bluuebunny/crossref_metadata_2025 huggingface dataset:
Pegloticase: A Novel Agent for Treatment-Refractory Gout
Authors: Shannon Jennifer A , Cole Sabrina W
Published: March 2012

Objective:

To evaluate efficacy and safety of pegloticase, approved by the Food and Drug Administration in September 2010 for treatment of patients with chronic treatment-refractory gout.

Data Sources:

Literature searches were conducted using PubMed (1948–January 2012), TOXLINE, international Pharmaceutical Abstracts (1970-January 2012), and Google Scholar using the terms pegloticase, puricase, PEG-uricase, gout, uricase, and Krystexxa. Results were limited to English-language publications. References from selected articles were reviewed to identify additional citations.

Study Selection and Data Extraction:

Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of pegloticase for the treatment of chronic treatment-refractory gout were included.

Data Synthesis:

Pegloticase represents a novel intravenous treatment option for patients who have chronic gout refractory to other available treatments. Pegloticase is a recombinant uricase and achieves therapeutic effects by catalyzing oxidation of uric acid to allantoin, resulting in decreased uric acid concentrations. Results of published trials demonstrate the ability of pegloticase to maintain uric acid concentrations below 7 mg/dL in patients with chronic gout, Data supporting reduction of gout flares are limited. Pegloticase is well tolerated but associated with gout flares and infusion reactions. Other adverse events include nausea, dizziness, and back pain. During Phase 3 trials, 2 patients in the pegloticase biweekly group and 1 in the monthly group experienced heart failure exacerbation; another patient in the monthly group experienced a nonfatal myocardial infarction. Providers should exercise caution before administering pegloticase to patients with cardiovascular disease. The cost burden and safety profile may limit its use in practice, in addition to limited data available to support decreases in patient-centered outcomes (eg, gouty attacks).

Conclusions:

Pegloticase is an effective option for patients with symptomatic gout for whom current uric acid-lowering therapies are ineffective or contraindicated.
Brentuximab Vedotin: A New Age in the Treatment of Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma
Authors: Minich Stephanie S
Published: March 2012

Objective:

To review the clinical trial data, pharmacology, pharmacokinetics, and adverse effects of brentuximab vedotin.

Data Sources:

A literature search was performed using MEDLINE and PubMed (both 1966–October 2011), as well as the American Society of Hematology abstracts (2000–January 2012), using the primary search terms brentuximab vedotin, SGN-35, Hodgkin lymphoma (HL), and anaplastic large cell lymphoma (ALCL).

Study Selection and Data Extraction:

Published and ongoing clinical studies and abstracts in the English language that detail the pharmacology, pharmacokinetics, safety, and clinical efficacy of brentuximab vedotin in the treatment of HL and ALCL were included in this review.

Data Synthesis:

Brentuximab vedotin is an antibody drug conjugate that combines the anti-CD30 antibody, cAC10, with the synthetic tubulin disrupting agent monomethyl auristatin E. A Phase 1 trial in patients with relapsed and refractory HL or systemic ALCL supported a dose of 1.8 mg/kg every 3 weeks, The drug was well tolerated, with the majority of adverse reactions being grade 1 or 2 in severity. Common toxicities included fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. Phase 2 studies in the same patient populations illustrated objective response rates of 73–86% with an acceptable toxicity profile. Based on results of these Phase 2 trials, the Food and Drug Administration granted approval of brentuximab vedotin in August 2011 for the treatment of relapsed and refractory HL or ALCL.

Conclusions:

Phase 1 and 2 clinical trial data indicate that brentuximab vedotin is efficacious and safe in patients with relapsed and refractory CD30-positive lymphomas. This agent is being investigated in combination with chemotherapy to further elucidate its role in lymphoma therapy.
Circulating MicroRNA miR-323-3p as a Biomarker of Ectopic Pregnancy
Authors: Zhao Zhen , Zhao Qiuhong , Warrick Joshua , Lockwood Christina M , Woodworth Alison , Moley Kelle H , Gronowski Ann M
Published: March 2012

BACKGROUND

The use of serum human chorionic gonadotropin (hCG) and progesterone to identify patients with ectopic pregnancy (EP) has been shown to have poor clinical utility. Pregnancy-associated circulating microRNAs (miRNAs) have been proposed as potential biomarkers for the diagnosis of pregnancy-associated complications. This proof-of-concept study examined the diagnostic accuracy of various miRNAs to detect EP in an emergency department (ED) setting.

METHODS

This study was a retrospective case–control analysis of 89 women who presented to the ED with vaginal bleeding and/or abdominal pain/cramping and received a diagnosis of viable intrauterine pregnancy (VIP), spontaneous abortion (SA), or EP. Serum hCG and progesterone concentrations were measured by immunoassays. The serum concentrations of miRNAs miR-323-3p, miR-517a, miR-519d, and miR-525-3p were measured with TaqMan real-time PCR. Statistical analysis was performed to determine the clinical utility of these biomarkers, both as single markers and as multimarker panels for EP.

RESULTS

Concentrations of serum hCG, progesterone, miR-517a, miR-519d, and miR-525-3p were significantly lower in EP and SA cases than in VIP cases (P < 0.01). In contrast, the concentration of miR-323-3p was significantly increased in EP cases, compared with SA and VIP cases (P < 0.01). As a single marker, miR-323-3p had the highest sensitivity of 37.0% (at a fixed specificity of 90%). In comparison, the combined panel of hCG, progesterone, and miR-323-3p yielded the highest sensitivity (77.8%, at a fixed specificity of 90%). A stepwise analysis that used hCG first, added progesterone, and then added miR-323-3p yielded a 96.3% sensitivity and a 72.6% specificity.

CONCLUSIONS

Pregnancy-associated miRNAs, especially miR-323-3p, added substantial diagnostic accuracy to a panel including hCG and progesterone for the diagnosis of EP.
Critical Role of Connexin 43 in Secondary Expansion of Traumatic Spinal Cord Injury
Authors: Huang Chunlan , Han Xiaoning , Li Xi , Lam Eric , Peng Weiguo , Lou Nanhong , Torres Arnulfo , Yang Meixiang , Garre Juan Mauricio , Tian Guo-Feng , Bennett Michael V. L. , Nedergaard Maiken , Takano Takahiro
Published: March 2012

Spinal cord injury (SCI) is often complicated by secondary injury as a result of the innate inflammatory response to tissue trauma and swelling. Previous studies have shown that excessive ATP release from peritraumatic regions contributes to the inflammatory response to SCI by activation of low-affinity P2X7 receptors. Because connexin hemichannels constitute an important route for astrocytic ATP release, we here evaluated the impact on post-traumatic ATP release of deletion of connexins (Cx30/Cx43) in astrocytes.In vivobioluminescence imaging showed a significant reduction in ATP release after weight-drop injury in mice with deletion of Cx43 compared with Cx43-expressing littermates, both on a Cx30 knockout background. Moreover, astrogliosis and microglia activation were reduced in peritraumatic areas of those mice lacking Cx43; motor recovery was also significantly improved, and the traumatic lesion was smaller. Combined, these observations are consistent with a contribution by astrocytic hemichannels to post-traumatic ATP release that aggravates secondary injury and restrains functional recovery after experimental spinal cord injury. Connexins may thereby constitute a new therapeutic target in spinal cord injury.
Ongoing Cortical Activity at Rest: Criticality, Multistability, and Ghost Attractors
Authors: Deco Gustavo , Jirsa Viktor K.
Published: March 2012

The ongoing activity of the brain at rest, i.e., under no stimulation and in absence of any task, is astonishingly highly structured into spatiotemporal patterns. These spatiotemporal patterns, called resting state networks, display low-frequency characteristics (<0.1 Hz) observed typically in the BOLD-fMRI signal of human subjects. We aim here to understand the origins of resting state activity through modeling via a global spiking attractor network of the brain. This approach offers a realistic mechanistic model at the level of each single brain area based on spiking neurons and realistic AMPA, NMDA, and GABA synapses. Integrating the biologically realistic diffusion tensor imaging/diffusion spectrum imaging-based neuroanatomical connectivity into the brain model, the resultant emerging resting state functional connectivity of the brain network fits quantitatively best the experimentally observed functional connectivity in humans when the brain network operates at the edge of instability. Under these conditions, the slow fluctuating (<0.1 Hz) resting state networks emerge as structured noise fluctuations around a stable low firing activity equilibrium state in the presence of latent “ghost” multistable attractors. The multistable attractor landscape defines a functionally meaningful dynamic repertoire of the brain network that is inherently present in the neuroanatomical connectivity.
Coding of Apparent Motion in the Thalamic Nucleus of the Rat Vibrissal Somatosensory System
Authors: Ego-Stengel Valérie , Le Cam Julie , Shulz Daniel E.
Published: March 2012

While exploring objects, rats make multiple contacts using their whiskers, thereby generating complex patterns of sensory information. The cerebral structures that process this information in the somatosensory system show discrete patterns of anatomically distinct units, each corresponding to one whisker. Moreover, the feedforward and feedback connections are remarkably topographic, with little cross-whisker divergence before reaching the cortical network. Despite this parallel design, information processing from several whiskers has been reported in subcortical nuclei. Here, we explored whether sensory neurons in the ventral posterior medial nucleus (VPM) of the thalamus encode emergent properties of complex multiwhisker stimulations. Using a 24-whisker stimulator, we tested the responses of VPM neurons to sequences of caudal deflections that generated an apparent motion in eight different directions across the whiskerpad. Overall, 45% of neurons exhibited an evoked increase in firing rate significantly selective to the direction of apparent motion of the global stimulus. Periods of suppression of firing rate were often observed, but were generally not selective. Global motion selectivity of VPM neurons could occur regardless of the extent and spatial organization of their receptive fields, and of their selectivity for the direction of motion of their principal whisker. To investigate whether the global selectivity could be due to corticothalamic feedback connections, we inactivated the barrel cortex while repeating the stimulation protocol. For most VPM neurons, the direction selectivity decreased but was still present. These results suggest that nonlinear processing of stimuli from different whiskers emerges in subcortical nuclei and is amplified by the corticofugal feedback.
Identification of Modulators of Hair Cell Regeneration in the Zebrafish Lateral Line
Authors: Namdaran Parhum , Reinhart Katherine E. , Owens Kelly N. , Raible David W. , Rubel Edwin W
Published: March 2012

The external location of the zebrafish lateral line makes it a powerful model for studying mechanosensory hair cell regeneration. We have developed a chemical screen to identify FDA-approved drugs and biologically active compounds that modulate hair cell regeneration in zebrafish. Of the 1680 compounds evaluated, we identified two enhancers and six inhibitors of regeneration. The two enhancers, dexamethasone and prednisolone, are synthetic glucocorticoids that potentiated hair cell numbers during regeneration and also induced hair cell addition in the absence of damage. BrdU analysis confirmed that the extra hair cells arose from mitotic activity. We found that dexamethasone and prednisolone, like other glucocorticoids, suppress zebrafish caudal fin regeneration, indicating that hair cell regeneration occurs by a distinctly different process. Further analyses of the regeneration inhibitors revealed that two of the six, flubendazole and topotecan, significantly suppress hair cell regeneration by preventing proliferation of hair cell precursors. Flubendazole halted support cell division in M-phase, possibly by interfering with normal microtubule activity. Topotecan, a topoisomerase inhibitor, killed both hair cells and proliferating hair cell precursors. A third inhibitor, fulvestrant, moderately delayed hair cell regeneration by reducing support cell proliferation. Our observation that hair cells do not regenerate when support cell proliferation is impeded confirms previous observations that cell division is the primary route for hair cell regeneration after neomycin treatment in zebrafish.
Contextual Fear Memories Formed in the Absence of the Dorsal Hippocampus Decay Across Time
Authors: Zelikowsky Moriel , Bissiere Stephanie , Fanselow Michael S.
Published: March 2012

Mammals suffering damage to the hippocampus display a dramatic loss of explicit, recently formed memories (retrograde amnesia). In contrast, deficits in the ability to form new memories following hippocampal damage (anterograde amnesia) can be overcome with sufficient training. By combining contextual fear conditioning with lesions of the dorsal hippocampus in rats, we discovered that while animals can form long-term contextual fear memories in the absence of the hippocampus, these memories decay with time, lacking the permanence that is a hallmark characteristic of normal fear memories. These findings indicate that while it is initially possible to acquire explicit memories when the hippocampus is compromised, these memories cannot transfer from a recent to remote state. This suggests that memories formed outside the hippocampus may nevertheless require the hippocampus to undergo systems consolidation, which has important clinical implications for the treatment of memory disorders.
The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss
Authors: Purro Silvia A. , Dickins Ellen M. , Salinas Patricia C.
Published: March 2012

Extensive evidence supports a central role for amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD). Synaptic loss mediated by Aβ in early stages of the disease might contribute to cognitive impairments. However, little is known about the mechanism by which Aβ induces the loss of synapses. The expression of the Wnt antagonist Dickkopf-1 (Dkk1) is increased in brains of AD patients and in AD transgenic mouse models, suggesting that dysfunction of Wnt signaling could contribute to AD pathology. Here we report that acute exposure to Aβ oligomers induces Dkk1 expression together with the loss of synaptic sites. Importantly, Dkk1-neutralizing antibodies suppress Aβ-induced synapse loss in mouse brain slices. In mature rat hippocampal neurons, Dkk1 decreases the number of synapses without affecting cell viability. Ultrastructural analyses revealed that Wnt blockade decreases the size of presynaptic and postsynaptic terminals. Time-lapse recordings of RFP-labeled stable synaptic sites demonstrate that Dkk1 induces the dispersal of synaptic components. These findings identify Dkk1 as a potential therapeutic target for the treatment of AD.
From Salience to Saccades: Multiple-Alternative Gated Stochastic Accumulator Model of Visual Search
Authors: Purcell Braden A. , Schall Jeffrey D. , Logan Gordon D. , Palmeri Thomas J.
Published: March 2012

We describe a stochastic accumulator model demonstrating that visual search performance can be understood as a gated feedforward cascade from a salience map to multiple competing accumulators. The model quantitatively accounts for behavior and predicts neural dynamics of macaque monkeys performing visual search for a target stimulus among different numbers of distractors. The salience accumulated in the model is equated with the spike trains recorded from visually responsive neurons in the frontal eye field. Accumulated variability in the firing rates of these neurons explains choice probabilities and the distributions of correct and error response times with search arrays of different set sizes if the accumulators are mutually inhibitory. The dynamics of the stochastic accumulators quantitatively predict the activity of presaccadic movement neurons that initiate eye movements if gating inhibition prevents accumulation before the representation of stimulus salience emerges. Adjustments in the level of gating inhibition can control trade-offs in speed and accuracy that optimize visual search performance.
Heterogeneous Nuclear Ribonucleoprotein K, an RNA-Binding Protein, Is Required for Optic Axon Regeneration inXenopus laevis
Authors: Liu Yuanyuan , Yu Hurong , Deaton Sarah K. , Szaro Ben G.
Published: March 2012

Axotomized optic axons ofXenopus laevis, in contrast to those of mammals, retain their ability to regenerate throughout life. To better understand the molecular basis for this successful regeneration, we focused on the role of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein (hnRNP) K, because it is required for axonogenesis during development and because several of its RNA targets are under strong post-transcriptional control during regeneration. At 11 d after optic nerve crush, hnRNP K underwent significant translocation into the nucleus of retinal ganglion cells (RGCs), indicating that the protein became activated during regeneration. To suppress its expression, we intravitreously injected an antisense Vivo-Morpholino oligonucleotide targeting hnRNP K. In uninjured eyes, it efficiently knocked down hnRNP K expression in only the RGCs, without inducing either an axotomy response or axon degeneration. After optic nerve crush, staining for multiple markers of regenerating axons showed no regrowth of axons beyond the lesion site with hnRNP K knockdown. RGCs nonetheless responded to the injury by increasing expression of multiple growth-associated RNAs and experienced no additional neurodegeneration above that normally seen with optic nerve injury. At the molecular level, hnRNP K knockdown during regeneration inhibited protein, but not mRNA, expression of several known hnRNP K RNA targets (NF-M, GAP-43) by compromising their efficient nuclear transport and disrupting their loading onto polysomes for translation. Our study therefore provides evidence of a novel post-transcriptional regulatory pathway orchestrated by hnRNP K that is essential for successful CNS axon regeneration.
Supramodal Parametric Working Memory Processing in Humans
Authors: Spitzer Bernhard , Blankenburg Felix
Published: March 2012

Previous studies of delayed-match-to-sample (DMTS) frequency discrimination in animals and humans have succeeded in delineating the neural signature of frequency processing in somatosensory working memory (WM). During retention of vibrotactile frequencies, stimulus-dependent single-cell and population activity in prefrontal cortex was found to reflect the task-relevant memory content, whereas increases in occipital alpha activity signaled the disengagement of areas not relevant for the tactile task. Here, we recorded EEG from human participants to determine the extent to which these mechanisms can be generalized to frequency retention in the visual and auditory domains. Subjects performed analogous variants of a DMTS frequency discrimination task, with the frequency information presented either visually, auditorily, or by vibrotactile stimulation. Examining oscillatory EEG activity during frequency retention, we found characteristic topographical distributions of alpha power over visual, auditory, and somatosensory cortices, indicating systematic patterns of inhibition and engagement of early sensory areas, depending on stimulus modality. The task-relevant frequency information, in contrast, was found to be represented in right prefrontal cortex, independent of presentation mode. In each of the three modality conditions, parametric modulations of prefrontal upper beta activity (20–30 Hz) emerged, in a very similar manner as recently found in vibrotactile tasks. Together, the findings corroborate a view of parametric WM as supramodal internal scaling of abstract quantity information and suggest strong relevance of previous evidence from vibrotactile work for a more general framework of quantity processing in human working memory.
Selective Glycine Receptor α2 Subunit Control of Crossover Inhibition between the On and Off Retinal Pathways
Authors: Nobles Regina D. , Zhang Chi , Müller Ulrike , Betz Heinrich , McCall Maureen A.
Published: March 2012

In the retina, the receptive fields (RFs) of almost all ganglion cells (GCs) are comprised of an excitatory center and a suppressive surround. The RF center arises from local excitatory bipolar cell (BC) inputs and the surround from lateral inhibitory inputs. Selective antagonists have been used to define the roles of GABAAand GABACreceptor-mediated input in RF organization. In contrast, the role of glycine receptor (GlyR) subunit-specific inhibition is less clear because the only antagonist, strychnine, blocks all GlyR subunit combinations. We used mice lacking the GlyRα2 (Glra2−/−) and GlyRα3 (Glra3−/−) subunits, or both (Glra2/3−/−), to explore their roles in GC RF organization. By comparing spontaneous and visually evoked responses of WT withGlra2−/−,Glra3−/−andGlra2/3−/−ON- and OFF-center GCs, we found that both GlyRα2 and GlyRα3 modulate local RF interactions. In the On pathway, both receptors enhance the excitatory center response; however, the underlying inhibitory mechanisms differ. GlyRα2 participates in crossover inhibition, whereas GlyRα3 mediates serial inhibition. In the Off pathway, GlyRα2 plays a similar role, again using crossover inhibition and enhancing excitatory responses within the RF center. Comparisons of single and double KOs indicate that GlyRα2 and GlyRα3 inhibition are independent and additive, consistent with the finding that they use different inhibitory circuitry. These findings are the first to define GlyR subunit-specific control of visual function and GlyRα2 subunit-specific control of crossover inhibition in the retina.
FBL2 Regulates Amyloid Precursor Protein (APP) Metabolism by Promoting Ubiquitination-Dependent APP Degradation and Inhibition of APP Endocytosis
Authors: Watanabe Tomomichi , Hikichi Yukiko , Willuweit Antje , Shintani Yasushi , Horiguchi Takashi
Published: March 2012

The ubiquitin–proteasome pathway is a major protein degradation pathway whose dysfunction is now widely accepted as a cause of neurodegenerative diseases, including Alzheimer's disease. Here we demonstrate that the F-box and leucine rich repeat protein2 (FBL2), a component of the E3 ubiquitin ligase complex, regulates amyloid precursor protein (APP) metabolism through APP ubiquitination. FBL2 overexpression decreased the amount of secreted amyloid β (Aβ) peptides and sAPPβ, whereas FBL2 mRNA knockdown by siRNA increased these levels. FBL2 overexpression also decreased the amount of intracellular Aβ in Neuro2a cells stably expressing APP with Swedish mutation. FBL2 bound with APP specifically at its C-terminal fragment (CTF), which promoted APP/CTF ubiquitination. FBL2 overexpression also accelerated APP proteasome-dependent degradation and decreased APP protein localization in lipid rafts by inhibiting endocytosis. These effects were not observed in an F-box-deleted FBL2 mutant that does not participate in the E3 ubiquitin ligase complex. Furthermore, a reduced insoluble Aβ and Aβ plaque burden was observed in the hippocampus of 7-month-old FBL2 transgenic mice crossed with double-transgenic mice harboring APPswe and PS1M146Vtransgenes. These findings indicate that FBL2 is a novel and dual regulator of APP metabolism through FBL2-dependent ubiquitination of APP.
Minocycline-Preconditioned Neural Stem Cells Enhance Neuroprotection after Ischemic Stroke in Rats
Authors: Sakata Hiroyuki , Niizuma Kuniyasu , Yoshioka Hideyuki , Kim Gab Seok , Jung Joo Eun , Katsu Masataka , Narasimhan Purnima , Maier Carolina M. , Nishiyama Yasuhiro , Chan Pak H.
Published: March 2012

Transplantation of neural stem cells (NSCs) offers a novel therapeutic strategy for stroke; however, massive grafted cell death following transplantation, possibly due to a hostile host brain environment, lessens the effectiveness of this approach. Here, we have investigated whether reprogramming NSCs with minocycline, a broadly used antibiotic also known to possess cytoprotective properties, enhances survival of grafted cells and promotes neuroprotection in ischemic stroke. NSCs harvested from the subventricular zone of fetal rats were preconditioned with minocyclinein vitroand transplanted into rat brains 6 h after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from days 0–28 after stroke. Forin vitroexperiments, NSCs were subjected to oxygen–glucose deprivation and reoxygenation. Cell viability and antioxidant gene expression were analyzed. Minocycline preconditioning protected the grafted NSCs from ischemic reperfusion injury via upregulation of Nrf2 and Nrf2-regulated antioxidant genes. Additionally, preconditioning with minocycline induced the NSCs to release paracrine factors, including brain-derived neurotrophic factor, nerve growth factor, glial cell-derived neurotrophic factor, and vascular endothelial growth factor. Moreover, transplantation of the minocycline-preconditioned NSCs significantly attenuated infarct size and improved neurological performance, compared with non-preconditioned NSCs. Minocycline-induced neuroprotection was abolished by transfecting the NSCs with Nrf2-small interfering RNA before transplantation. Thus, preconditioning with minocycline, which reprograms NSCs to tolerate oxidative stress after ischemic reperfusion injury and express higher levels of paracrine factors through Nrf2 up-regulation, is a simple and safe approach to enhance the effectiveness of transplantation therapy in ischemic stroke.
Dissociating Modality-Specific and Supramodal Neural Systems for Action Understanding
Authors: Spunt Robert P. , Lieberman Matthew D.
Published: March 2012

The neural basis of action understanding in humans remains disputed, with some research implicating the putative mirror neuron system (MNS) and some a mentalizing system (MZS) for inferring mental states. The basis for this dispute may be that action understanding is a heterogeneous construct: actions can be understood from sensory information about body movements or from language about action, and with the goal of understanding the implementation (“how”) or motive (“why”) of an action. Although extant research implicates the MNS in understanding implementation and the MZS in understanding motive, it remains unknown to what extent these systems subserve modality-specific or supramodal functions in action understanding. While undergoing fMRI, 21 volunteers considered the implementation (“How is she doing it?”) and motive (“Why is she doing it?”) for actions presented in video or text. Bilateral parietal and right frontal areas of the MNS showed a modality-specific association with perceiving actions in videos, while left-hemisphere MNS showed a supramodal association with understanding implementation. Largely left-hemisphere MZS showed a supramodal association with understanding motive; however, connectivity among the MZS and MNS during the inference of motive was modality specific, being significantly stronger when motive was understood from actions in videos compared to text. These results support a tripartite model of MNS and MZS contributions to action understanding, where distinct areas of the MNS contribute to action perception (“perceiving what”) and the representation of action implementation (“knowing how”), while the MZS supports an abstract, modality-independent representation of the mental states that explain action performance (“knowing why”).
A Membrane Pool Retrieved via Endocytosis Overshoot at Nerve Terminals: A Study of Its Retrieval Mechanism and Role
Authors: Xue Lei , McNeil Benjamin D. , Wu Xin-Sheng , Luo Fujun , He Liming , Wu Ling-Gang
Published: March 2012

Endocytosis overshoot, which retrieves more membrane than vesicles just being exocytosed, occurs at nerve terminals and non-neuronal secretory cells. The mechanism that retrieves the overshoot membrane pool and the role of this pool remain largely unknown. We addressed this issue at the rat calyx of Held nerve terminal with capacitance measurements. We found that every calyx contained an overshoot pool ∼1.8 times the readily releasable pool. Retrieval of this pool required large calcium influx, and was inhibited by blockers of calcium/calmodulin-activated calcineurin and dynamin, suggesting the involvement of calcineurin and dynamin in endocytosis overshoot. Depletion of the overshoot pool slowed down compensatory endocytosis, whereas recovery of the overshoot pool via exocytosis that deposited stranded vesicles to the plasma membrane led to recovery of compensatory endocytosis, suggesting that the overshoot pool enhances endocytosis efficiency. These results suggest that the overshoot pool exists at every nerve terminal, is of limited size arising from vesicles stranded at the plasma membrane, is retrieved via calcium/calmodulin/calcineurin and dynamin signaling pathway, and can enhance endocytosis efficiency. Potential mechanisms for how the endocytosis overshoot pool enhances endocytosis efficiency are discussed.
Efficient “Pop-Out” Visual Search Elicits Sustained Broadband Gamma Activity in the Dorsal Attention Network
Authors: Ossandón Tomas , Vidal Juan R. , Ciumas Carolina , Jerbi Karim , Hamamé Carlos M. , Dalal Sarang S. , Bertrand Olivier , Minotti Lorella , Kahane Philippe , Lachaux Jean-Philippe
Published: March 2012

An object that differs markedly from its surrounding—for example, a red cherry among green leaves—seems to pop out effortlessly in our visual experience. The rapid detection of salient targets, independently of the number of other items in the scene, is thought to be mediated by efficient search brain mechanisms. It is not clear, however, whether efficient search is actually an “effortless” bottom-up process or whether it also involves regions of the prefrontal cortex generally associated with top-down sustained attention. We addressed this question with intracranial EEG (iEEG) recordings designed to identify brain regions underlying a classic visual search task and correlate neural activity with target detection latencies on a trial-by-trial basis with high temporal precision recordings of these regions in epileptic patients. The spatio-temporal dynamics of single-trial spectral analysis of iEEG recordings revealed sustained energy increases in a broad gamma band (50–150 Hz) throughout the duration of the search process in the entire dorsal attention network both in efficient and inefficient search conditions. By contrast to extensive theoretical and experimental indications that efficient search relies exclusively on transient bottom-up processes in visual areas, we found that efficient search is mediated by sustained gamma activity in the dorsal lateral prefrontal cortex and the anterior cingulate cortex, alongside the superior parietal cortex and the frontal eye field. Our findings support the hypothesis that active visual search systematically involves the frontal-parietal attention network and therefore, executive attention resources, regardless of target saliency.
Distinct Causal Mechanisms of Attentional Guidance by Working Memory and Repetition Priming in Early Visual Cortex
Authors: Soto David , Llewelyn Dafydd , Silvanto Juha
Published: March 2012

Human attention may be guided by representations held in working memory (WM) and also by priming from implicit memory. Neurophysiological data suggest that WM and priming may be associated with distinct neural mechanisms, but this prior evidence is only correlative. Furthermore, the role of the visual cortex in attention biases from memory remains unclear, because most previous studies conflated memory and selection processes. Here, we manipulated memory and attention in an orthogonal fashion and used an interventional approach to demonstrate the functional significance of WM and priming states in visual cortex for attentional biasing. Observers searched for a Landolt target that was preceded by a nonpredictive color cue that either had to be held in WM for a later recognition test or merely attended (priming counterpart). The application of transcranial magnetic stimulation (TMS) over the occipital cortex modulated the impact of memory on search. Critically, the direction of this modulation depended on the memory state. In the WM condition, the application of TMS on validly cued trials (when the cue surrounded the sought target) enhanced search accuracy relative to the invalid trials (when the cue surrounded a distracter); the opposite pattern was observed in the priming condition. That the effects of occipital TMS on selection were contingent on memory context demonstrates that WM and priming represent distinct states in the early visual cortex that play a causal role in memory-based guidance of attention.
Corticotropin Releasing Factor Signaling in the Central Amygdala is Recruited during Binge-Like Ethanol Consumption in C57BL/6J Mice
Authors: Lowery-Gionta Emily G. , Navarro Montserrat , Li Chia , Pleil Kristen E. , Rinker Jennifer A. , Cox Benjamin R. , Sprow Gretchen M. , Kash Thomas L. , Thiele Todd E.
Published: March 2012

A well established body of work indicates a crucial role for corticotropin-releasing factor (CRF) in neurobiological responses associated with excessive dependence-like ethanol drinking in ethanol-vapor-exposed rodents. Recent evidence demonstrates a role for CRF in the modulation of binge-like ethanol consumption by nondependent mice, a behavior that can precede ethanol dependence. The CRF circuitry that is engaged by binge-like ethanol exposure, however, is unknown. Using converging approaches, we provide evidence that, similar to ethanol-vapor-induced increases in ethanol intake, CRF signaling in the central nucleus of the amygdala (CeA) is engaged during binge-like ethanol consumption by C57BL/6J mice. Specifically, we found that binge-like consumption of an ethanol solution (20% ethanol v/v) was attenuated by pretreatment with the CRF1R antagonists antalarmin, 4-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino-1-butanol, and NBI-27914 at doses (30 mg/kg, i.p.) that did not alter nonbinge-like ethanol consumption. Binge-like ethanol consumption resulted in significant increases of CRF immunoreactivity in the CeA immediately following ethanol drinking and 18–24 h following ethanol removal and also blocked the ability of CRF to enhance GABAergic transmission in the CeA 18–24 h following ethanol removal. Pretreatment with bilateral injections of antalarmin (1 μg/0.5 μl per side) into the CeA, but not the adjacent basolateral amygdala, significantly attenuated binge-like ethanol consumption. These findings suggest that CRF signaling in the CeA is recruited during excessive ethanol intake, before the development of dependence. We hypothesize that plastic changes in CRF signaling develop with repeated binge-like drinking episodes, contributing to the transition to dependence.
Purinergic signalling in the pancreas in health and disease
Authors: Burnstock G , Novak I
Published: March 2012

Pancreatic cells contain specialised stores for ATP. Purinergic receptors (P2 and P1) and ecto-nucleotidases are expressed in both endocrine and exocrine calls, as well as in stromal cells. The pancreas, especially the endocrine cells, were an early target for the actions of ATP. After the historical perspective of purinergic signalling in the pancreas, the focus of this review will be the physiological functions of purinergic signalling in the regulation of both endocrine and exocrine pancreas. Next, we will consider possible interaction between purinergic signalling and other regulatory systems and their relation to nutrient homeostasis and cell survival. The pancreas is an organ exhibiting several serious diseases – cystic fibrosis, pancreatitis, pancreatic cancer and diabetes – and some are associated with changes in life-style and are increasing in incidence. There is upcoming evidence for the role of purinergic signalling in the pathophysiology of the pancreas, and the new challenge is to understand how it is integrated with other pathological processes.
Dopant Uniformity and Concentration in Boron Doped Single Crystal Diamond Films
Authors: Demlow Shannon. N. , Berkun I. , Becker M. , Hogan T. , Grotjohn T.A.
Published: March 2012

High quality single crystal boron-doped diamond films are deposited in a microwave plasma-assisted CVD reactor with feedgas mixtures including hydrogen, methane, diborane, and carbon dioxide at reactor pressures of 160 Torr. The effect of diborane levels and other growth parameters on the incorporated boron levels are investigated, and the doping efficiency is calculated over a wide range of boron concentrations. The boron level is investigated using infrared absorption, and compared to SIMS measurements, and defects are shown to affect the doping uniformity.
Quantifying Protein Adsorption to Physically Crosslinked Gelatin-Based Networks
Authors: Neffe Axel T. , Pierce Benjamin F. , Blaszkiewicz Joanna , Lendlein Andreas
Published: March 2012

Physically crosslinked hydrogels based on gelatin functionalized with desaminotyrosine (DAT) (giving Gel-DAT) or desaminotyrosyl tyrosine (DATT) (resulting in Gel-DATT) have shown high potential as biomaterials. Here, protein adsorption to the functionalized gelatins in comparison to gelatin was quantified to see if the functionalization and chain organization of gelatins has an influence on the amount of proteins being adsorbed. For this purpose, gelatin, Gel-DAT, and Gel-DATT were incubated with water or aq. solutions of bovine serum albumin (BSA), fibrinogen, or fibronectin, respectively, at physiological concentrations. Protein concentrations in the supernatant were determined with the bicinchoninic acid (BCA) assay before and after the contact. BSA adsorption to the materials was influenced as well by the hydrophobicity of the material as the degree of swelling, with the observation that higher protein concentrations led to lower protein adsorption. The highest amount of fibronectin was adsorbed to Gel-DAT, followed by gelatin and Gel-DATT, with only small differences for different initial protein concentrations. Fibrinogen adsorption increased with increasing concentration. In the future, adsorption studies based on specific antibody-based techniques might enable quantification of the proteins also in competition assays and direct quantification of adsorbed material.
Occurrence of Aelurostrongylus abstrusus (Railliet, 1898) larvae (Nematoda: Metastrongylidae) infecting Achatina (Lissachatina) fulica Bowdich, 1822 (Mollusca: Gastropoda) in the Amazon region
Authors: Andrade-Porto Sanny Maria de , Souza Kelly Cristina Pereira de , Cárdenas Melissa Querido , Roque Rosemary A. , Pimpão Daniel Mansur , Araújo Cleusa Suzana , Malta José Celso de Oliveira
Published: March 2012

Achatina fulica or "giant African snail" is an exotic species, considered to be one of the world's hundred most invasive species, causing serious environmental damages. In the present study we report, for the first time, the occurrence of Aelurostrongylus abstrusus infecting A.fulica in the Amazon region. This nematode is described parasitizing mainly the pulmonary system of felines, which causes "aelurostrongilose", also known as feline cardio-pulmonary strongyloidosis. New morphometric data of third stage larvae are presented herein. The present study demonstrated that 40% of all the snails were infected by A. abstrusus. Achatina fulica specimens were collected from three different areas in Manaus namely: rural; east and west areas. The east area presents the highest prevalence of 80%. The large number of A.fulica found in inhabited areas increases the chances of emergent zoonoses, which highlights the need of further studies so as to better control this disease.
Novo gênero Neotropical de Spintharinae (Araneae, Theridiidae)
Authors: Marques Maria Aparecida L. , Buckup Erica Helena , Rodrigues Everton Nei Lopes
Published: March 2012

Neopisinus gen. nov. é proposto com designação da espécie-tipo Neopisisnus fiapo sp. nov., com base em ambos os sexos, do Rio Grande do Sul, Brasil. Neopisinus distingue-se de todos os gêneros de Spintharinae pelo palpo do macho com enorme condutor trífido, com duas projeções afiladas e uma com ápice bifurcado; pela forma característica da apófise tegular de theridioideos com um lobo terminal e outro dorsal. Nas fêmeas, epígino com aberturas inconspícuas junto à fenda transversal no terço anterior e, internamente, por um espessamento mediano-longitudinal tubular, por onde correm os ductos de copulação em seu percurso inicial. Neopisinus urucu sp. nov. é descrita do norte do Brasil, com base em ambos os sexos. Sete espécies são transferidas de Episinus para Neopisinus: N. bigibbosus (O. P.-Cambridge, 1896), N. bruneoviridis (Mello-Leitão, 1948), N. cognatus (O. P.-Cambridge, 1893), N. gratiosus (Bryant, 1940), N. longipes (Keyserling, 1884), N. putus (O. P.-Cambridge, 1894) e N. recifensis (Levi, 1964). São descritos pela primeira vez o macho de N. longipes e a fêmea de N. recifensis. Novas ocorrências e ilustrações são apresentadas para N. bruneoviridis.
Regulação emocional no trabalho: um estudo de caso após desastre aéreo
Authors: Gondim Sonia Maria Guedes , Borges-Andrade Jairo Eduardo
Published: March 2012

Um dos objetivos deste estudo foi analisar as estratégias de regulação emocional dos profissionais de uma empresa aérea brasileira após acidente fatal ocorrido em 2006. Participaram do estudo qualitativo 47 aeroviários: agentes de aeroportos, profissionais de recursos humanos, comandantes, comissários e copilotos. Os dados foram coletados em janeiro de 2007, em entrevistas grupais guiadas por um roteiro semiestruturado. A duração de cada uma delas variou de 1 a 2 horas, e foram realizadas em uma sala no próprio aeroporto ou na sede da empresa. Após esclarecimentos sobre os objetivos da pesquisa e consentimento livre dos participantes, as entrevistas foram gravadas para posterior identificação das demandas de trabalho surgidas após o acidente e das estratégias de regulação emocional usadas. As estratégias de ação profunda (seleção de situação e reavaliação cognitiva) se apresentaram centrais nos discursos dos aeroviários, mais do que as estratégias superficiais (supressão de emoções ou manifestações fisiológicas). Os resultados ainda revelaram que a certeza de que a empresa não tinha culpa no acidente contribuiu positivamente. Mesmo diante de muitas e diversificadas demandas de trabalho emocional, os aeroviários relataram menos impactos negativos em seu bem-estar e mais lealdade organizacional e investimento nas mudanças de seus estados internos emocionais.
Experiência em clínica do trabalho com bancários adoecidos por Ler/ Dort
Authors: Santos Júnior Adalberto Vital dos , Mendes Ana Magnólia , Araujo Luciane Kozicz Reis
Published: March 2012

O estudo apresenta intervenção em clínica do trabalho, com grupos de bancários acometidos de LER/DORT, fundamentada na psicodinâmica do trabalho. Participaram 13 trabalhadores aposentados e afastados do trabalho, subdivididos em dois grupos. Foram realizadas 10 sessões com cada grupo. Os dados produzidos foram examinados com base na análise dos núcleos de sentidos. Os resultados evidenciaram que mecanismos organizacionais, como as promessas simbólicas, estimulam a sobrecarga do corpo para a mediação do medo e da ansiedade, favorecendo o processo de adoecimento. Essa experiência mostrou-se positiva para os participantes ressignificarem seu processo de adoecimento por um espaço de discussão onde as vivências de prazer-sofrimento e os modos de mediação foram compartilhados.
O uso de testes do degrau para a avaliação da capacidade de exercício em pacientes com doenças pulmonares crônicas
Authors: Andrade Carlos Henrique Silva de , Cianci Reinaldo Giovanini , Malaguti Carla , Dal Corso Simone
Published: March 2012

Os testes do degrau são utilizados para avaliar a capacidade física. Devido à diversidade desses testes, o objetivo desta revisão foi descrever os protocolos utilizados em indivíduos saudáveis e naqueles com doença pulmonar crônica. Os testes do degrau utilizados em indivíduos saudáveis tiveram várias modificações ao longo dos anos. Na maioria dos testes, a duração é variável (90 s-10 min), mas a altura do degrau (23,0-50,8 cm) e o ritmo (22,5-35,0 degraus/min) permanecem constantes durante todo o teste. Entretanto, a utilização de uma altura fixa e de ritmo constante pode deixar de promover uma intensidade de trabalho adequada para indivíduos com diferentes níveis de aptidão física, e, portanto, a carga de trabalho pode estar acima ou abaixo da capacidade individual. Dessa forma, os protocolos foram modificados com a introdução de mudanças na altura do degrau e no ritmo durante o teste. Desde o final dos anos 70, os testes do degrau têm sido utilizados em pacientes com doenças pulmonares crônicas. Os protocolos são diversificados, com ajustes na altura do degrau (15-30 cm), ritmo (autocadenciado ou externamente cadenciado) e duração (90 s-10 min). Entretanto, a diversidade desses protocolos e a variedade de desfechos estudados impedem a determinação do melhor protocolo a ser utilizado em indivíduos com doenças pulmonares crônicas. Parece que os protocolos mais curtos com elevado ritmo seriam mais adequados para avaliar a dessaturação de oxigênio relacionada ao exercício na doença pulmonar crônica. Testes limitados por sintomas seriam mais apropriados para avaliar a tolerância ao exercício. São necessários estudos comparando diferentes protocolos de teste do degrau em relação a sua reprodutibilidade, validade e habilidade de quantificar respostas a intervenções, especialmente em indivíduos com doença pulmonar.
An Evaluation of Communication Apprehension in Adolescents with Velopharyngeal Inadequacy
Authors: Dzioba Agnieszka , Husein Murad , Dworschak-Stokan Anne , Doyle Philip C.
Published: March 2012

Objective

This investigation evaluated the construct of communication apprehension (CA) in adolescents with velopharyngeal inadequacy (VPI).

Design

Prospective comparative study.

Settings

The investigation was conducted in a hospital-based clinic, voice laboratory, and the homes of participants.

Participants

Two groups of children participated in this study. The first group was composed of 14 children between the ages of 8 and 14 years who attended the velopharyngeal inadequacy (VPI) clinic at our institution, and the second group was composed of 14 age-matched children from the community with no history of speech or voice disorders.

Interventions

The study involved completion of the Measure of Elementary Communication Apprehension (MECA) by all 28 participants (14 experimental and 14 control subjects). Reliability of the subjects’ responses to the MECA was also evaluated.

Outcome Measures

Communication apprehension scores obtained from the MECA were the main focus of the study.

Results

Children with VPI experienced significantly higher levels of CA than did those in the control group. Moderate-to-good reliability of the MECA was found.

Conclusions

Based on these data, children with VPI may be experiencing increased levels of CA. Consequently, the experience of high CA has the potential to affect the communication performance and social functioning of children with VPI.