human brain networks. This architecture embodies an inherently complex relationship between connection topology, the spatial arrangement of network elements, and the resulting network cost and functional performance. An exploration of these interacting factors and driving forces may reveal salient network features that are critically important for shaping and constraining the brain's topological organization and its evolvability. Several studies have pointed to an economic balance between network cost and network efficiency with networks organized in an 'economical' small-world favouring high communication efficiency at a low wiring cost. In this study, we define and explore a network morphospace in order to characterize different aspects of communication efficiency in human brain networks. Using a multi-objective evolutionary approach that approximates a Pareto-optimal set within the morphospace, we investigate the capacity of anatomical brain networks to evolve towards topologies that exhibit optimal information processing features while preserving network cost. This approach allows us to investigate network topologies that emerge under specific selection pressures, thus providing some insight into the selectional forces that may have shaped the network architecture of existing human brains. more...

The human brain displays heterogeneous organization in both structure and function. Here we develop a method to characterize brain regions and networks in terms of information-theoretic measures. We look at how these measures scale when larger spatial regions as well as larger connectome sub-networks are considered. This framework is applied to human brain fMRI recordings of resting-state activity and DSI-inferred structural connectivity. We find that strong functional coupling across large spatial distances distinguishes functional hubs from unimodal low-level areas, and that this long-range functional coupling correlates with structural long-range efficiency on the connectome. We also find a set of connectome regions that are both internally integrated and coupled to the rest of the brain, and which resemble previously reported resting-state networks. Finally, we argue that information-theoretic measures are useful for characterizing the functional organization of the brain at multiple scales. more...

The complex relationship between structural and functional connectivity, as measured by noninvasive imaging of the human brain, poses many unresolved challenges and open questions. Here, we apply analytic measures of network communication to the structural connectivity of the human brain and explore the capacity of these measures to predict resting-state functional connectivity across three independently acquired datasets. We focus on the layout of shortest paths across the network and on two communication measures--search information and path transitivity--which account for how these paths are embedded in the rest of the network. Search information is an existing measure of information needed to access or trace shortest paths; we introduce path transitivity to measure the density of local detours along the shortest path. We find that both search information and path transitivity predict the strength of functional connectivity among both connected and unconnected node pairs. They do so at levels that match or significantly exceed path length measures, Euclidean distance, as well as computational models of neural dynamics. This capacity suggests that dynamic couplings due to interactions among neural elements in brain networks are substantially influenced by the broader network context adjacent to the shortest communication pathways. more...

High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the gray matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9-0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies., (© 2013 Elsevier Inc. All rights reserved.) more...

Background: 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., Methods and Findings: We explored several discrete distribution models to CEL counts observed in nine MS patients undergoing a monthly MRI for 48 months. All patients were enrolled in the study free of immunosuppressive drugs, except for intravenous methylprednisolone or oral prednisone taper for a clinical relapse. Analyses were performed with the nonlinear mixed-effect modelling software NONMEM 7.2. Although several models were able to adequately characterize the observed CEL dynamics, the negative binomial distribution model had the best predictive ability. Significant improvements in fitting were observed when the CEL counts from previous months were incorporated to predict the current month's CEL count. The predictive capacity of the model was validated using a second cohort of fourteen patients who underwent monthly MRIs during 6-months. This analysis also identified and quantified the effect of steroids for the relapse treatment., Conclusions: The model was able to characterize the observed relapsing-remitting CEL dynamic and to quantify the inter-patient variability. Moreover, the nature of the effect of steroid treatment suggested that this therapy helps resolve older CELs yet does not affect newly appearing active lesions in that month. This model could be used for design of future longitudinal studies and clinical trials, as well as for the evaluation of new therapies. more...

Hierarchy seems to pervade complexity in both living and artificial systems. Despite its relevance, no general theory that captures all features of hierarchy and its origins has been proposed yet. Here we present a formal approach resulting from the convergence of theoretical morphology and network theory that allows constructing a 3D morphospace of hierarchies and hence comparing the hierarchical organization of ecological, cellular, technological, and social networks. Embedded within large voids in the morphospace of all possible hierarchies, four major groups are identified. Two of them match the expected from random networks with similar connectivity, thus suggesting that nonadaptive factors are at work. Ecological and gene networks define the other two, indicating that their topological order is the result of functional constraints. These results are consistent with an exploration of the morphospace, using in silico evolved networks. more...

Importance: The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia., Objective: To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics., Design: Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls., Setting: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands., Participants: Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES: Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics., Results: Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling., Conclusions: Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics. more...

Graph theoretical analysis has played a key role in characterizing global features of the topology of complex networks, describing diverse systems such as protein interactions, food webs, social relations and brain connectivity. How system elements communicate with each other depends not only on the structure of the network, but also on the nature of the system's dynamics which are constrained by the amount of knowledge and resources available for communication processes. Complementing widely used measures that capture efficiency under the assumption that communication preferentially follows shortest paths across the network ("routing"), we define analytic measures directed at characterizing network communication when signals flow in a random walk process ("diffusion"). The two dimensions of routing and diffusion efficiency define a morphospace for complex networks, with different network topologies characterized by different combinations of efficiency measures and thus occupying different regions of this space. We explore the relation of network topologies and efficiency measures by examining canonical network models, by evolving networks using a multi-objective optimization strategy, and by investigating real-world network data sets. Within the efficiency morphospace, specific aspects of network topology that differentially favor efficient communication for routing and diffusion processes are identified. Charting regions of the morphospace that are occupied by canonical, evolved or real networks allows inferences about the limits of communication efficiency imposed by connectivity and dynamics, as well as the underlying selection pressures that have shaped network topology. more...

Network studies of human brain structural connectivity have identified a specific set of brain regions that are both highly connected and highly central. Recent analyses have shown that these putative hub regions are mutually and densely interconnected, forming a "rich club" within the human brain. Here we show that the set of pathways linking rich club regions forms a central high-cost, high-capacity backbone for global brain communication. Diffusion tensor imaging (DTI) data of two sets of 40 healthy subjects were used to map structural brain networks. The contributions to network cost and communication capacity of global cortico-cortical connections were assessed through measures of their topology and spatial embedding. Rich club connections were found to be more costly than predicted by their density alone and accounted for 40% of the total communication cost. Furthermore, 69% of all minimally short paths between node pairs were found to travel through the rich club and a large proportion of these communication paths consisted of ordered sequences of edges ("path motifs") that first fed into, then traversed, and finally exited the rich club, while passing through nodes of increasing and then decreasing degree. The prevalence of short paths that follow such ordered degree sequences suggests that neural communication might take advantage of strategies for dynamic routing of information between brain regions, with an important role for a highly central rich club. Taken together, our results show that rich club connections make an important contribution to interregional signal traffic, forming a central high-cost, high-capacity backbone for global brain communication. more...

Selective prevention programs in the Responsible Dispensing of Beverages (DRA - Dispensación Responsable de Bebidas Alcohólicas) have provided varying evidence of their effectiveness in other countries. In Spain, however, data is only available for the implementation of DRA in Barcelona. This article has two aims: to assess the effectiveness of an intervention in DRA with waiters in Pamplona, and to evaluate individual and group results in order to identify areas for improvement. The sample consisted of 40 hostelry professionals who participated in one of the 4 courses of DRA. Questionnaires were used to measure pre-/post-knowledge, attitudes, perceived self-efficacy and expectations about the training. We present descriptive analyses of all the variables and individual and overall results of the evolution of each participant. The DRA program provides overall data of significant improvements in knowledge, attitudes and expectations. The results show the need to consider the analysis of the evolution of individual subjects in each item. more...

At least two rate-limiting mechanisms in vesicle trafficking operate at mouse Schaffer collateral synapses, but their molecular/physical identities are unknown. The first mechanism determines the baseline rate at which reserve vesicles are supplied to a readily releasable pool. The second causes the supply rate to depress threefold when synaptic transmission is driven hard for extended periods. Previous models invoked depletion of a reserve vesicle pool to explain the reductions in the supply rate, but the mass-action assumption at their core is not compatible with kinetic measurements of neurotransmission under maximal-use conditions. Here we develop a new theoretical model of rate-limiting steps in vesicle trafficking that is compatible with previous and new measurements. A physical interpretation is proposed where local reserve pools consisting of four vesicles are tethered to individual release sites and are replenished stochastically in an all-or-none fashion. We then show that the supply rate depresses more rapidly in synapsin knock-outs and that the phenotype can be fully explained by changing the value of the single parameter in the model that would specify the size of the local reserve pools. Vesicle-trafficking rates between pools were not affected. Finally, optical imaging experiments argue against alternative interpretations of the theoretical model where vesicle trafficking is inhibited without reserve pool depletion. This new conceptual framework will be useful for distinguishing which of the multiple molecular and cell biological mechanisms involved in vesicle trafficking are rate limiting at different levels of synaptic throughput and are thus candidates for physiological and pharmacological modulation. more...

Background: 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., Results: The model represents five concepts: central tolerance (T-cell generation by the thymus), T-cell activation, T-cell memory, cross-regulation (negative feedback) between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system., Conclusion: The relapsing dynamic in MS derives from the emergent properties of the immune system operating in a pathological state, a fact that has implications for predicting disease course and developing new therapies for MS. more...

Background: 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)., Methods: We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center., Results: We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later., Conclusions: The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability. more...

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. more...

Decision making can be regarded as the outcome of cognitive processes leading to the selection of a course of action among several alternatives. Borrowing a central measurement from information theory, Shannon entropy, we quantified the uncertainties produced by decisions of participants within an economic decision task under different configurations of reward probability and time. These descriptors were used to obtain blood oxygen level-dependent (BOLD) signal correlates of uncertainty and two clusters codifying the Shannon entropy of task configurations were identified: a large cluster including parts of the right middle cingulate cortex (MCC) and left and right pre-supplementary motor areas (pre-SMA) and a small cluster at the left anterior thalamus. Subsequent functional connectivity analyses using the psycho-physiological interactions model identified areas involved in the functional integration of uncertainty. Results indicate that clusters mostly located at frontal and temporal cortices experienced an increased connectivity with the right MCC and left and right pre-SMA as the uncertainty was higher. Furthermore, pre-SMA was also functionally connected to a rich set of areas, most of them associative areas located at occipital and parietal lobes. This study provides a map of the human brain segregation and integration (i.e., neural substrate and functional connectivity respectively) of the uncertainty associated to an economic decision making paradigm. more...

In this paper we explore the concept of hierarchy as a quantifiable descriptor of ordered structures, departing from the definition of three conditions to be satisfied for a hierarchical structure: order, predictability, and pyramidal structure. According to these principles, we define a hierarchical index taking concepts from graph and information theory. This estimator allows to quantify the hierarchical character of any system susceptible to be abstracted in a feedforward causal graph, i.e., a directed acyclic graph defined in a single connected structure. Our hierarchical index is a balance between this predictability and pyramidal condition by the definition of two entropies: one attending the onward flow and the other for the backward reversion. We show how this index allows to identify hierarchical, antihierarchical, and nonhierarchical structures. Our formalism reveals that departing from the defined conditions for a hierarchical structure, feedforward trees and the inverted tree graphs emerge as the only causal structures of maximal hierarchical and antihierarchical systems respectively. Conversely, null values of the hierarchical index are attributed to a number of different configuration networks; from linear chains, due to their lack of pyramid structure, to full-connected feedforward graphs where the diversity of onward pathways is canceled by the uncertainty (lack of predictability) when going backward. Some illustrative examples are provided for the distinction among these three types of hierarchical causal graphs. more...

The feed-forward relationship naturally observed in time-dependent processes and in a diverse number of real systems-such as some food webs and electronic and neural wiring-can be described in terms of the so-called directed acyclic graphs (DAGs). An important ingredient of the analysis of such networks is a proper comparison of their observed architecture against an ensemble of randomized graphs, thereby quantifying the randomness of the real systems with respect to suitable null models. This approximation is particularly relevant when the finite size and/or large connectivity of real systems make inadequate a comparison with the predictions obtained from the so-called configuration model. In this paper we analyze two methods of DAG randomization as defined by the desired combination of two topological invariants (directed degree sequence and component distributions) aimed to be preserved. A highly ordered DAG, called snake graph, and an Erdös-Rényi DAG were used to validate the performance of the algorithms. Finally, three real case studies, namely, the C. elegans cell lineage network, a Ph.D. student-supervisor network, and the Milgram's citation network, were analyzed using each randomization method. Results show how the interpretation of degree-degree relations in DAGs with respect to their randomized ensembles depends on the topological invariants imposed. more...

The immunopathogenesis of type I autoimmune hepatitis (AIH-I) might involve the deregulation of different cellular processes. Here, we investigated the liver expression of selected cytokines and genes of regulatory cell populations in children both at diagnosis and during biochemical remission following immunosuppressive treatment (AIH-Ir). We found a higher Vα24, IFN-γ, FoxP3, IL-27p28, IL-12p40 and IL-21 expression at diagnosis as well as a positive correlation between IL-21 and transaminase levels. Interestingly, only IFN-γ and FoxP3 were decreased in AIH-Ir. An "AIH-I phenotype" (high Vα24, IFN-γ and FoxP3 expression at diagnosis) was observed in only 5 out of 22 AIH-Ir patients but not in controls. These results indicate a local deregulation of the innate and adaptive immune responses with an increased transcriptional activity of immunoregulatory cells at diagnosis. In addition, IL-21 is highlighted as a mediator of liver injury. AIH-Ir is characterized by a partial reversal of the deregulated response., (Copyright © 2010 Elsevier Inc. All rights reserved.) more...

This study aims to incorporate patients' perspective in the design of a systematic review of scientific literature on the effectiveness of degenerative ataxias (DA) treatments. 53 patients with DA from different regions of Spain were consulted using the Delphi method, with three rounds via e-mail. In the first round, obtained information was on treatments used and relevant self-perceived health problems related to DA. The following two rounds were used to prioritize and achieve a consensus on the answers. The participation rate was 100% for all rounds. The most relevant self-perceived health problems were limitations in activities of daily living (ADL), visual and auditory problems and diminished self-esteem. The bibliographic search for the systematic review was enriched by these patient contributions. No study offered information on treatment effectiveness for the following problems prioritized by patients: ADL, social relationships, disease acceptance and quality of life. Thus some of the self-perceived DA-related health problems identified by the patients have never been investigated and should be considered to improve future research projects which should be adapted to meet patients' needs. Effective participation of patients can extend the value of systematic reviews to ensure they respond to both clinicians' information needs and patients' expectations. more...

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. more...

Objective: To evaluate the usefulness of a non-invasive clinical score to predict liver fibrosis in the steatosis associated with morbid obesity., Patients and Methods: We included 88 patients, who underwent bariatric surgery in the Sanitary Area of León, Spain, and who showed a liver biopsy with steatosis greater than 5%. This is a retrospective study in which the rate of fibrosis is calculated from tests performed during the preoperative period, and is then compared to data from intraoperative hepatic biopsies. The analysis population was grouped according to the presence of advanced fibrosis in the liver biopsy (grade 3-4) or its absence (grade 0-2). The cutoff used for diagnosing advanced fibrosis was 0.676 (high cutoff point), and the cutoff point to exclude advanced fibrosis was -1.455 (low cutoff)., Results: The prevalence of advanced fibrosis in the histological samples was 5.5%, and 65.9% of patients had no fibrosis. The cutoff for a low negative predictive value was 100%, and sensitivity was 100%. The cutoff point for a high positive predictive value was 1.7%, and specificity was 31.3%., Conclusions: This scoring system for morbidly obese patients eligible for bariatric surgery allows to identify those without advanced fibrosis, but cannot predict who may have advanced fibrosis. more...

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. more...

Background: To analyse the diagnostic concordance between the paediatric and mental health (MH) services., Materials and Methods: Two hundred and seven patients from 0 to 16 years referred from paediatrics to the Estella Mental Health Centre during 2006 and 2007. Concordance between global Kappa Index and specific diagnosis was calculated with Epidat 3.1. An analysis was made for each diagnostic category of the percentage of cases where the diagnosis made in paediatrics was confirmed in Mental Health., Results: The global diagnostic concordance between both medical care levels has a Kappa Index of 0.58. There is a wide variability in the concordance between the different diagnoses. The concordance is weak (0.2-0.4) for specific developmental disorder, affective disorders and adaptative disorders. A moderate concordance (0.41-0.6) is obtained for mental retardation, pervasive developmental disorder, z diagnostics, and sibling rivalry disorder. Concordance is good for attention deficit disorder with hyperactivity, anxiety disorder and conduct disorder. Finally, the diagnostic concordance is very good for enuresis and encopresis and for eating disorders., Conclusions: The diagnostic concordance obtained between paediatric services and the mental health centre is moderate. A wide variability is obtained in the concordance between different diagnoses. more...

Background: The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability., Objective: To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis., Design: Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging-derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices., Setting: Multiple sclerosis center, University of Navarra, Pamplona, Spain., Patients: Sixty-one patients with multiple sclerosis., Main Outcome Measure: Mapping of WM regions contributing to GM atrophy in the optic pathway., Results: Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region., Conclusions: Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well. more...

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. more...

Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans. more...

Human leukocyte antigen DR2 (HLA-DR2) is a well-established genetic risk factor for multiple sclerosis (MS). However, it is still unknown whether this factor is associated with a specific disease phenotype, and in particular, to a regional distribution of white matter (WM) lesion phenotype on magnetic resonance imaging (MRI). On a voxel-by-voxel basis, we analyzed the T1 and T2 MRI-derived lesion maps of 50 patients with MS in order to determine the possible influence of HLA-DR2 genotype on the lesional MRI pattern at early stages of the disease. HLA-DR2 was present in 15 (30%) patients of our cohort. They displayed similar WM lesion distribution as the subjects without this factor. Thus, lesion distribution in MS seems to be independent of the DR2 genotype. more...

Background: Recent developments have meant that network theory is making an important contribution to the topological study of biological networks, such as protein-protein interaction (PPI) networks. The identification of differentially expressed genes in DNA array experiments is a source of information regarding the molecular pathways involved in disease. Thus, considering PPI analysis and gene expression studies together may provide a better understanding of multifactorial neurodegenerative diseases such as Multiple Sclerosis (MS) and Alzheimer disease (AD). The aim of this study was to assess whether the parameters of degree and betweenness, two fundamental measures in network theory, are properties that differentiate between implicated (seed-proteins) and non-implicated nodes (neighbors) in MS and AD. We used experimentally validated PPI information to obtain the neighbors for each seed group and we studied these parameters in four networks: MS-blood network; MS-brain network; AD-blood network; and AD-brain network., Results: Specific features of seed-proteins were revealed, whereby they displayed a lower average degree in both diseases and tissues, and a higher betweenness in AD-brain and MS-blood networks. Additionally, the heterogeneity of the processes involved indicate that these findings are not pathway specific but rather that they are spread over different pathways., Conclusion: Our findings show differential centrality properties of proteins whose gene expression is impaired in neurodegenerative diseases. more...

The brain white matter (WM) in multiple sclerosis (MS) suffers visible and non-visible (normal-appearing WM (NAWM)) changes in conventional magnetic resonance (MR) images. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Our aim was to assess the usefulness of FD analysis in the measurement of WM abnormalities in conventional MR images in patients with MS, particularly to detect NAWM changes. First, we took on a voxel-based morphometry approach optimized for MS to obtain the segmented brain. Then, the FD of the whole grey-white matter interface (WM border) and skeletonized WM was calculated in patients with MS and healthy controls. To assess the FD of the NAWM, we focused our analysis on single sections without lesions at the centrum semiovale level. We found that patients with MS had a significant decrease in the FD of the entire brain WM compared with healthy controls. Such a decrease of the FD was detected not only on MR image sections with MS lesions but also on single sections with NAWM. Taken together, the results showed that FD identifies changes in the brain of patients with MS, including in NAWM, even at an early phase of the disease. Thus, FD might become a useful marker of diffuse damage of the central nervous system in MS. more...

Context: The mechanisms of postnatal adrenal zonation remain unclear., Objective: To provide a clue for a possible role of estrogens in adrenarche, we studied the expression of estrogen receptor (ER)alpha, ERbeta, G protein-coupled receptor (GPR)30, and cP450aromatase (cP450arom) in human adrenal tissue., Design: Human adrenal tissue was collected from three postnatal age groups (Grs): Gr 1, younger than 3 months (n = 12), fetal zone involution; Gr 2, 3 months to 6 yr (n = 17), pre-adrenarche; and Gr 3, older than 6-20 yr (n = 12), post-adrenarche period., Results: ERbeta mRNA in Grs 1 and 3 was higher than in Gr 2 (P < 0.05). By immunohistochemistry and laser capture microdissection followed by RT-PCR, ERbeta was expressed in zona reticularis and fetal zone, GPR30 in zona glomerulosa (ZG) and adrenal medulla, while ERalpha mRNA and protein were undetectable. cP450arom mRNA in Gr 3 was higher than in Grs 1 and 2 (P < 0.05), and localized to ZG and adrenal medulla by laser capture microdissection. cP450arom Immunoreactivity was observed in adrenal medulla in the three Grs and in subcapsular ZG of Gr 3. Double-immunofluorescence studies revealed that cP450arom and chromogranin A only colocalize in adrenal medulla of subjects younger than 18 months. In these samples, exon 1.b-derived transcript was 3.5-fold higher, while exon 1.a-, 1.c-, and 1.d-derived transcripts were 3.3-, 1.9-, and 1.7-fold lower, respectively, than in subjects older than 6 yr., Conclusions: Our results suggest that estrogens produced locally in adrenal medulla would play a role in zona reticularis functional differentiation through ERbeta. The cP450arom and GPR30 expression in subcapsular ZG, colocalizing with a high-cell proliferation index, previously reported, suggests a local GPR30-dependent estrogen action in proliferation and migration of progenitor adrenal cells. more...

In this paper, a study examining high-risk situations for relapse is presented. The sample consisted of 72 participants (51 male and 21 female) who had relapsed after having received a residential psychological treatment for drug addition in a therapeutic community in Spain. In order to analyze what personal, environmental or social factors were the most immediate triggers of relapse, a personal interview, using the Relapse Interview, was administered to each one of the relapsed patients. Results showed that most of the relapses took place during the first year after completing the treatment program. Likewise, the factors most frequently cited for relapse were the following: to cope with negative emotional states (49.5%), to be unable to resist temptations or impulses to consume (17.5%), to test personal control (10.3%) and to cope with interpersonal conflicts (9.3%). Results indicate thatmost factors were of an intrapersonal nature. Implications of these results for further research and clinical practice are commented upon. more...

Objective: We analyzed the characteristics of the patients with bladder neoplasms who developed a multiple malignant primary neoplasm (MMPN) in the health district of León, the impact on survival and the prognostic variables., Material and Methods: We have used the data from the Tumor Registry of the Hospital of León and selected all those patients who were diagnosed of a bladder tumor between 1993 and 2002. They were classified into two groups: the first with 71 patients with MMPN and a second group with 159 patients with single bladder tumors diagnosed between 1996 and 1997., Results: Incidence of MMPN was of 7.1 percent. More than half of the patients had familial oncologic background. The second most frequently diagnosed neoplasms were urologic, followed by gastrointestinal and respiratory. Survival of patients with MMPN was 21 percent lower than single neoplasms. Variables with prognosis significance were the stage of the second neoplasm, diagnosis of a second urologic neoplasm and surgery treatment for the second tumor., Conclusions: MMPN in patients with bladder tumors are frequent in our geographic area. The high frequency of familial oncologic antecedents in these patients suggest a genetic background. Prognosis of MMPN patients is worse than single tumors patients, but no differences were observed regarding prognosis in patients with synchronous or metachronous MMPN. more...

Objective: Needle-knife sphincterotomy (NKS) is used to achieve biliary access when routine cannulation methods have been unsuccessful. The aim of this study was to analyze the results of NNS in patients with an inaccessible common bile duct (difficult cannulation) using standard techniques in endoscopic retrograde cholangiopancreatography and the factors associated with the success of this procedure and complications., Material and Methods: We performed a prospective study of 72 patients who underwent NKS performed by the same endoscopist (J.E.) because of difficult cannulation of the common bile duct between January 1998 and December 2004. The results were analyzed in terms of successful biliary access, whether this was achieved in one or more sessions, its possible association with the underlying disease, and the incidence and severity of complications., Results: Seventy-two NKS were performed from a total of 1062 sphincterotomies (6.7%). A total of 77.7% of the patients underwent prior implantation of a pancreatic prosthesis (NKS-PP). The final diagnosis was: choledocholithiasis (31.9%), cancer of the pancreas (16.6%), cholangiocarcinoma (13.8%), benign stenosis (8.3%), dysfunction of the sphincter of Oddi (6.9%), normal (6.9%), and miscellaneous (13.8%). Cannulation was successful in 87.5% (63/72), and was achieved in the first session in 73% (46/63). Biliary access was achieved in 72.7% of patients (16/22) with biliopancreatic neoplasms versus 94% (47/50) of those with other diagnoses (p = 0.03). Eleven patients (15.2%) presented 12 complications (16.6%) (6 pancreatitis, 4 cholangitis, 1 papillary hemorrhage, and 1 portal vein filling). The use of a pancreatic prosthesis was related to a higher success rate and significantly fewer complications (p = 0.03)., Conclusions: NKS-PP can be a safe procedure in patients with difficult cannulation of the common bile duct. The presence of biliopancreatic neoplasm is a risk factor for failure to achieve biliary access compared with other diagnoses. The complication rate was similar to that found in other studies. No cases of severe pancreatitis or perforations were found. more...

Malignant gastroduodenal obstruction may cause significant morbidity. Insertion of enteral prostheses as a palliative treatment is an acceptable option to achieve an appropriate gastric voiding without the morbidity associated to palliative surgery, with a lesser procedure-related mortality and a lower cost, while providing a better quality of life. Its is important to unify and consolidate the endoscopic procedure for the placement of enteral prostheses, avoiding variations that may preclude an adequate analysis of this procedure outcome. more...

To investigate the immunopathogenic mechanisms of type I autoimmune hepatitis in children, we analyzed by quantitative or semiquantitative reverse transcription-polymerase chain reaction the expression of cytokines interferon (IFN)-gamma, interleukin (IL)-12p40, IL-18, IL-4, IL-10, and IL-12R beta 2. In addition, liver and peripheral blood was collected to investigate the expression of the natural killer T (NKT) cell marker V alpha 24. The presence of NKT cells in hepatic lesions were also identified by immunohistochemistry. The analysis was performed on liver biopsies from 25 children with type I autoimmune hepatitis. As disease controls, we included six children with hepatitis C virus-related chronic hepatitis and nine control livers. The expression of IFN-gamma and IL-12p40 was not detected in controls but was clearly upregulated in pathologic biopsies. In addition, these samples showed an increased expression of IL-18 (p = 0.0003), IL-4 (p = 0.0055), and IL-12R beta 2 (p = 0.007). Western blot analysis confirmed the expression of IL-12p40 and IL-18. However, for IL-18, we detected only the immature biologically inactive polypeptide. The V alpha 24 transcripts were found increased in the liver (p = 0.0007) where V alpha 24(+) cells were also localized, but decreased in peripheral blood mononuclear cells (p = 0.041). In addition to a type I immune response, NKT cells might play a substantial role in the pathogenesis of type I autoimmune hepatitis in children. more...

Primary leiomyosarcoma of the liver is a rare entity and fewer than 100 cases have been reported in the medical literature. Even more unusual is the association with another previous tumour. We report the case of a 84-year-old man who had been treated for a gastric non-Hodgkin lymphoma two years previously. He presented with a painful mass in the right upper abdomen. An ultrasound scan showed a large mass in the right lobe of the liver and chest radiography showed pulmonary metastases. Liver biopsy was performed and immunohistochemical analysis revealed a malignant leiomyosarcoma. We discuss this case and review the available literature. more...

Aim: To determine the degree of association between serum alpha-1-antitrypsin levels and its phenotypes as well as its clinical expression., Patients and Methods: The alpha-1-antitrypsin genotype was identified using polymerase chain reaction followed by restriction enzyme digest in 212 patients in whom serum alpha-1-antitrypsin determination had been requested. The reasons for the request, the existence of pulmonary or liver disease, clinical diagnoses and functional repercussions were analyzed., Results: Two hundred and twelve patients were evaluated (68% males; mean age: 34 20 years). In 23 patients (10.8%) a deficiency variant was found (one or two M alleles were lacking) and in 8 patients (3.8%) the genotype was ZZ. All patients with MM genotype had alpha-1-antitrypsin levels of 75 mg/dl or higher while none of the patients with ZZ genotype had levels higher than 40 ml/dl. All the patients with ZZ genotype showed alterations: 3 had pulmonary emphysema, 1 had chronic obstructive pulmonary disease and 4 had hypertransaminasemia. One patient with pulmonary emphysema had severe respiratory insufficiency while in the remaining patients with respiratory problems, respiratory insufficiency was slight or moderate. None of the patients with hypertransaminasemia showed echographic signs of portal hypertension or clinical or laboratory signs of reduced liver function., Conclusions: There is a close association between alpha-1-antitrypsin levels and the different genotypes. Consequently, in basal conditions with serum alpha-1-antitrypsin levels higher than 75 mg/dl genotyping is not required. The functional repercussions of deficiency variants in young adults is slight. more...