Active dendrites enhance neuronal dynamic range

Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the last decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of active dendritic trees is a highly non-linear function of their afferent rate, attaining extremely large dynamic ranges (above 50 dB). Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease of dynamic range.Comment: 20 pages, 6 figure

A Computational Study on the Role of Gap Junctions and Rod Ih Conductance in the Enhancement of the Dynamic Range of the Retina

Recent works suggest that one of the roles of gap junctions in sensory systems is to enhance their dynamic range by avoiding early saturation in the first processing stages. In this work, we use a minimal conductance-based model of the ON rod pathways in the vertebrate retina to study the effects of electrical synaptic coupling via gap junctions among rods and among AII amacrine cells on the dynamic range of the retina. The model is also used to study the effects of the maximum conductance of rod hyperpolarization activated current Ih on the dynamic range of the retina, allowing a study of the interrelations between this intrinsic membrane parameter with those two retina connectivity characteristics. Our results show that for realistic values of Ih conductance the dynamic range is enhanced by rod-rod coupling, and that AII-AII coupling is less relevant to dynamic range amplification in comparison with receptor coupling. Furthermore, a plot of the retina output response versus input intensity for the optimal parameter configuration is well fitted by a power law with exponent . The results are consistent with predictions of more theoretical works and suggest that the earliest expression of gap junctions along the rod pathways, together with appropriate values of rod Ih conductance, has the highest impact on vertebrate retina dynamic range enhancement

Convergence among Non-Sister Dendritic Branches: An Activity-Controlled Mean to Strengthen Network Connectivity

The manner by which axons distribute synaptic connections along dendrites remains a fundamental unresolved issue in neuronal development and physiology. We found in vitro and in vivo indications that dendrites determine the density, location and strength of their synaptic inputs by controlling the distance of their branches from those of their neighbors. Such control occurs through collective branch convergence, a behavior promoted by AMPA and NMDA glutamate receptor activity. At hubs of convergence sites, the incidence of axo-dendritic contacts as well as clustering levels, pre- and post-synaptic protein content and secretion capacity of synaptic connections are higher than found elsewhere. This coupling between synaptic distribution and the pattern of dendritic overlapping results in ‘Economical Small World Network’, a network configuration that enables single axons to innervate multiple and remote dendrites using short wiring lengths. Thus, activity-mediated regulation of the proximity among dendritic branches serves to pattern and strengthen neuronal connectivity

In vivo Expansion of Naïve CD4+CD25high FOXP3+ Regulatory T Cells in Patients with Colorectal Carcinoma after IL-2 Administration

Regulatory T cells (Treg cells) are increased in context of malignancies and their expansion can be correlated with higher disease burden and decreased survival. Initially, interleukin 2 (IL-2) has been used as T-cell growth factor in clinical vaccination trials. In murine models, however, a role of IL-2 in development, differentiation, homeostasis, and function of Treg cells was established. In IL-2 treated cancer patients a further Treg-cell expansion was described, yet, the mechanism of expansion is still elusive. Here we report that functional Treg cells of a naïve phenotype - as determined by CCR7 and CD45RA expression - are significantly expanded in colorectal cancer patients. Treatment of 15 UICC stage IV colorectal cancer patients with IL-2 in a phase I/II peptide vaccination trial further enlarges the already increased naïve Treg-cell pool. Higher frequencies of T-cell receptor excision circles in naïve Treg cells indicate IL-2 dependent thymic generation of naïve Treg cells as a mechanism leading to increased frequencies of Treg cells post IL-2 treatment in cancer patients. This finding could be confirmed in naïve murine Treg cells after IL-2 administration. These results point to a more complex regulation of Treg cells in context of IL-2 administration. Future strategies therefore might aim at combining IL-2 therapy with novel strategies to circumvent expansion and differentiation of naïve Treg cells

Children's health care assistance according to their families: a comparison between models of Primary Care

OBJECTIVE To compare the health assistance models of Basic Traditional Units (UBS) with the Family Health Strategy (ESF) units for presence and extent of attributes of Primary Health Care (APS), specifically in the care of children. METHOD A cross-sectional study of a quantitative approach with families of children attended by the Public Health Service of Colombo, Paraná. The Primary Care Assessment Tool (PCA-Tool) was applied to parents of 482 children, 235 ESF units and 247 UBS units covering all primary care units of the municipality, between June and July 2012. The results were analyzed according to the PCA-Tool manual. RESULTS ESF units reached a borderline overall score for primary health care standards. However, they fared better in their attributes of Affiliation, Integration of care coordination, Comprehensiveness, Family Centeredness and Accessibility of use, while the attributes of Community Guidance/Orientation, Coordination of Information Systems, Longitudinality and Access attributes were rated as insufficient for APS. UBS units had low scores on all attributes. CONCLUSION The ESF units are closer to the principles of APS (Primary Health Care), but there is need to review actions of child care aimed at the attributes of APS in both care models, corroborating similar studies from other regions of Brazil

Profound Depletion of HIV-1 Transcription in Patients Initiating Antiretroviral Therapy during Acute Infection

Early intervention resulted in profound depletion of PBMC expressing HIV-1 RNA. This is contrary to chronically infected patients who predominantly showed continuous UsRNA expression on cART. Thus, antiretroviral treatment initiated during the acute phase of infection prevented establishment or expansion of long-lived transcriptionally active viral cellular reservoirs in peripheral blood

Ambiente familiar e transtorno de déficit de atenção e hiperatividade

OBJECTIVE: To analyze factors associated with attention-deficit and hyperactivity disorder in children. METHODS: This is a longitudinal study about behavior problems in schoolchildren that was carried out in the city of São Gonçalo (Southeastern Brazil) in 2005. A total of 479 students from public schools was analyzed, selected through three-stage cluster sampling. The Child Behavior Checklist was used to measure the outcome. A questionnaire was administered to parents/guardians concerning the exposure factors, which were: child's and family's profile, family relationship variables, physical and psychological violence. The log-binomial regression model with a hierarchical approach was employed in the analysis. RESULTS: Higher intelligence quotient was inversely associated with the frequency of the disorder (PR=0.980 [95%CI 0.963;0.998]). The prevalence of the disorder in the children was higher when there was family dysfunction than among families with a better way of relating (PR=2.538 [95%CI 1.572; 4.099]). Children who suffered verbal abuse from the mother had a prevalence 3.7 times higher than the ones not exposed to this situation in the last year (PR=4.7 [95%CI 1.254;17.636]). CONCLUSIONS: Negative family relationships are associated with symptoms of Attention-Deficit and Hyperactivity Disorder. Its association with the intelligence quotient reiterates the importance of the genetic and environmental basis at the origin of the disorder.OBJETIVO: Analisar fatores associados a transtorno de déficit de atenção e hiperatividade em crianças. MÉTODOS: Estudo longitudinal sobre problemas de comportamento em crianças escolares de São Gonçalo, RJ, em 2005. Foram analisados 479 escolares da rede pública selecionados por amostragem por conglomerados em três estágios. Foi utilizada a escala Child Behavior Checklist para medição do desfecho. Foi aplicado um questionário para pais/responsáveis acerca dos fatores de exposição analisados: perfil da criança e da família, variáveis de relacionamento familiar, violências físicas e psicológicas. O modelo regressão log-binomial com enfoque hierarquizado foi empregado para a análise. RESULTADOS: Quociente de inteligência mais alto associou-se inversamente à frequência do transtorno (RP = 0,980 [IC95% 0,963;0,998]). A prevalência de transtorno nas crianças foi maior quando havia disfunção familiar do que entre famílias com melhor forma de se relacionar (RP = 2,538 [IC95% 1,572;4,099]). Crianças que sofriam agressão verbal pela mãe apresentaram prevalência 3,7 vezes maior do que aquelas não expostas a essa situação no último ano (RP = 4,7 [IC95% 1,254;17,636]). CONCLUSÕES: Relações familiares negativas estão associadas aos sintomas de transtorno de déficit de atenção e hiperatividade. Sua associação com quociente de inteligência reitera a importância da base genética e ambiental na origem do transtorno.OBJETIVO: Analizar factores asociados a trastorno por déficit de atención e hiperactividad en niños. MÉTODOS: Estudio longitudinal sobre problemas de comportamiento en niños escolares de Sao Gonçalo, Sureste de Brasil, en 2005. Se analizaron 479 escolares de la red pública seleccionados por muestreo por conglomerados en tres fases. Se utilizó la escala Child Behavior Checklist para medir el resultado. Se aplicó un cuestionario para padres/responsables sobre los factores de exposición analizados: perfil del niño y de la familia, variables de relación familiar, violencias físicas y psicológicas. El modelo de regresión log-binomial con enfoque jerarquizado se empleó en el análisis. RESULTADOS: Cociente de inteligencia elevado se asoció inversamente con la frecuencia del trastorno (RP= 0,980 [IC95% 0,963;0,998]). La prevalencia de trastorno fue mayor en los niños con disfunción familiar que entre las familias con buena relación (RP=2,538 [IC95% 1,572;4,009]). Niños que sufrían agresión verbal por parte de la madre presentaron prevalencia 3,7 veces mayor que aquellos no expuestos a esa situación en el último año (RP=4,7 [IC95% 1,254;17,636]). CONCLUSIONES: Relaciones familiares negativas están asociadas a los síntomas de trastornos por déficit de atención e hiperactividad. Su asociación con el cociente de inteligencia reitera la importancia de la base genética y ambiental en el origen del trastorno

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway