Neuroanatomical differences attributable to aging and gender have been well documented, and these differences may be associated with differences in behaviors and cognitive performance. However, little is known about the dynamic organization of anatomical connectivity within the cerebral cortex, which may underlie population differences in brain function. In this study, we investigated age and sex effects on the anatomical connectivity patterns of 95 normal subjects ranging in age from 19 to 85 years. Using the connectivity probability derived from diffusion magnetic resonance imaging tractography, we characterized the cerebral cortex as a weighted network of connected regions. This approach captures the underlying organization of anatomical connectivity for each subject at a regional level. Advanced graph theoretical analysis revealed that the resulting cortical networks exhibited "small-world" character (i.e., efficient information transfer both at local and global scale). In particular, the precuneus and posterior cingulate gyrus were consistently observed as centrally connected regions, independent of age and sex. Additional analysis revealed a reduction in overall cortical connectivity with age. There were also changes in the underlying network organization that resulted in decreased local efficiency, and also a shift of regional efficiency from the parietal and occipital to frontal and temporal neocortex in older brains. In addition, women showed greater overall cortical connectivity and the underlying organization of their cortical networks was more efficient, both locally and globally. There were also distributed regional differences in efficiency between sexes. Our results provide new insights into the substrates that underlie behavioral and cognitive differences in aging and sex.

The online version of this article has a Supplementary Appendix. BackgroundThe prognostic value of cytogenetic findings in chronic myelomonocytic leukemia is unclear. Our purpose was to evaluate the independent prognostic impact of cytogenetic abnormalities in a large series of patients with chronic myelomonocytic leukemia included in the database of the Spanish Registry of Myelodysplastic Syndromes. Design and MethodsWe studied 414 patients with chronic myelomonocytic leukemia according to WHO criteria and with a successful conventional cytogenetic analysis at diagnosis. Different patient and disease characteristics were examined by univariate and multivariate methods to establish their relationship with overall survival and evolution to acute myeloid leukemia. ResultsPatients with abnormal karyotype (110 patients, 27%) had poorer overall survival (P=0.001) and higher risk of acute myeloid leukemia evolution (P=0.010). Based on outcome analysis, three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). Overall survival at five years for patients in the low, intermediate, and high risk cytogenetic categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed that this new CMMLspecific cytogenetic risk stratification was an independent prognostic variable for overall survival (P=0.001). Additionally, patients belonging to the high-risk cytogenetic category also had a higher risk of acute myeloid leukemia evolution on univariate (P=0.001) but not multivariate analysis. ConclusionsCytogenetic findings have a strong prognostic impact in patients with chronic myelomonocytic leukemia.Key words: chronic myelomonocytic leukemia, CMML, cytogenetic. leukemia. Haematologica 2011;96(3):375-383. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Such E, Cervera J, Costa D, Solé F, Vallespí T, Luño E, Collado R, Calasanz MJ, Hernández-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Cañizo C, Gómez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, and Sanz GF. Cytogenetic risk stratification in chronic myelomonocytic Cytogenetic risk stratification in chronic myelomonocytic leukemia

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Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8-8.4 year; late childhood: 8.5-11.3 year; early adolescence: 11.4-14.7 year; late adolescence: 14.8-18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.

Neuroimaging studies in autism spectrum disorders (ASDs) have provided inconsistent evidence of cortical abnormality. This is probably due to the small sample sizes used in most studies, and important differences in sample characteristics, particularly age, as well as to the heterogeneity of the disorder. To address these issues, we assessed abnormalities in ASD within the Autism Brain Imaging Data Exchange data set, which comprises data from approximately 1100 individuals (~6-55 years). A subset of these data that met stringent quality control and inclusion criteria (560 male subjects; 266 ASD; age = 6-35 years) were used to compute age-specific differences in cortical thickness in ASD and the relationship of any such differences to symptom severity of ASD. Our results show widespread increased cortical thickness in ASD, primarily left lateralized, from 6 years onwards, with differences diminishing during adulthood. The severity of symptoms related to social affect and communication correlated with these cortical abnormalities. These results are consistent with the conjecture that developmental patterns of cortical thickness abnormalities reflect delayed cortical maturation and highlight the dynamic nature of morphological abnormalities in ASD.

IntroductionTreatment of patients with multiple myeloma (MM) is disappointing. In this regard, the Southwest Oncology Group (SWOG) experience on standard dose therapy in 7 consecutive, large phase 3 studies has shown median survival times of less than 3 years, irrespective of the treatment given. 1 In addition, the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) group found that increased doses of conventional chemotherapy did not result in significant prolongation of survival. 2 Finally, meta-analysis of 6633 patients from 27 randomized trials failed to show any superiority of combination chemotherapy over melphalan/ prednisone in terms of duration of response and survival. 3 Furthermore, the Nordic Myeloma Study Group reported no survival improvement in conventionally treated younger patients with myeloma in the past 2 decades. 4 These limitations led to the current tendency to offer high-dose therapy (HDT)/stem cell support to MM patients as part of the frontline treatment. 5 Two randomized trials conducted by the Intergroup Français du Myeloma (IFM) and the Medical Research Council (MRC) showed that HDT significantly increased complete remission (CR), event-free survival (EFS), and overall survival (OS) compared with conventional chemotherapy. 5,6 However, 2 other randomized trials, reported in abstract form, failed to show any superiority of autologous J.B. and J.S.M. created the initial concept/design of the trial, analyzed and interpreted the data, wrote the manuscript, modified subsequent drafts, and finalized the manuscript; L.R. and A. Sureda contributed to analysis and interpretation of the data and to drafting the manuscript; J.B., J.S.M., L.R., and A. Sureda brought a significant number of patients to the study; M.F. participated in the analysis of the data and in the updating process throughout the study period; and J.M.R., J.D.-M., J.G.-L., M.V.M., L.P., J.F.-C, J.M.M., P.G., F.C., M.C., J.T., S.G., M.J.M., A.B., A. Soler, and L.F. participated in the conception/design of the study, included patients, provided the PETHEMA database with the patient data and periodic updating, and actively discussed the progress of the trial at the annual PETHEMA meetings. All the authors are members of PETHEMA and reviewed and approval the final version of the manuscript.An Inside Blood analysis of this article appears in the front of this issue.Reprints: Joan Bladé , Hematology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: jblade@clinic.ub.es.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on March 22, 2019. by guest www.bloodjournal.org From transplantation. 7,8 The objective of the present study was to investigate, in a prospective randomized trial, the efficacy of HDT intensification therapy compared with continuation with conventional chemotherapy in patients wit...

This article reviews progress and challenges in model driven EEG/fMRI fusion with a focus on brain oscillations. Fusion is the combination of both imaging modalities based on a cascade of forward models from ensemble of post-synaptic potentials (ePSP) to net primary current densities (nPCD) to EEG; and from ePSP to vasomotor feed forward signal (VFFSS) to BOLD. In absence of a model, data driven fusion creates maps of correlations between EEG and BOLD or between estimates of nPCD and VFFS. A consistent finding has been that of positive correlations between EEG alpha power and BOLD in both frontal cortices and thalamus and of negative ones for the occipital region. For model driven fusion we formulate a neural mass EEG/fMRI model coupled to a metabolic hemodynamic model. For exploratory simulations we show that the Local Linearization (LL) method for integrating stochastic differential equations is appropriate for highly nonlinear dynamics. It has been successfully applied to small and medium sized networks, reproducing the described EEG/BOLD correlations. A new LL-algebraic method allows simulations with hundreds of thousands of neural populations, with connectivities and conduction delays estimated from diffusion weighted MRI. For parameter and state estimation, Kalman filtering combined with the LL method estimates the innovations or prediction errors. From these the likelihood of models given data are obtained. The LL-innovation estimation method has been already applied to small and medium scale models. With improved Bayesian computations the practical estimation of very large scale EEG/fMRI models shall soon be possible.

SUMMARYIn vivo cell lineage-tracing studies in the vertebrate retina have revealed that the sizes and cellular compositions of retinal clones are highly variable. It has been challenging to ascertain whether this variability reflects distinct but reproducible lineages among many different retinal progenitor cells (RPCs) or is the product of stochastic fate decisions operating within a population of more equivalent RPCs. To begin to distinguish these possibilities, we developed a method for long-term videomicroscopy to follow the lineages of rat perinatal RPCs cultured at clonal density. In such cultures, cell-cell interactions between two different clones are eliminated and the extracellular environment is kept constant, allowing us to study the cell-intrinsic potential of a given RPC. Quantitative analysis of the reconstructed lineages showed that the mode of division of RPCs is strikingly consistent with a simple stochastic pattern of behavior in which the decision to multiply or differentiate is set by fixed probabilities. The variability seen in the composition and order of cell type genesis within clones is well described by assuming that each of the four different retinal cell types generated at this stage is chosen stochastically by differentiating neurons, with relative probabilities of each type set by their abundance in the mature retina. Although a few of the many possible combinations of cell types within clones occur at frequencies that are incompatible with a fully stochastic model, our results support the notion that stochasticity has a major role during retinal development and therefore possibly in other parts of the central nervous system.