bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline characteristics and hospital mortality in the Acute Heart Failure Database (AHEAD) Main registry
Authors: Spinar Jindrich , Parenica Jiri , Vitovec Jiri , Widimsky Petr , Linhart Ales , Fedorco Marian , Malek Filip , Cihalik Cestmír , Spinarová Lenka , Miklik Roman , Felsoci Marian , Bambuch Miroslav , Dusek Ladislav , Jarkovsky Jiri
Published: December 2011

Introduction

The prognosis of patients hospitalized with acute heart failure (AHF) is poor and risk stratification may help clinicians guide care. The objectives of the Acute Heart Failure Database (AHEAD) registry are to assess patient characteristics, etiology, treatment and outcome of AHF.

Methods

The AHEAD main registry includes patients hospitalized for AHF in seven centers with a Catheterization Laboratory Service in the Czech Republic. The data were collected from September 2006 to October 2009. The inclusion criteria for the database adhere to the European guidelines for AHF (2005) and patients were systematically classified according to the basic syndromes, type and etiology of AHF.

Results

Of 4,153 patients, 12.7% died during hospitalization. The median length of hospitalization was 7.1 days. Mean age of patients was 71.5 ± 12.4 years; men were younger (68.6 ± 12.4 years) compared to women (75.5 ± 11.5 years) (P < 0.001). De-novo heart failure was seen in 58.3% of the patients. According to the classification of heart failure syndromes, acute decompensated heart failure (ADHF) was reported in 55.3%, hypertensive AHF in 4.4%, pulmonary edema in 18.4%, cardiogenic shock in 14.7%, high output failure in 3.3%, and right heart failure in 3.8%. The mortality of cardiogenic shock was 62.7%, of right AHF 16.7%, of pulmonary edema 7.1%, of high output HF 6.1%, whereas the mortality of hypertensive AHF or ADHF was < 2.5%. According to multivariate analyses, low systolic blood pressure, low cholesterol level, hyponatremia, hyperkalemia, the use of inotropic agents and norepinephrine were predictive parameters for in-hospital mortality in patients without cardiogenic shock. Severe left ventricular dysfunction and renal insufficiency were predictive parameters for mortality in patients with cardiogenic shock. Invasive ventilation and age over 70 years were the most important predictive factors for mortality in both genders with or without cardiogenic shock.

Conclusions

The AHEAD Main registry provides up-to-date information on the etiology, treatment and hospital outcomes of patients hospitalized with AHF. The results highlight the highest risk patients.
VEGFA Family Isoforms Regulate Spermatogonial Stem Cell Homeostasis in Vivo
Authors: Caires Kyle C. , de Avila Jeanene M. , Cupp Andrea S. , McLean Derek J.
Published: December 2011

The objective of the present study was to investigate vascular endothelial growth factor A (VEGFA) isoform regulation of cell fate decisions of spermatogonial stem cells (SSC) in vivo. The expression pattern and cell-specific distribution of VEGF isoforms, receptors, and coreceptors during testis development postnatal d 1–180 suggest a nonvascular function for VEGF regulation of early germ cell homeostasis. Populations of undifferentiated spermatogonia present shortly after birth were positive for VEGF receptor activation as demonstrated by immunohistochemical analysis. Thus, we hypothesized that proangiogenic isoforms of VEGF (VEGFA164) stimulate SSC self-renewal, whereas antiangiogenic isoforms of VEGF (VEGFA165b) induce differentiation of SSC. To test this hypothesis, we used transplantation to assay the stem cell activity of SSC obtained from neonatal mice treated daily from postnatal d 3–5 with 1) vehicle, 2) VEGFA164, 3) VEGFA165b, 4) IgG control, 5) anti-VEGFA164, and 6) anti-VEGFA165b. SSC transplantation analysis demonstrated that VEGFA164 supports self-renewal, whereas VEGFA165b stimulates differentiation of mouse SSC in vivo. Gene expression analysis of SSC-associated factors and morphometric analysis of germ cell populations confirmed the effects of treatment on modulating the biological activity of SSC. These findings indicate a nonvascular role for VEGF in testis development and suggest that a delicate balance between VEGFA164 and VEGFA165b isoforms orchestrates the cell fate decisions of SSC. Future in vivo and in vitro experimentation will focus on elucidating the mechanisms by which VEGFA isoforms regulate SSC homeostasis.
Immunological Applications of Stem Cells in Type 1 Diabetes
Authors: Fiorina Paolo , Voltarelli Julio , Zavazava Nicholas
Published: December 2011

Current approaches aiming to cure type 1 diabetes (T1D) have made a negligible number of patients insulin-independent. In this review, we revisit the role of stem cell (SC)-based applications in curing T1D. The optimal therapeutic approach for T1D should ideally preserve the remaining β-cells, restore β-cell function, and protect the replaced insulin-producing cells from autoimmunity. SCs possess immunological and regenerative properties that could be harnessed to improve the treatment of T1D; indeed, SCs may reestablish peripheral tolerance toward β-cells through reshaping of the immune response and inhibition of autoreactive T-cell function. Furthermore, SC-derived insulin-producing cells are capable of engrafting and reversing hyperglycemia in mice. Bone marrow mesenchymal SCs display a hypoimmunogenic phenotype as well as a broad range of immunomodulatory capabilities, they have been shown to cure newly diabetic nonobese diabetic (NOD) mice, and they are currently undergoing evaluation in two clinical trials. Cord blood SCs have been shown to facilitate the generation of regulatory T cells, thereby reverting hyperglycemia in NOD mice. T1D patients treated with cord blood SCs also did not show any adverse reaction in the absence of major effects on glycometabolic control. Although hematopoietic SCs rarely revert hyperglycemia in NOD mice, they exhibit profound immunomodulatory properties in humans; newly hyperglycemic T1D patients have been successfully reverted to normoglycemia with autologous nonmyeloablative hematopoietic SC transplantation. Finally, embryonic SCs also offer exciting prospects because they are able to generate glucose-responsive insulin-producing cells. Easy enthusiasm should be mitigated mainly because of the potential oncogenicity of SCs.
A Consideration of User Financial Incentives to Address Health Inequalities
Authors: Oliver Adam , Brown Lawrence D.
Published: December 2011

Health inequalities and user financial incentives to encourage health-related behavior change are two topical issues in the health policy discourse, and this article attempts to combine the two; namely, we try to address whether the latter can be used to reduce the former in the contexts of the United Kingdom and the United States. Payments for some aspects of medical adherence may offer a promising way to address, to some extent, inequalities in health and health care in both countries. However, payments for more sustained behavior change, such as that associated with smoking cessation and weight loss, have thus far shown little long-term effect, although more research that tests the effectiveness of different incentive mechanism designs, informed by the findings of behavioral economics, ought to be undertaken. Many practical, political, ethical, and ideological objections can be waged against user financial incentives in health, and this article reviews a number of them, but the justifiability of and limits to these incentives require more academic and public discourse so as to gain a better understanding of the circumstances in which they can legitimately be used.
The Role of Law in Public Health Preparedness: Opportunities and Challenges
Authors: Jacobson Peter D. , Wasserman Jeffrey , Botoseneanu Anda , Silverstein Amy , Wu Helen W.
Published: December 2011

We report the results of a study designed to assess and evaluate how the law shapes the public health system's preparedness activities. Based on 144 qualitative interviews conducted in nine states, we used a model that compared the objective legal environment with how practitioners perceived the laws. Most local public health and emergency management professionals relied on what they perceived the legal environment to be rather than on an adequate understanding of the objective legal requirements. Major reasons for the gap include the lack of legal training for local practitioners and the difficulty of obtaining clarification and consistent legal advice regarding public health preparedness. Narrowing the gap would most likely improve preparedness outcomes. We conclude that there are serious deficiencies in legal preparedness that can undermine effective responses to public health emergencies. Correcting the lack of legal knowledge, coupled with eliminating delays in resolving legal issues and questions during public health emergencies, could have measurable consequences on reducing morbidity and mortality.
An analysis of the rebound of the body in backward human running
Authors: Cavagna G. A. , Legramandi M. A. , La Torre A.
Published: December 2011

Step frequency and energy expenditure are greater in backward running than in forward running. The differences in the motion of the centre of mass of the body associated with these findings are not known. These differences were measured here on nine trained subjects during backward and forward running steps on a force platform at 3–17 km h–1. In contrast to previous reports, we found that the maximal upward acceleration of the centre of mass and the aerial phase, averaged over the whole speed range, are greater in backward running than in forward running (15.7 versus 13.2 m s–2, P=1.9×10–6 and 0.098 versus 0.072 s, P=2.4×10–5, respectively). Opposite to forward running, the impulse on the ground is directed more vertically during the push at the end of stance than during the brake at the beginning of stance. The higher step frequency in backward running is explained by a greater mass-specific vertical stiffness of the bouncing system (499 versus 352 s–2, P=2.3×10–11) resulting in a shorter duration of the lower part of the vertical oscillation of the centre of mass when the force is greater than body weight, with a similar duration of the upper part when the force is lower than body weight. As in a catapult, muscle–tendon units are stretched more slowly during the brake at the beginning of stance and shorten more rapidly during the push at the end of stance. We suggest that the catapult-like mechanism of backward running, although requiring greater energy expenditure and not providing a smoother ride, may allow a safer stretch–shorten cycle of muscle–tendon units.
An integrative modeling approach to elucidate suction-feeding performance
Authors: Holzman Roi , Collar David C. , Mehta Rita S. , Wainwright Peter C.
Published: December 2011

Research on suction-feeding performance has mostly focused on measuring individual underlying components such as suction pressure, flow velocity, ram or the effects of suction-induced forces on prey movement during feeding. Although this body of work has advanced our understanding of aquatic feeding, no consensus has yet emerged on how to combine all of these variables to predict prey-capture performance. Here, we treated the aquatic predator–prey encounter as a hydrodynamic interaction between a solid particle (representing the prey) and the unsteady suction flows around it, to integrate the effects of morphology, physiology, skull kinematics, ram and fluid mechanics on suction-feeding performance. We developed the suction-induced force-field (SIFF) model to study suction-feeding performance in 18 species of centrarchid fishes, and asked what morphological and functional traits underlie the evolution of feeding performance on three types of prey. Performance gradients obtained using SIFF revealed that different trait combinations contribute to the ability to feed on attached, evasive and (strain-sensitive) zooplanktonic prey because these prey types impose different challenges on the predator. The low overlap in the importance of different traits in determining performance also indicated that the evolution of suction-feeding ability along different ecological axes is largely unconstrained. SIFF also yielded estimates of feeding ability that performed better than kinematic traits in explaining natural patterns of prey use. When compared with principal components describing variation in the kinematics of suction-feeding events, SIFF output explained significantly more variation in centrarchid diets, suggesting that the inclusion of more mechanistic hydrodynamic models holds promise for gaining insight into the evolution of aquatic feeding performance.
The occurrence of two types of fast skeletal myosin heavy chains from abdominal muscle of kuruma shrimp Marsupenaeus japonicus and their different tissue distribution
Authors: Koyama Hiroki , Akolkar Dadasaheb B. , Shiokai Takafumi , Nakaya Misako , Piyapattanakorn Sanit , Watabe Shugo
Published: December 2011

Shrimps belong to the class Crustacea, which forms a large, diverse group in the invertebrates. However, the physiology and biochemistry of their skeletal muscles have been poorly understood compared with those from vertebrates including mammals and fish. The present study focused on myosin, the major protein in skeletal muscle, from adult specimens of kuruma shrimp Marsupenaeus japonicus. Two types of the gene encoding myosin heavy chain (MHC), a large subunit of the myosin molecule, were cloned from abdominal fast skeletal muscle and defined as MHCa and MHCb. Protein analysis revealed that the MHCa isoform was expressed at a higher level than the MHCb isoform. The full-length cDNA clones of MHCa and MHCb consisted of 5929 bp and 5955 bp, respectively, which encoded 1912 and 1910 amino acids, respectively. Both were classified into fast muscle type by comparison with the partially deduced amino acid sequences of fast-type and slow-type (S1, slow twitch) MHCs reported previously for the American lobster Homarus americanus. The amino acid identities between MHCa and MHCb of kuruma shrimp were 78%, 60% and 72% in the regions of subfragment-1, subfragment-2 and light meromyosin, respectively, and 71% in total. In situ hybridisation using anti-sense RNA-specific probes, along with northern blot analysis using different tissues from abdominal muscle, revealed the different localisation of MHCa and MHCb transcripts in abdominal fast skeletal muscle, suggesting their distinct physiological functions.
Age-Related Changes in Right Middle Frontal Gyrus Volume Correlate with Altered Episodic Retrieval Activity
Authors: Rajah M. Natasha , Languay Rafael , Grady Cheryl L.
Published: December 2011

Age-related deficits in episodic retrieval have been associated with volume reductions in the middle frontal gyrus (MFG). However, it remains unclear how this age-related reduction in MFG volume correlates with neural activity during retrieval. To address this, we conductedin vivovolumetry of the frontal cortex in young and older human adults and found more volume loss on the right than on the left MFG with age. We then examined how left and right MFG volume correlated with fMRI activity during successful retrieval of item, spatial context, and temporal context information in both age groups. In young adults, larger right MFG volume was positively correlated with greater activity in a commonly found episodic retrieval network that included bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal cortex. Within this network, left DLPFC and right inferior parietal cortex activity predicted memory performance. In older adults, a positive structure–function association in DLPFC for either left or right MFG/DLPFC was not observed. Instead, right MFG volume was negatively correlated with activity in several regions in older adults, including the parahippocampal cortex (PHC) and anterior cingulate. Less activity in the PHC region predicted better item memory, and less activity in the anterior cingulate predicted better spatial context accuracy in older adults. We conclude that age-related change in the structure–function association in MFG/DLPFC impacts retrieval activity and performance, and those older adults with larger right MFG volume attempt to compensate for this change by modifying activity in other brain regions to help retrieval performance.
Iron and Iron Regulatory Proteins in Amoeboid Microglial Cells Are Linked to Oligodendrocyte Death in Hypoxic Neonatal Rat Periventricular White Matter through Production of Proinflammatory Cytokines and Reactive Oxygen/Nitrogen Species
Authors: Rathnasamy Gurugirijha , Ling Eng-Ang , Kaur Charanjit
Published: December 2011

This study was aimed to examine the role of iron in causing periventricular white matter (PWM) damage following a hypoxic injury in the developing brain. Along with iron, the expression of iron regulatory proteins (IRPs) and transferrin receptor (TfR), which are involved in iron acquisition, was also examined in the PWM by subjecting 1-d-old Wistar rats to hypoxia. Apart from an increase in iron levels in PWM, Perls' iron staining showed an increase of intracellular iron in the preponderant amoeboid microglial cells (AMCs) in the tissue. In response to hypoxia, the protein levels of IRP1, IRP2, and TfR in PWM and AMCs were significantly increased. In primary microglial cultures, administration of iron chelator deferoxamine reduced the generation of iron-induced reactive oxygen and nitrogen species and proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Primary oligodendrocytes treated with conditioned medium from hypoxic microglia exhibited reduced glutathione levels, increased lipid peroxidation, upregulated caspase-3 expression, and reduced proliferation. This was reversed to control levels on treatment with conditioned medium from deferoxamine treated hypoxic microglia; also, there was reduction in apoptosis of oligodendrocytes. The present results suggest that excess iron derived primarily from AMCs might be a mediator of oligodendrocyte cell death in PWM following hypoxia in the neonatal brain.
Neurons in Dorsal Visual Area V5/MT Signal Relative Disparity
Authors: Krug Kristine , Parker Andrew J.
Published: December 2011

Judgments of visual depth rely crucially on the relative binocular disparity between two visual features. While areas of ventral visual cortex contain neurons that signal the relative disparity between spatially adjacent visual features, the same tests in dorsal visual areas yield little evidence for relative disparity selectivity. We investigated the sensitivity of neurons in dorsal visual area V5/MT of macaque monkeys to relative disparity, using two superimposed, transparent planes composed of dots moving in opposite directions. The separation of the planes in depth specifies their relative disparity, while absolute disparity can be altered independently by changing the binocular depth of the two planes with respect to the monkey's fixation point. Many V5/MT neurons were tuned to relative disparity, independent of the absolute disparities of the individual planes. For the two plane stimulus, neuronal responses were often linearly related to responses to the absolute disparity of each component plane presented individually, but some aspects of relative disparity tuning were not explained by linear combination. Selectivity for relative disparity could not predict whether neuronal firing was related to the monkeys' perceptual reports of the rotation direction of structure-from-motion figures centered on the plane of fixation. In sum, V5/MT neurons are not just selective for absolute disparity, but also code for relative disparity between visual features. This selectivity may be important for segmentation and depth order of moving visual features, particularly the processing of three-dimensional information in scenes viewed by an actively moving observer.
Downregulation of Parvalbumin at Cortical GABA Synapses Reduces Network Gamma Oscillatory Activity
Authors: Volman Vladislav , Behrens M. Margarita , Sejnowski Terrence J.
Published: December 2011

Postmortem and functional imaging studies of patients with psychiatric disorders, including schizophrenia, are consistent with a dysfunction of interneurons leading to compromised inhibitory control of network activity. Parvalbumin (PV)-expressing, fast-spiking interneurons interacting with pyramidal neurons generate cortical gamma oscillations (30–80 Hz) that synchronize cortical activity during cognitive processing. In postmortem studies of schizophrenia patients, these interneurons show reduced PV and glutamic acid decarboxylase 67 (GAD67), an enzyme that synthesizes GABA, but the consequences of this downregulation are unclear. We developed a biophysically realistic and detailed computational model of a cortical circuit including asynchronous release from GABAergic interneurons to investigate how reductions in PV and GABA affect gamma oscillations induced by sensory stimuli. Networks with reduced GABA were disinhibited and had altered gamma oscillations in response to stimulation; PV-deficient GABA synapses had increased asynchronous release of GABA, which decreased the level of excitation and reduced gamma-band activity. Combined reductions of PV and GABA resulted in a diminished gamma-band oscillatory activity in response to stimuli, similar to that observed in schizophrenia patients. Our results suggest a mechanism by which reduced GAD67 and PV in fast-spiking interneurons may contribute to cortical dysfunction in schizophrenia and related psychiatric disorders.
First-Pass Selectivity for Semantic Categories in Human Anteroventral Temporal Lobe
Authors: Chan Alexander M. , Baker Janet M. , Eskandar Emad , Schomer Donald , Ulbert Istvan , Marinkovic Ksenija , Cash Sydney S. , Halgren Eric
Published: December 2011

How the brain encodes the semantic concepts represented by words is a fundamental question in cognitive neuroscience. Hemodynamic neuroimaging studies have robustly shown that different areas of posteroventral temporal lobe are selectively activated by images of animals versus manmade objects. Selective responses in these areas to words representing animals versus objects are sometimes also seen, but they are task-dependent, suggesting that posteroventral temporal cortex may encode visual categories, while more anterior areas encode semantic categories. Here, using the spatiotemporal resolution provided by intracranial macroelectrode and microelectrode arrays, we report category-selective responses to words representing animals and objects in human anteroventral temporal areas including inferotemporal, perirhinal, and entorhinal cortices. This selectivity generalizes across tasks and sensory modalities, suggesting that it represents abstract lexicosemantic categories. Significant category-specific responses are found in measures sensitive to synaptic activity (local field potentials, high gamma power, current sources and sinks) and unit-firing (multiunit and single-unit activity). Category-selective responses can occur at short latency (as early as 130 ms) in middle cortical layers and thus are extracted in the first pass of activity through the anteroventral temporal lobe. This activation may provide input to posterior areas for iconic representations when required by the task, as well as to the hippocampal formation for categorical encoding and retrieval of memories, and to the amygdala for emotional associations. More generally, these results support models in which the anteroventral temporal lobe plays a primary role in the semantic representation of words.
Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression
Authors: Schwarz Jaclyn M. , Hutchinson Mark R. , Bilbo Staci D.
Published: December 2011

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of theIL-10gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.
Insulin-Like Growth Factor Signaling Regulates the Timing of Sensory Cell Differentiation in the Mouse Cochlea
Authors: Okano Takayuki , Xuan Shouhong , Kelley Matthew W.
Published: December 2011

The mammalian auditory sensory epithelium, the organ of Corti, is a highly ordered cellular structure that comprises two types of auditory hair cells and several types of nonsensory supporting cells. During embryogenesis, a stereotyped sequence of cellular and molecular events is required for its development. These processes are assumed to be regulated by multiple growth and transcription factors. However, the majority of these factors have not been identified. One potential regulator of cochlear development is the insulin-like growth factor (IGF) signaling family. To examine the roles of the IGF pathway in inner ear formation, cochleae fromIgf1rmutant mice were analyzed. Deletion ofIgf1rleads to several changes in inner ear development including a shortened cochlear duct, a decrease in the total number of cochlear hair cells, and defects in the formation of the semicircular canals. In addition, maturation of the cochlear sensory epithelium was delayed at the transition point between cellular proliferation and differentiation. To determine the molecular basis for these defects, inhibition of IGF signaling was replicated pharmacologicallyin vitro. Results indicated that IGF signaling regulates cochlear length and hair cell number as well asAtoh1expression through the phosphatidylinositol 3-kinase/Akt signaling pathway. These results demonstrate novel roles for IGF signaling in inner ear development including regulation of vestibular formation, length of the cochlear duct, and the number of cochlear hair cells. The results also provide new insights regarding the pathological processes that underlie auditory defects in the absence of IGF signaling in both humans and mice.
Noise in Brain Activity Engenders Perception and Influences Discrimination Sensitivity
Authors: Bernasconi Fosco , De Lucia Marzia , Tzovara Athina , Manuel Aurelie L. , Murray Micah M. , Spierer Lucas
Published: December 2011

Behavioral and brain responses to identical stimuli can vary with experimental and task parameters, including the context of stimulus presentation or attention. More surprisingly, computational models suggest that noise-related random fluctuations in brain responses to stimuli would alone be sufficient to engender perceptual differences between physically identical stimuli. In two experiments combining psychophysics and EEG in healthy humans, we investigated brain mechanisms whereby identical stimuli are (erroneously) perceived as different (higher vs lower in pitch or longer vs shorter in duration) in the absence of any change in the experimental context. Even though, as expected, participants' percepts to identical stimuli varied randomly, a classification algorithm based on a mixture of Gaussians model (GMM) showed that there was sufficient information in single-trial EEG to reliably predict participants' judgments of the stimulus dimension. By contrasting electrical neuroimaging analyses of auditory evoked potentials (AEPs) to the identical stimuli as a function of participants' percepts, we identified the precise timing and neural correlates (strength vs topographic modulations) as well as intracranial sources of these erroneous perceptions. In both experiments, AEP differences first occurred ∼100 ms after stimulus onset and were the result of topographic modulations following from changes in the configuration of active brain networks. Source estimations localized the origin of variations in perceived pitch of identical stimuli within right temporal and left frontal areas and of variations in perceived duration within right temporoparietal areas. We discuss our results in terms of providing neurophysiologic evidence for the contribution of random fluctuations in brain activity to conscious perception.
Encoding of Both Positive and Negative Reward Prediction Errors by Neurons of the Primate Lateral Prefrontal Cortex and Caudate Nucleus
Authors: Asaad Wael F. , Eskandar Emad N.
Published: December 2011

Learning can be motivated by unanticipated success or unexpected failure. The former encourages us to repeat an action or activity, whereas the latter leads us to find an alternative strategy. Understanding the neural representation of these unexpected events is therefore critical to elucidate learning-related circuits. We examined the activity of neurons in the lateral prefrontal cortex (PFC) and caudate nucleus of monkeys as they performed a trial-and-error learning task. Unexpected outcomes were widely represented in both structures, and neurons driven by unexpectedly negative outcomes were as frequent as those activated by unexpectedly positive outcomes. Moreover, both positive and negative reward prediction errors (RPEs) were represented primarily by increases in firing rate, unlike the manner in which dopamine neurons have been observed to reflect these values. Interestingly, positive RPEs tended to appear with shorter latency than negative RPEs, perhaps reflecting the mechanism of their generation. Last, in the PFC but not the caudate, trial-by-trial variations in outcome-related activity were linked to the animals' subsequent behavioral decisions. More broadly, the robustness of RPE signaling by these neurons suggests that actor-critic models of reinforcement learning in which the PFC and particularly the caudate are considered primarily to be “actors” rather than “critics,” should be reconsidered to include a prominent evaluative role for these structures.
Decrease in Calcium Concentration Triggers Neuronal Retinoic Acid Synthesis during Homeostatic Synaptic Plasticity
Authors: Wang Hui-Li , Zhang Zhenjie , Hintze Maik , Chen Lu
Published: December 2011

Blockade of synaptic activity induces homeostatic plasticity, in part by stimulating synthesis of all-transretinoic acid (RA), which in turn increases AMPA receptor synthesis. However, the synaptic signal that triggers RA synthesis remained unknown. Using multiple activity-blockade protocols that induce homeostatic synaptic plasticity, here we show that RA synthesis is activated whenever postsynaptic Ca2+entry is significantly decreased and that RA is required for upregulation of synaptic strength under these homeostatic plasticity conditions, suggesting that Ca2+plays an inhibitory role in RA synthesis. Consistent with this notion, we demonstrate that both transient Ca2+depletion by membrane-permeable Ca2+chelators and chronic blockage of L-type Ca2+-channels induces RA synthesis. Moreover, the source of dendritic Ca2+entry that regulates RA synthesis is not specific because mild depolarization with KCl is sufficient to reverse synaptic scaling induced by L-type Ca2+-channel blocker. By expression of a dihydropyridine-insensitive L-type Ca2+channel, we further show that RA acts cell autonomously to modulate synaptic transmission. Our findings suggest that, in synaptically active neurons, modest “basal” levels of postsynaptic Ca2+physiologically suppress RA synthesis, whereas in synaptically inactive neurons, decreases in the resting Ca2+levels induce homeostatic plasticity by stimulating synthesis of RA that then acts in a cell-autonomous manner to increase AMPA receptor function.
Contextual Knowledge Configures Attentional Control Networks
Authors: DiQuattro Nicholas E. , Geng Joy J.
Published: December 2011

Contextual cues are predictive and provide behaviorally relevant information; they are not the main objective of the current task but can make behavior more efficient. Using fMRI, we investigated the brain networks involved in representing contextual information and translating it into an attentional control signal. Human subjects performed a visual search task for a low-contrast target accompanied by a single non-target that was either perceptually similar or more salient (i.e., higher contrast). Shorter reaction times (RTs) and higher accuracy were found on salient trials, suggesting that the salient item was rapidly identified as a non-target and immediately acts as a spatial “anti-cue” to reorient attention to the target. The relative saliency of the non-target determined BOLD responses in the left temporoparietal junction (TPJ) and inferior frontal gyrus (IFG). IFG correlated with RT specifically on salient non-target trials. In contrast, bilateral dorsal frontoparietal regions [including the frontal eye fields (FEFs)] were correlated with RT in all conditions. Effective connectivity analyses using dynamic causal modeling found an excitatory pathway from TPJ to IFG to FEF, suggesting that this was the pathway by which the contextual cue was translated into an attentional control signal that facilitated behavior. Additionally, the connection from FEF to TPJ was negatively modulated during target-similar trials, consistent with the inhibition of TPJ by dorsal attentional control regions during top-down serial visual search. We conclude that left TPJ and IFG form a sensory-driven network that integrates contextual knowledge with ongoing sensory information to provide an attentional control signal to FEF.
Neuron-Specific Effects of Interleukin-1β Are Mediated by a Novel Isoform of the IL-1 Receptor Accessory Protein
Authors: Huang Yangyang , Smith Dirk E. , Ibáñez-Sandoval Osvaldo , Sims John E. , Friedman Wilma J.
Published: December 2011

In the CNS, interleukin-1β (IL-1β) is synthesized and released during injury, infection, and disease, mediating inflammatory responses. However, IL-1β is also present in the brain under physiological conditions, and can influence hippocampal neuronal function. Several cell-specific IL-1-mediated signaling pathways and functions have been identified in neurons and astrocytes, but their mechanisms have not been fully defined. In astrocytes, IL-1β induced both the p38 MAPK and NF-κB (nuclear factor κB) pathways regulating inflammatory responses, however in hippocampal neurons IL-1β activated p38 but not NF-κB. Additionally, IL-1β induced Src phosphorylation at 0.01 ng/ml in hippocampal neurons, a dose 1000-fold lower than that used to stimulate inflammatory responses. IL-1 signaling requires the type 1 IL-1 receptor and the IL-1 receptor accessory protein (IL-1RAcP) as a receptor partner. We previously reported a novel isoform of the IL-1RAcP, IL-1RAcPb, found exclusively in CNS neurons. In this study, we demonstrate that AcPb specifically mediates IL-1β activation of p-Src and potentiation of NMDA-induced calcium influx in mouse hippocampal neurons in a dose-dependent manner. Mice lacking the AcPb, but retaining the AcP, isoform were deficient in IL-1β regulation of p-Src in neurons. AcPb also played a modulatory role in the activation of p38 MAPK, but had no effect on NF-κB signaling. The restricted expression of AcPb in CNS neurons, therefore, governs specific neuronal signaling and functional responses to IL-1β.
Chondroitinase ABC Combined with Neurotrophin NT-3 Secretion and NR2D Expression Promotes Axonal Plasticity and Functional Recovery in Rats with Lateral Hemisection of the Spinal Cord
Authors: García-Alías Guillermo , Petrosyan Hayk A. , Schnell Lisa , Horner Philip J. , Bowers William J. , Mendell Lorne M. , Fawcett James W. , Arvanian Victor L.
Published: December 2011

Elevating spinal levels of neurotrophin NT-3 (NT3) while increasing expression of the NR2D subunit of the NMDA receptor using a HSV viral construct promotes formation of novel multisynaptic projections from lateral white matter (LWM) axons to motoneurons in neonates. However, this treatment is ineffective after postnatal day 10. Because chondroitinase ABC (ChABC) treatment restores plasticity in the adult CNS, we have added ChABC to this treatment and applied the combination to adult rats receiving a left lateral hemisection (Hx) at T8. All hemisected animals initially dragged the ipsilateral hindpaw and displayed abnormal gait. Rats treated with ChABC or NT3/HSV-NR2D recovered partial hindlimb locomotor function, but animals receiving combined therapy displayed the most improved body stability and interlimb coordination [Basso-Beattie-Bresnahan (BBB) locomotor scale and gait analysis]. Electrical stimulation of the left LWM at T6 did not evoke any synaptic response in ipsilateral L5 motoneurons of control hemisected animals, indicating interruption of the white matter. Only animals with the full combination treatment recovered consistent multisynaptic responses in these motoneurons indicating formation of a detour pathway around the Hx. These physiological findings were supported by the observation of increased branching of both cut and intact LWM axons into the gray matter near the injury. ChABC-treated animals displayed more sprouting than control animals and those receiving NT3/HSV-NR2D; animals receiving the combination of all three treatments showed the most sprouting. Our results indicate that therapies aimed at increasing plasticity, promoting axon growth and modulating synaptic function have synergistic effects and promote better functional recovery than if applied individually.
Prion Protein Promotes Growth Cone Development through Reggie/Flotillin-Dependent N-Cadherin Trafficking
Authors: Bodrikov Vsevolod , Solis Gonzalo P. , Stuermer Claudia A. O.
Published: December 2011

The role of prion protein (PrP) is insufficiently understood partially because PrP-deficient (−/−) neurons from C57BL/6J mice seem to differentiate normally and are functionally mildly impaired. Here, we reassessed this notion and, unexpectedly, discovered that PrP−/−hippocampal growth cones were abnormally small and poor in filopodia and cargo-containing vesicles. Based on our findings that PrP-PrPtrans-interaction recruits E-cadherin to cell contact sites and reggie microdomains, and that reggies are essential for growth by regulating membrane trafficking, we reasoned that PrP and reggie might promote cargo (N-cadherin) delivery via PrP-reggie-connected signaling upon PrP activation (by PrP-Fc-inducedtrans-interaction). In wild-type but not PrP−/−neurons, PrP activation led to (1) enhanced PrP-reggie cocluster formation, (2) reggie-associated fyn and MAP kinase activation, (3) Exo70 and N-cadherin (cargo) recruitment to reggie, (4) the preference of the growth cone for PrP-Fc as substrate, and (5) longer neurites. Conversely, PrP-reggie-induced N-cadherin recruitment was blocked by mutant TC10, the GTPase downstream of reggie, triggering exocyst-assisted cargo delivery. This implies that PrP functions in reggie-mediated signaling and cargo trafficking, thus promoting growth cone complexity and vitality and thereby growth cone elongation.
Rapid Disruption of Axon–Glial Integrity in Response to Mild Cerebral Hypoperfusion
Authors: Reimer Michell M. , McQueen Jamie , Searcy Luke , Scullion Gillian , Zonta Barbara , Desmazieres Anne , Holland Philip R. , Smith Jessica , Gliddon Catherine , Wood Emma R. , Herzyk Pawel , Brophy Peter J. , McCulloch James , Horsburgh Karen
Published: December 2011

Myelinated axons have a distinct protein architecture essential for action potential propagation, neuronal communication, and maintaining cognitive function. Damage to myelinated axons, associated with cerebral hypoperfusion, contributes to age-related cognitive decline. We sought to determine early alterations in the protein architecture of myelinated axons and potential mechanisms after hypoperfusion. Using a mouse model of hypoperfusion, we assessed changes in proteins critical to the maintenance of paranodes, nodes of Ranvier, axon–glial integrity, axons, and myelin by confocal laser scanning microscopy. As early as 3 d after hypoperfusion, the paranodal septate-like junctions were damaged. This was marked by a progressive reduction of paranodal Neurofascin signal and a loss of septate-like junctions. Concurrent with paranodal disruption, there was a significant increase in nodal length, identified by Nav1.6 staining, with hypoperfusion. Disruption of axon–glial integrity was also determined after hypoperfusion by changes in the spatial distribution of myelin-associated glycoprotein staining. These nodal/paranodal changes were more pronounced after 1 month of hypoperfusion. In contrast, the nodal anchoring proteins AnkyrinG and Neurofascin 186 were unchanged and there were no overt changes in axonal and myelin integrity with hypoperfusion. A microarray analysis of white matter samples indicated that there were significant alterations in 129 genes. Subsequent analysis indicated alterations in biological pathways, including inflammatory responses, cytokine-cytokine receptor interactions, blood vessel development, and cell proliferation processes. Our results demonstrate that hypoperfusion leads to a rapid disruption of key proteins critical to the stability of the axon–glial connection that is mediated by a diversity of molecular events.
Astrocyte Calcium Signaling Transforms Cholinergic Modulation to Cortical PlasticityIn Vivo
Authors: Takata Norio , Mishima Tsuneko , Hisatsune Chihiro , Nagai Terumi , Ebisui Etsuko , Mikoshiba Katsuhiko , Hirase Hajime
Published: December 2011

Global brain state dynamics regulate plasticity in local cortical circuits, but the underlying cellular and molecular mechanisms are unclear. Here, we demonstrate that astrocyte Ca2+signaling provides a critical bridge between cholinergic activation, associated with attention and vigilance states, and somatosensory plasticity in mouse barrel cortexin vivo. We investigated first whether a combined stimulation of mouse whiskers and the nucleus basalis of Meynert (NBM), the principal source of cholinergic innervation to the cortex, leads to enhanced whisker-evoked local field potential. This plasticity is dependent on muscarinic acetylcholine receptors (mAChR) andN-methyl-d-aspartic acid receptors (NMDARs). During the induction of this synaptic plasticity, we find that astrocytic [Ca2+]iis pronouncedly elevated, which is blocked by mAChR antagonists. The elevation of astrocytic [Ca2+]iis crucial in this type of synaptic plasticity, as the plasticity could not be induced in inositol-1,4,5-trisphosphate receptor type 2 knock-out (IP3R2-KO) mice, in which astrocytic [Ca2+]isurges are diminished. Moreover, NBM stimulation led to a significant increase in the extracellular concentration of the NMDAR coagonistd-serine in wild-type mice when compared to IP3R2-KO mice. Finally, plasticity in IP3R2-KO mice could be rescued by externally supplyingd-serine. Our data present coherent lines ofin vivoevidence for astrocytic involvement in cortical plasticity. These findings suggest an unexpected role of astrocytes as a gate for cholinergic plasticity in the cortex.
Limites da representação na metapsicologia freudiana
Authors: Campos Érico Bruno Viana
Published: December 2011

Este artigo objetiva analisar os limites da teoria da representação na metapsicologia freudiana. É um trabalho de pesquisa teórico-conceitual da psicanálise, por meio de uma metodologia de análise histórica e epistemológica dos textos de Freud. A metapsicologia freudiana fundamenta-se em uma teoria das pulsões que é tributária dos princípios de uma teoria da representação mental. Porém, as alterações exigidas pela introdução dos conceitos de narcisismo e de identificação, além do reconhecimento da compulsão à repetição como algo além do princípio do prazer, levaram a uma remodelação da teoria das pulsões, a uma nova descrição tópica e a uma reformulação na teoria da angústia. A hipótese é que a teoria representacional encontra limites em duas direções distintas: a identificação e a impossibilidade de representação como, respectivamente, um além e um aquém da metapsicologia freudiana.
Análise quantitativa do palato duro em diferentes tipologias faciais de respiradores nasais e orais
Authors: Berwig Luana Cristina , Silva Ana Maria Toniolo da , Côrrea Eliane Castilhos Rodrigues , Moraes Anaelena Bragança de , Montenegro Márlon Munhoz , Ritzel Rodrigo Agne
Published: December 2011

OBJETIVO: comparar as dimensões do palato duro em diferentes tipologias faciais de crianças respiradoras nasais e orais. MÉTODO: a amostra foi constituída por 54 crianças, na faixa etária entre sete e 11 anos, distribuídas em grupos conforme o tipo facial e o modo respiratório. O tipo facial foi obtido por meio da análise cefalométrica de Ricketts, e o modo respiratório foi determinado a partir da avaliação fonoaudiológica e do diagnóstico otorrinolaringológico. Para realização de medidas transversais, verticais e do comprimento anteroposterior do palato duro, foram obtidos modelos em gesso do arco dental maxilar. Para comparação das dimensões do palato duro entre os grupos, foram utilizados testes paramétricos e não paramétricos, ao nível de significância de 5%. RESULTADOS: não foi verificada diferença estatisticamente significante nas medidas do palato duro entre as crianças braquifaciais, mesofaciais e dolicofaciais. Verificou-se diferença estatisticamente significante na distância entre os segundos pré-molares nos diferentes tipos faciais das crianças respiradoras nasais e orais, sendo que esta diferença não foi detectada nas comparações múltiplas. CONCLUSÃO: as dimensões do palato duro não diferiram quando analisadas em diferentes tipos faciais independente do modo respiratório. Porém, evidenciou-se diferença na distância entre os segundos pré-molares quando o tipo facial foi analisado nos respiradores nasais e orais.
Avaliação da restrição de participação, em idosos, antes e após a intervenção fonoaudiológica
Authors: Magalhães Ruth , Iório Maria Cecilia Martinelli
Published: December 2011

OBJETIVO: estudar os efeitos da intervenção fonoaudiológica por meio da adaptação de próteses auditivas na restrição de participação em atividades de vida diária do idoso, segundo as variáveis sexo e faixa etária. MÉTODO: participaram do estudo 50 idosos, 23 do sexo feminino e 27 do sexo masculino. Os idosos foram distribuídos em dois grupos etários: Grupo 1 - com 24 idosos, 11 do sexo feminino e 13 do sexo masculino, com idade entre 60 e 74 anos ; Grupo 2 - com 26 idosos, 12 do sexo feminino e 14 do sexo masculino, com idade igual ou superior a 75 anos. Os idosos foram avaliados antes e um ano após a adaptação das próteses auditivas, por meio de questionário HHIE. Foram realizados acompanhamentos bimensais, totalizando sete reuniões, a fim de garantir o uso efetivo das próteses auditivas. O método estatístico incluiu estatísticas descritivas e análise de variância. RESULTADOS: a análise do HHIE revelou que houve redução significante da restrição de participação nas Escalas Emocional e Social no período pós intervenção, nas duas faixas etárias, tanto no sexo masculino quanto no feminino. CONCLUSÃO: há menor autopercepção das restrições de participação após a intervenção fonoaudiológica nas Escalas Social e Emocional do questionário HHIE.