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Find video protocols related to scientific articles indexed in Pubmed.
Effects of Performance Measure Implementation on Clinical Manager and Provider Motivation.
J Gen Intern Med
PUBLISHED: 09-20-2014
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Clinical performance measurement has been a key element of efforts to transform the Veterans Health Administration (VHA). However, there are a number of signs that current performance measurement systems used within and outside the VHA may be reaching the point of maximum benefit to care and in some settings, may be resulting in negative consequences to care, including overtreatment and diminished attention to patient needs and preferences. Our research group has been involved in a long-standing partnership with the office responsible for clinical performance measurement in the VHA to understand and develop potential strategies to mitigate the unintended consequences of measurement.
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Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension.
Hypertension
PUBLISHED: 09-15-2014
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Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin-converting enzyme 2 (ACE2) and its enzymatic product, angiotensin-(1-7) [Ang-(1-7)] contribute to the pathogenesis of pulmonary hypertension (PH). However, long-term repetitive delivery of ACE2 or Ang-(1-7) would require enhanced protein stability and ease of administration to improve patient compliance. Chloroplast expression of therapeutic proteins enables their bioencapsulation within plant cells to protect against gastric enzymatic degradation and facilitates long-term storage at room temperature. Besides, fusion to a transmucosal carrier helps effective systemic absorption from the intestine on oral delivery. We hypothesized that bioencapsulating ACE2 or Ang-(1-7) fused to the cholera nontoxin B subunit would enable development of an oral delivery system that is effective in treating PH. PH was induced in male Sprague Dawley rats by monocrotaline administration. Subset of animals was simultaneously treated with bioencapsulaed ACE2 or Ang-(1-7) (prevention protocol). In a separate set of experiments, drug treatment was initiated after 2 weeks of PH induction (reversal protocol). Oral feeding of rats with bioencapsulated ACE2 or Ang-(1-7) prevented the development of monocrotaline-induced PH and improved associated cardiopulmonary pathophysiology. Furthermore, in the reversal protocol, oral ACE2 or Ang-(1-7) treatment significantly arrested disease progression, along with improvement in right heart function, and decrease in pulmonary vessel wall thickness. In addition, a combination therapy with ACE2 and Ang-(1-7) augmented the beneficial effects against monocrotaline-induced lung injury. Our study provides proof-of-concept for a novel low-cost oral ACE2 or Ang-(1-7) delivery system using transplastomic technology for pulmonary disease therapeutics.
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Nodding syndrome-a new hypothesis and new direction for research.
Int. J. Infect. Dis.
PUBLISHED: 08-23-2014
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Nodding syndrome (NS) is an unexplained neurological illness that mainly affects children aged between 5 and 15 years. NS has so far been reported from South Sudan, northern Uganda, and Tanzania, but in spite of extensive investigations, the aetiology remains unknown. We hypothesize that blackflies (Diptera: Simuliidae) infected with Onchocerca volvulus microfilariae may also transmit another pathogen. This may be a novel neurotropic virus or an endosymbiont of the microfilariae, which causes not only NS, but also epilepsy without nodding. This hypothesis addresses many of the questions about NS that researchers have previously been unable to answer. An argument in favour of the hypothesis is the fact that in Uganda, the number of new NS cases decreased (with no new cases reported since 2013) after ivermectin coverage was increased and with the implementation of a programme of aerial spraying and larviciding of the large rivers where blackflies were breeding. If confirmed, our hypothesis will enable new strategies to control NS outbreaks.
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Differential effects of sertraline in a predator exposure animal model of post-traumatic stress disorder.
Front Behav Neurosci
PUBLISHED: 07-30-2014
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Serotonin (5-HT), norepinephrine (NE), and other neurotransmitters are modulated in post-traumatic stress disorder (PTSD). In addition, pro-inflammatory cytokines (PIC) are elevated during the progression of the disorder. Currently, the only approved pharmacologic treatments for PTSD are the selective-serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, but their efficacy in treating PTSD is marginal at best. In combat-related PTSD, SSRIs are of limited effectiveness. Thus, this study sought to analyze the effects of the SSRI sertraline on inflammation and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. We hypothesized that sertraline would diminish inflammatory components and increase 5-HT but might also affect levels of other neurotransmitters, particularly NE. PTSD-like effects were induced in male Sprague-Dawley rats (n = 6/group × 4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1 h on days 1 and 11 of a 31-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, treatment group animals were injected intraperitoneally (i.p.) with sertraline HCl at 10 mg/kg for 7 consecutive days, while controls received i.p. vehicle. The animals were subsequently sacrificed on day 8. Sertraline attenuated inflammatory markers and normalized 5-HT levels in the central nervous system (CNS). In contrast, sertraline produced elevations in NE in the CNS and systemic circulation of SSRI treated PTSD and control groups. This increase in NE suggests SSRIs produce a heightened noradrenergic response, which might elevate anxiety in a clinical setting.
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Insights from advanced analytics at the Veterans Health Administration.
Health Aff (Millwood)
PUBLISHED: 07-10-2014
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Health care has lagged behind other industries in its use of advanced analytics. The Veterans Health Administration (VHA) has three decades of experience collecting data about the veterans it serves nationwide through locally developed information systems that use a common electronic health record. In 2006 the VHA began to build its Corporate Data Warehouse, a repository for patient-level data aggregated from across the VHA's national health system. This article provides a high-level overview of the VHA's evolution toward "big data," defined as the rapid evolution of applying advanced tools and approaches to large, complex, and rapidly changing data sets. It illustrates how advanced analysis is already supporting the VHA's activities, which range from routine clinical care of individual patients--for example, monitoring medication administration and predicting risk of adverse outcomes--to evaluating a systemwide initiative to bring the principles of the patient-centered medical home to all veterans. The article also shares some of the challenges, concerns, insights, and responses that have emerged along the way, such as the need to smoothly integrate new functions into clinical workflow. While the VHA is unique in many ways, its experience may offer important insights for other health care systems nationwide as they venture into the realm of big data.
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Congenital intestinal duplication in an adult.
J. Gastrointest. Surg.
PUBLISHED: 05-16-2014
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Congenital intestinal duplication is an anomaly most commonly diagnosed in children under the age of 2. Rarely, it is seen in adults who remain asymptomatic or present with vague abdominal symptoms. Here, we describe the case of a 33-year-old female who was diagnosed intraoperatively with congenital intestinal duplication after suffering from a year of vague abdominal complaints.
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Motor cortex microcircuit simulation based on brain activity mapping.
Neural Comput
PUBLISHED: 04-07-2014
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The deceptively simple laminar structure of neocortex belies the complexity of intra- and interlaminar connectivity. We developed a computational model based primarily on a unified set of brain activity mapping studies of mouse M1. The simulation consisted of 775 spiking neurons of 10 cell types with detailed population-to-population connectivity. Static analysis of connectivity with graph-theoretic tools revealed that the corticostriatal population showed strong centrality, suggesting that would provide a network hub. Subsequent dynamical analysis confirmed this observation, in addition to revealing network dynamics that cannot be readily predicted through analysis of the wiring diagram alone. Activation thresholds depended on the stimulated layer. Low stimulation produced transient activation, while stronger activation produced sustained oscillations where the threshold for sustained responses varied by layer: 13% in layer 2/3, 54% in layer 5A, 25% in layer 5B, and 17% in layer 6. The frequency and phase of the resulting oscillation also depended on stimulation layer. By demonstrating the effectiveness of combined static and dynamic analysis, our results show how static brain maps can be related to the results of brain activity mapping.
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Neural decoding with kernel-based metric learning.
Neural Comput
PUBLISHED: 03-31-2014
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In studies of the nervous system, the choice of metric for the neural responses is a pivotal assumption. For instance, a well-suited distance metric enables us to gauge the similarity of neural responses to various stimuli and assess the variability of responses to a repeated stimulus-exploratory steps in understanding how the stimuli are encoded neurally. Here we introduce an approach where the metric is tuned for a particular neural decoding task. Neural spike train metrics have been used to quantify the information content carried by the timing of action potentials. While a number of metrics for individual neurons exist, a method to optimally combine single-neuron metrics into multineuron, or population-based, metrics is lacking. We pose the problem of optimizing multineuron metrics and other metrics using centered alignment, a kernel-based dependence measure. The approach is demonstrated on invasively recorded neural data consisting of both spike trains and local field potentials. The experimental paradigm consists of decoding the location of tactile stimulation on the forepaws of anesthetized rats. We show that the optimized metrics highlight the distinguishing dimensions of the neural response, significantly increase the decoding accuracy, and improve nonlinear dimensionality reduction methods for exploratory neural analysis.
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Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension.
Cardiovasc. Res.
PUBLISHED: 03-25-2014
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Understanding the novel signalling pathways involved in the pathogenesis of hypertension is vital for the development of effective therapeutic strategies. Recent evidence suggests a role for Toll-like receptor (TLR) 4 in the development of cardiovascular diseases. Although brain has been implicated in the pathogenesis of hypertension, the role of brain TLR4 in hypertension is largely unexplored. Therefore, we investigated the role of brain TLR4 in angiotensin (Ang) II-induced hypertension and whether central TLR4 blockade has cardioprotective effects in hypertension.
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Serial assessment of weight-bearing lower extremity alignment radiographs after open-wedge high tibial osteotomy.
Arthroscopy
PUBLISHED: 03-04-2014
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The purpose of this study was to perform a serial assessment of the radiologic parameters of the mechanical axis (MA) and the weight-bearing line (WBL) using a weight-bearing anteroposterior (AP) long-standing view of the lower extremity to determine whether the postoperative MA and WBL change with time.
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Role of TLR4 in lipopolysaccharide-induced acute kidney injury: protection by blueberry.
Free Radic. Biol. Med.
PUBLISHED: 02-19-2014
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Inflammation has been implicated in the pathophysiology of kidney disorders. Previous studies have documented the contributions of various inflammatory cascades in the development of kidney and other organ dysfunctions. The Toll-like receptor 4 (TLR4) inflammatory pathway is a major contributor of inflammation in the kidney. Interestingly, lipopolysaccharide (LPS), a specific ligand for TLR4, has been shown to induce acute kidney injury (AKI) in animal models. We have previously studied the beneficial effects of nonpharmacological agents, particularly blueberries (BB), in attenuating inflammation and oxidative stress. We hypothesize that BB protect against the LPS-induced AKI by inhibiting TLR4 activation and kidney injury markers. Twelve-week-old male Sprague-Dawley rats received a BB solution or saline intragastric gavage for 2 days. One group of BB and saline-gavaged animals was injected with LPS (10 mg/kg bw). Another group of rats was injected with VIPER (0.1 mg/kg iv), a TLR4-specific inhibitory peptide, 2 h before LPS administration. Compared to LPS-administered rats, the BB-pretreated animals exhibited improved glomerular filtration rate, elevated renal blood flow, and a reduced renal vascular resistance. In addition, a reduction in the rate of production of free radicals, namely total reactive oxygen species (ROS) and superoxide, was observed in the BB-supplemented LPS group. Gene and protein expressions for TLR4, proinflammatory cytokine, and acute kidney injury markers were also attenuated in animals that were pretreated with BB as measured by real time RT-PCR and Western blotting, respectively. These results in the BB-pretreated group were consistent with those in the VIPER-treated rats, and indicate that BB protects against AKI by inhibiting TLR4 and its subsequent effect on inflammatory and oxidative stress pathways.
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A tensor-product-kernel framework for multiscale neural activity decoding and control.
Comput Intell Neurosci
PUBLISHED: 01-28-2014
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Brain machine interfaces (BMIs) have attracted intense attention as a promising technology for directly interfacing computers or prostheses with the brain's motor and sensory areas, thereby bypassing the body. The availability of multiscale neural recordings including spike trains and local field potentials (LFPs) brings potential opportunities to enhance computational modeling by enriching the characterization of the neural system state. However, heterogeneity on data type (spike timing versus continuous amplitude signals) and spatiotemporal scale complicates the model integration of multiscale neural activity. In this paper, we propose a tensor-product-kernel-based framework to integrate the multiscale activity and exploit the complementary information available in multiscale neural activity. This provides a common mathematical framework for incorporating signals from different domains. The approach is applied to the problem of neural decoding and control. For neural decoding, the framework is able to identify the nonlinear functional relationship between the multiscale neural responses and the stimuli using general purpose kernel adaptive filtering. In a sensory stimulation experiment, the tensor-product-kernel decoder outperforms decoders that use only a single neural data type. In addition, an adaptive inverse controller for delivering electrical microstimulation patterns that utilizes the tensor-product kernel achieves promising results in emulating the responses to natural stimulation.
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Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder.
Behav. Brain Res.
PUBLISHED: 01-28-2014
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Reactive oxygen species (ROS) and pro-inflammatory cytokines (PIC) are upregulated in post-traumatic stress disorder (PTSD). Histone deacetylase inhibitors (HDACi) modify genetic transcription and can diminish ROS and PIC escalation. They can also modulate levels of neurotransmitters such as catecholamines and serotonin (5-HT). Thus, this study sought to analyze the effects of the HDACi valproic acid (VA) on oxidative stress, inflammation, and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. PTSD-like effects were induced in male Sprague-Dawley rats (n=6/group×4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1h on days 1, 11, and 40 of a 40-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, the treatment group (PTSD+VA) and control group (Control+VA) rats were given VA in their drinking water for 30 days. The rats were then euthanized and their brains were dissected to remove the hippocampus and prefrontal cortex (PFC). Whole blood was collected to assess systemic oxidative stress. ROS and PIC mRNA and protein elevation in the PTSD group were normalized with VA. Anxiety decreased in this group via improved performance on the elevated plus-maze (EPM). No changes were attributed to VA in the control group, and no improvements were noted in the vehicle groups. Results indicate VA can attenuate oxidative stress and inflammation, enhance fear extinction, and correct neurotransmitter aberrancies in a rat model of PTSD.
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Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards.
Mol Autism
PUBLISHED: 01-17-2014
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There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI).
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Emerging concepts in hypertension.
Antioxid. Redox Signal.
PUBLISHED: 01-08-2014
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Cellular redox balance is vital in health and disease. In this Forum, we highlight the importance of reactive oxygen species (ROS) in the regulation of redox balance in different organ systems of the body and ROS contribution to the development of hypertension. The Forum examines interactions between oxidative and nitrosative stress in the brain, vasculature, and kidney, and redox effect on end-organ damage and hypertension. Furthermore, the Forum examines the role of immune cells in the modulation of hypertension. We also introduce a new role for endoplasmic reticulum stress in the induction of ROS and its possible contribution to the development of hypertension. Finally, we explore the clinical relevance of increased ROS in the setting of human hypertension.
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A Blueberry-Enriched Diet Improves Renal Function and Reduces Oxidative Stress in Metabolic Syndrome Animals: Potential Mechanism of TLR4-MAPK Signaling Pathway.
PLoS ONE
PUBLISHED: 01-01-2014
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Metabolic syndrome (MetS) is characterized by a cluster of health factors that indicate a higher risk for cardio-renal diseases. Recent evidence indicates that antioxidants from berries are alternative to attenuate oxidative stress and inflammation. We tested the hypothesis that inflammation-induced renal damage is triggered by the activation of TLR4, and subsequent modulation of redox-sensitive molecules and mitogen-activated protein kinase (MAPK) pathway.
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Predator exposure/psychosocial stress animal model of post-traumatic stress disorder modulates neurotransmitters in the rat hippocampus and prefrontal cortex.
PLoS ONE
PUBLISHED: 01-01-2014
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Post-Traumatic Stress Disorder (PTSD) can develop in response to a traumatic event involving a threat to life. To date, no diagnostic biomarkers have been identified for PTSD. Recent research points toward physiological abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, sympathoadrenal medullary and immune system that may be implicated in the disorder. The modulation of neurotransmitters is another possible mechanism, but their role in the progression of PTSD is poorly understood. Low serotonin (5-HT) may be a factor, but it may not be the only neurotransmitter affected as modulation affects levels of other neurotransmitters. In this study, we hypothesized the predator exposure/psychosocial stress rodent model of PTSD may alter levels of 5-HT and other neurotransmitters in the rat hippocampus and prefrontal cortex (PFC). Male Sprague-Dawley rats were used in this experiment. We induced PTSD via a predator exposure/psychosocial stress model, whereby rats were placed in a cage with a cat for 1 hour on days 1 and 11 of the 31-day experiment. Rats also received psychosocial stress via daily cage cohort changes. On day 32, the rats were sacrificed and the brains dissected to remove the hippocampus and PFC. Norepinephrine (NE), 5-Hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), dopamine (DA), and 3,4-Dihydroxyphenylacetic acid (DOPAC), and 5-HT levels in the hippocampus and PFC were measured with high-performance liquid chromatography (HPLC). In the hippocampus, 5-HT and HVA were lower, while NE and DOPAC were higher, in the PTSD group vs. controls. In the PFC, only 5-HT was lower, while NE, DA, and DOPAC were higher, in the PTSD group vs. controls. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also examined and confirmed our findings. These results demonstrate that the predator exposure/psychosocial stress model of PTSD produces neurotransmitter changes similar to those seen in human patients and may cause a heightened noradrenergic response.
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Alarming epidemics of human immunodeficiency virus and hepatitis C virus among injection drug users in the northwestern bordering state of Punjab, India: prevalence and correlates.
Int J STD AIDS
PUBLISHED: 12-18-2013
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In this study 1155 injection drug users receiving targeted intervention in five cities of Punjab were surveyed; three cities (Amritsar, Taran-Taran, Batala) were in districts sharing international border with Pakistan and the rest two were Jalandhar and Ludhiana. Information on socio-demography, substance use and sexual practices were collected; blood samples were tested for biologic markers. HIV and HCV antibody (HCVAb) prevalence in injection drug users were 29 and 49%, respectively. Of the HCVAb seroreactive injection drug users, 33% had HIV as well. HIV prevalence in young injection drug users (?19 years), estimated as surrogate for HIV incidence, was high at 12% and HCVAb in this subgroup was 27%. Herpes simplex virus 2 antibody (IgG) was detected in 10% injection drug users; 2% had syphilis. Alcohol use prevalence was high and frequency of use concerning. In multivariate analyses, city of residence closer to international border and >1 year duration of injecting drug were associated with HIV and HCVAb. Furthermore, irregular supply of syringes and needles was associated with HCVAb seroreactive status of injection drug users (adjusted odds ratio 1.7; 95% CI 1.3-2.3; P?
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Information-theoretic metric learning: 2-D linear projections of neural data for visualization.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 10-11-2013
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Intracortical neural recordings are typically high-dimensional due to many electrodes, channels, or units and high sampling rates, making it very difficult to visually inspect differences among responses to various conditions. By representing the neural response in a low-dimensional space, a researcher can visually evaluate the amount of information the response carries about the conditions. We consider a linear projection to 2-D space that also parametrizes a metric between neural responses. The projection, and corresponding metric, should preserve class-relevant information pertaining to different behavior or stimuli. We find the projection as a solution to the information-theoretic optimization problem of maximizing the information between the projected data and the class labels. The method is applied to two datasets using different types of neural responses: motor cortex neuronal firing rates of a macaque during a center-out reaching task, and local field potentials in the somatosensory cortex of a rat during tactile stimulation of the forepaw. In both cases, projected data points preserve the natural topology of targets or peripheral touch sites. Using the learned metric on the neural responses increases the nearest-neighbor classification rate versus the original data; thus, the metric is tuned to distinguish among the conditions.
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Cholera surveillance in Uganda: an analysis of notifications for the years 2007-2011.
J. Infect. Dis.
PUBLISHED: 10-09-2013
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Cholera outbreaks have occurred periodically in Uganda since 1971. The country has experienced intervals of sporadic cases and localized outbreaks, occasionally resulting in prolonged widespread epidemics.
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Reinforcement learning of two-joint virtual arm reaching in a computer model of sensorimotor cortex.
Neural Comput
PUBLISHED: 09-18-2013
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Neocortical mechanisms of learning sensorimotor control involve a complex series of interactions at multiple levels, from synaptic mechanisms to cellular dynamics to network connectomics. We developed a model of sensory and motor neocortex consisting of 704 spiking model neurons. Sensory and motor populations included excitatory cells and two types of interneurons. Neurons were interconnected with AMPA/NMDA and GABAA synapses. We trained our model using spike-timing-dependent reinforcement learning to control a two-joint virtual arm to reach to a fixed target. For each of 125 trained networks, we used 200 training sessions, each involving 15 s reaches to the target from 16 starting positions. Learning altered network dynamics, with enhancements to neuronal synchrony and behaviorally relevant information flow between neurons. After learning, networks demonstrated retention of behaviorally relevant memories by using proprioceptive information to perform reach-to-target from multiple starting positions. Networks dynamically controlled which joint rotations to use to reach a target, depending on current arm position. Learning-dependent network reorganization was evident in both sensory and motor populations: learned synaptic weights showed target-specific patterning optimized for particular reach movements. Our model embodies an integrative hypothesis of sensorimotor cortical learning that could be used to interpret future electrophysiological data recorded in vivo from sensorimotor learning experiments. We used our model to make the following predictions: learning enhances synchrony in neuronal populations and behaviorally relevant information flow across neuronal populations, enhanced sensory processing aids task-relevant motor performance and the relative ease of a particular movement in vivo depends on the amount of sensory information required to complete the movement.
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Tactile information processing in primate hand somatosensory cortex (S1) during passive arm movement.
J. Neurophysiol.
PUBLISHED: 08-14-2013
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Motor output mostly depends on sensory input, which also can be affected by action. To further our understanding of how tactile information is processed in the primary somatosensory cortex (S1) in dynamic environments, we recorded neural responses to tactile stimulation of the hand in three awake monkeys under arm/hand passive movement and rest. We found that neurons generally responded to tactile stimulation under both conditions and were modulated by movement: with a higher baseline firing rate, a suppressed peak rate, and a smaller dynamic range during passive movement than during rest, while the area under the response curve was stable across these two states. By using an information theory-based method, the mutual information between tactile stimulation and neural responses was quantified with rate and spatial coding models under the two conditions. The two potential encoding models showed different contributions depending on behavioral contexts. Tactile information encoded with rate coding from individual units was lower than spatial coding of unit pairs, especially during movement; however, spatial coding had redundant information between unit pairs. Passive movement regulated the mutual information, and such regulation might play different roles depending on the encoding strategies used. The underlying mechanisms of our observation most likely come from a bottom-up strategy, where neurons in S1 were regulated through the activation of the peripheral tactile/proprioceptive receptors and the interactions between these different types of information.
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Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A).
PLoS Pathog.
PUBLISHED: 05-01-2013
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Botulinum neurotoxin serotype A (BoNT/A) causes transient muscle paralysis by entering motor nerve terminals (MNTs) where it cleaves the SNARE protein Synaptosomal-associated protein 25 (SNAP25206) to yield SNAP25197. Cleavage of SNAP25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. The specific uptake of BoNT/A into pre-synaptic nerve terminals is a tightly controlled multistep process, involving a combination of high and low affinity receptors. Interestingly, the C-terminal binding domain region of BoNT/A, HC/A, is homologous to fibroblast growth factors (FGFs), making it a possible ligand for Fibroblast Growth Factor Receptors (FGFRs). Here we present data supporting the identification of Fibroblast Growth Factor Receptor 3 (FGFR3) as a high affinity receptor for BoNT/A in neuronal cells. HC/A binds with high affinity to the two extra-cellular loops of FGFR3 and acts similar to an agonist ligand for FGFR3, resulting in phosphorylation of the receptor. Native ligands for FGFR3; FGF1, FGF2, and FGF9 compete for binding to FGFR3 and block BoNT/A cellular uptake. These findings show that FGFR3 plays a pivotal role in the specific uptake of BoNT/A across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions.
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The rat Digit Abduction Score (DAS) assay: a physiological model for assessing botulinum neurotoxin-induced skeletal muscle paralysis.
Toxicon
PUBLISHED: 02-26-2013
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Botulinum neurotoxins (BoNT) are approved for a number of therapeutic indications, including blepharospasm, cervical dystonia and hyperhidrosis, and have also shown efficacy in a variety of pain disorders. The potency of any given BoNT preparation can be routinely assessed by using the Digit Abduction Score (DAS) assay, which measures the local muscle weakening efficacy of BoNT following injection into mouse hindlimb muscle. While most studies have employed mice to assess BoNT efficacy in the DAS, few have utilized rats. In this study, we applied the DAS assay to a rat model and compared the potency of IM-BOTOX(®) (onabotulinumtoxinA) injections between two separate hind limb muscles, gastrocnemius and tibialis anterior (TA). The results demonstrated that the DAS assay can be performed on rats with similar criteria and parameters as for mice. Moreover in the rat, BoNT can be injected into either the gastrocnemius or TA muscle to elicit similar DAS scoring responses. Interestingly, onabotulinumtoxinA potency in the rat DAS was ?3-fold higher following TA injections than gastrocnemius injections. Additionally, our data showed that the durational kinetics of onabotulinumtoxinA in the rat DAS are approximately twice as long as in the mouse DAS. These results position the rat DAS as a more flexible model for examining the mechanisms of BoNT diffusion and muscle paralysis, while mouse DAS can be used for physiological screening of BoNT because of the potential for higher throughput. Overall, these data confirm the utility of the DAS assay for characterizing the physiological potency of BoNT and related compounds.
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(Pro)renin receptor mediates both angiotensin II-dependent and -independent oxidative stress in neuronal cells.
PLoS ONE
PUBLISHED: 02-02-2013
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The binding of renin or prorenin to the (pro)renin receptor (PRR) promotes angiotensin (Ang) II formation and mediates Ang II-independent signaling pathways. In the central nervous system (CNS), Ang II regulates blood pressure via inducing oxidative stress; however, the role of PRR-mediated Ang II-independent signaling pathways in oxidative stress in the CNS remains undefined. To address this question, Neuro-2A cells were infected with control virus or an adeno-associated virus encoding the human PRR. Human PRR over-expression alone increased ROS levels, NADPH oxidase activity, as well as NADPH oxidase (NOX) isoforms 2 and 4 mRNA expression levels and these effects were not blocked by losartan. Moreover, the increase in NOX 2 and NOX 4 mRNA levels, NADPH oxidase activity, and ROS levels induced by PRR over-expression was prevented by mitogen activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MAPK/ERK1/2) inhibition, and phosphoinositide 3 kinase/Akt (IP3/Akt) inhibition, indicating that PRR regulates NOX activity and ROS formation in neuro-2A cells through Ang II-independent ERK1/2 and IP3/Akt activation. Interestingly, at a concentration of 2 nM or higher, prorenin promoted Ang II formation, and thus further increased the ROS levels in cultured Neuro-2A cells via PRR. In conclusion, human PRR over-expression induced ROS production through both angiotensin II-dependent and -independent mechanisms. We showed that PRR-mediated angiotensin II-independent ROS formation is associated with activation of the MAPK/ERK1/2 and PI3/Akt signaling pathways and up-regulation of mRNA level of NOX 2 and NOX4 isoforms in neuronal cells.
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Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 01-31-2013
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Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "off-target" effect of enhancing the enzymatic activity of ACE2 in vitro.
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SMART Syndrome (Stroke-Like Migraine Attacks After Radiation Therapy) in Adult and Pediatric Patients.
J. Child Neurol.
PUBLISHED: 01-29-2013
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SMART syndrome (stroke-like migraine attacks after radiation therapy) is a rare condition that involves complex migraines with focal neurologic findings in patients following cranial irradiation for central nervous system malignancies. Little is known about the mechanisms behind the disorder, making successful treatment challenging. We report 2 new cases of SMART syndrome in pediatric patients as well as review all documented cases of the syndrome. Each of our 2 pediatric patients suffered multiple episodes. Attacks were characterized by severe headache, visual disturbance, aphasia, and weakness. Recovery occurred over several days to weeks. The data from all documented reports of SMART syndrome indicate a greater prevalence for male gender. An age-dependent pattern of onset was also observed, with a greater variability of syndrome onset in patients who received cranial irradiation at a younger age. SMART appears to be a reversible, recurrent long-term complication of radiation therapy with possible age- and gender-related influences.
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Cortical plasticity induced by spike-triggered microstimulation in primate somatosensory cortex.
PLoS ONE
PUBLISHED: 01-24-2013
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Electrical stimulation of the nervous system for therapeutic purposes, such as deep brain stimulation in the treatment of Parkinsons disease, has been used for decades. Recently, increased attention has focused on using microstimulation to restore functions as diverse as somatosensation and memory. However, how microstimulation changes the neural substrate is still not fully understood. Microstimulation may cause cortical changes that could either compete with or complement natural neural processes, and could result in neuroplastic changes rendering the region dysfunctional or even epileptic. As part of our efforts to produce neuroprosthetic devices and to further study the effects of microstimulation on the cortex, we stimulated and recorded from microelectrode arrays in the hand area of the primary somatosensory cortex (area 1) in two awake macaque monkeys. We applied a simple neuroprosthetic microstimulation protocol to a pair of electrodes in the area 1 array, using either random pulses or pulses time-locked to the recorded spiking activity of a reference neuron. This setup was replicated using a computer model of the thalamocortical system, which consisted of 1980 spiking neurons distributed among six cortical layers and two thalamic nuclei. Experimentally, we found that spike-triggered microstimulation induced cortical plasticity, as shown by increased unit-pair mutual information, while random microstimulation did not. In addition, there was an increased response to touch following spike-triggered microstimulation, along with decreased neural variability. The computer model successfully reproduced both qualitative and quantitative aspects of the experimental findings. The physiological findings of this study suggest that even simple microstimulation protocols can be used to increase somatosensory information flow.
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Towards a naturalistic brain-machine interface: hybrid torque and position control allows generalization to novel dynamics.
PLoS ONE
PUBLISHED: 01-24-2013
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Realization of reaching and grasping movements by a paralytic person or an amputee would greatly facilitate her/his activities of daily living. Towards this goal, control of a computer cursor or robotic arm using neural signals has been demonstrated in rodents, non-human primates and humans. This technology is commonly referred to as a Brain-Machine Interface (BMI) and is achieved by predictions of kinematic parameters, e.g. position or velocity. However, execution of natural movements, such as swinging baseball bats of different weights at the same speed, requires advanced planning for necessary context-specific forces in addition to kinematic control. Here we show, for the first time, the control of a virtual arm with representative inertial parameters using real-time neural control of torques in non-human primates (M. radiata). We found that neural control of torques leads to ballistic, possibly more naturalistic movements than position control alone, and that adding the influence of position in a hybrid torque-position control changes the feedforward behavior of these BMI movements. In addition, this level of control was achievable utilizing the neural recordings from either contralateral or ipsilateral M1. We also observed changed behavior of hybrid torque-position control under novel external dynamic environments that was comparable to natural movements. Our results demonstrate that inclusion of torque control to drive a neuroprosthetic device gives the user a more direct handle on the movement execution, especially when dealing with novel or changing dynamic environments. We anticipate our results to be a starting point of more sophisticated algorithms for sensorimotor neuroprostheses, eliminating the need of fully automatic kinematic-to-dynamic transformations as currently used by traditional kinematic-based decoders. Thus, we propose that direct control of torques, or other force related variables, should allow for more natural neuroprosthetic movements by the user.
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Angiotensin II causes imbalance between pro- and anti-inflammatory cytokines by modulating GSK-3? in neuronal culture.
Br. J. Pharmacol.
PUBLISHED: 01-10-2013
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Emerging evidence indicates that the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines (AICs) within the brain is an important determinant in the outcome of hypertension. However, the mechanism by which this dysregulation occurs is not known. We aimed to investigate whether AngII induces imbalance between PIC and AIC by modulating downstream transcription factors, NF?B and cyclic AMP response element-binding protein (CREB), and whether AngII-induced effects are mediated by glycogen synthase kinase-3? (GSK-3?).
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Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model.
PLoS ONE
PUBLISHED: 01-01-2013
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This study sought to analyze specific pathophysiological mechanisms involved in the progression of post-traumatic stress disorder (PTSD) by utilizing an animal model. To examine PTSD pathophysiology, we measured damaging reactive oxygen species and inflammatory cytokines to determine if oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation were upregulated in response to constant stress. Pre-clinical PTSD was induced in naïve, male Sprague-Dawley rats via a predator exposure/psychosocial stress regimen. PTSD group rats were secured in Plexiglas cylinders and placed in a cage with a cat for one hour on days 1 and 11 of a 31-day stress regimen. In addition, PTSD group rats were subjected to psychosocial stress whereby their cage cohort was changed daily. This model has been shown to cause heightened anxiety, exaggerated startle response, impaired cognition, and increased cardiovascular reactivity, all of which are common symptoms seen in humans with PTSD. At the conclusion of the predator exposure/psychosocial stress regimen, the rats were euthanized and their brains were dissected to remove the hippocampus, amygdala, and pre-frontal cortex (PFC), the three areas commonly associated with PTSD development. The adrenal glands and whole blood were also collected to assess systemic oxidative stress. Analysis of the whole blood, adrenal glands, and brain regions revealed oxidative stress increased during PTSD progression. In addition, examination of pro-inflammatory cytokine (PIC) mRNA and protein demonstrated neurological inflammatory molecules were significantly upregulated in the PTSD group vs. controls. These results indicate oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation may play a critical role in the development and further exacerbation of PTSD. Thus, PTSD may not be solely a neurological pathology but may progress as a systemic condition involving multiple organ systems.
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Use of frontal lobe hemodynamics as reinforcement signals to an adaptive controller.
PLoS ONE
PUBLISHED: 01-01-2013
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Decision-making ability in the frontal lobe (among other brain structures) relies on the assignment of value to states of the animal and its environment. Then higher valued states can be pursued and lower (or negative) valued states avoided. The same principle forms the basis for computational reinforcement learning controllers, which have been fruitfully applied both as models of value estimation in the brain, and as artificial controllers in their own right. This work shows how state desirability signals decoded from frontal lobe hemodynamics, as measured with near-infrared spectroscopy (NIRS), can be applied as reinforcers to an adaptable artificial learning agent in order to guide its acquisition of skills. A set of experiments carried out on an alert macaque demonstrate that both oxy- and deoxyhemoglobin concentrations in the frontal lobe show differences in response to both primarily and secondarily desirable (versus undesirable) stimuli. This difference allows a NIRS signal classifier to serve successfully as a reinforcer for an adaptive controller performing a virtual tool-retrieval task. The agents adaptability allows its performance to exceed the limits of the NIRS classifier decoding accuracy. We also show that decoding state desirabilities is more accurate when using relative concentrations of both oxyhemoglobin and deoxyhemoglobin, rather than either species alone.
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Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension.
PLoS ONE
PUBLISHED: 01-01-2013
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Dysfunction of brain renin-angiotensin system (RAS) components is implicated in the development of hypertension. We previously showed that angiotensin (Ang) II-induced hypertension is mediated by increased production of proinflammatory cytokines (PIC), including tumor necrosis factor (TNF), in brain cardiovascular regulatory centers such as the paraventricular nucleus (PVN). Presently, we tested the hypothesis that central TNF blockade prevents dysregulation of brain RAS components and attenuates Ang II-induced hypertension. Male Sprague-Dawley rats were implanted with radio-telemetry transmitters to measure mean arterial pressure (MAP) and subjected to intracerebroventricular (i.c.v.) infusion of etanercept (10 µg/kg/day) with/without concurrent subcutaneous 4-week Ang II (200 ng/kg/min) infusion. Chronic Ang II infusion resulted in a significant increase in MAP and cardiac hypertrophy, which was attenuated by inhibition of brain TNF with etanercept. Etanercept treatment also attenuated Ang II-induced increases in PIC and decreases in IL-10 expression in the PVN. Additionally, Ang II infusion increased expression of pro-hypertensive RAS components (ACE and AT1R), while decreasing anti-hypertensive RAS components (ACE2, Mas, and AT2 receptors), within the PVN. I.c.v. etanercept treatment reversed these changes. Ang II-infusion was associated with increased oxidative stress as indicated by increased NAD(P)H oxidase activity and super oxide production in the PVN, which was prevented by inhibition of TNF. Moreover, brain targeted TNF blockade significantly reduced Ang II-induced NOX-2 and NOX-4 mRNA and protein expression in the PVN. These findings suggest that chronic TNF blockade in the brain protects rats against Ang II-dependent hypertension and cardiac hypertrophy by restoring the balance between pro- and anti-hypertensive RAS axes and inhibiting PIC and oxidative stress genes and proteins in the PVN.
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An electric field model for prediction of somatosensory (S1) cortical field potentials induced by ventral posterior lateral (VPL) thalamic microstimulation.
IEEE Trans Neural Syst Rehabil Eng
PUBLISHED: 12-23-2011
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Microstimulation (MiSt) is used experimentally and clinically to activate localized populations of neural elements. However, it is difficult to predict-and subsequently control-neural responses to simultaneous current injection through multiple electrodes in an array. This is due to the unknown locations of neuronal elements in the extracellular medium that are excited by the superposition of multiple parallel current sources. We, therefore, propose a model that maps the computed electric field in the 3-D space surrounding the stimulating electrodes in one brain region to the local field potential (LFP) fluctuations evoked in a downstream region. Our model is trained with the recorded LFP waveforms in the primary somatosensory cortex (S1) resulting from MiSt applied in multiple electrode configurations in the ventral posterolateral nucleus (VPL) of the quiet awake rat. We then predict the cortical responses to MiSt in "novel" electrode configurations, a result that suggests that this technique could aid in the design of spatially optimized MiSt patterns through a multielectrode array.
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Electrostimulation as a prosthesis for repair of information flow in a computer model of neocortex.
IEEE Trans Neural Syst Rehabil Eng
PUBLISHED: 12-13-2011
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Damage to a cortical area reduces not only information transmitted to other cortical areas, but also activation of these areas. This phenomenon, whereby the dynamics of a follower area are dramatically altered, is typically manifested as a marked reduction in activity. Ideally, neuroprosthetic stimulation would replace both information and activation. However, replacement of activation alone may be valuable as a means of restoring dynamics and information processing of other signals in this multiplexing system. We used neuroprosthetic stimulation in a computer model of the cortex to repair activation dynamics, using a simple repetitive stimulation to replace the more complex, naturalistic stimulation that had been removed. We found that we were able to restore activity in terms of neuronal firing rates. Additionally, we were able to restore information processing, measured as a restoration of causality between an experimentally recorded signal fed into the in silico brain and a cortical output. These results indicate that even simple neuroprosthetics that do not restore lost information may nonetheless be effective in improving the functionality of surrounding areas of cortex.
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Angiotensin II-induced hypertension is modulated by nuclear factor-?Bin the paraventricular nucleus.
Hypertension
PUBLISHED: 11-21-2011
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Hypertension is considered a low-grade inflammatory condition, and understanding the role of transcription factors in guiding this response is pertinent. A prominent transcription factor that governs inflammatory responses and has become a focal point in hypertensive research is nuclear factor-?B (NF?B). Within the hypothalamic paraventricular nucleus (PVN), a known brain cardioregulatory center, NF?B becomes potentially even more important in ultimately coordinating the systemic hypertensive response. To definitively demonstrate the role of NF?B in the neurogenic hypertensive response, we hypothesized that PVN NF?B blockade would attenuate angiotensin II-induced hypertension. Twelve-week-old male Sprague-Dawley rats were implanted with radiotelemetry probes for blood pressure measurement and allowed a 7-day recovery. After baseline blood pressure recordings, rats were administered either continuous NF?B decoy oligodeoxynucleotide infusion or microinjection of a serine mutated adenoviral inhibitory-?B vector, or their respective controls, bilaterally into the PVN to inhibit NF?B at two levels of its activation pathway. Simultaneously, rats were implanted subcutaneously with an angiotensin II or saline-filled 14-day osmotic minipump. After the 2-week treatments, rats were euthanized and brain tissues collected for PVN analysis. Bilaterally inhibited NF?B rats had a decrease in blood pressure, NF?B p65 subunit activity, proinflammatory cytokines, and reactive oxygen species, including the angiotensin II type 1 receptor, angiotensin-converting enzyme, tumor necrosis factor, and superoxide in angiotensin II-treated rats. Moreover, after NF?B blockade, key protective antihypertensive renin-angiotensin system components were upregulated. This demonstrates the important role that transcription factor NF?B plays within the PVN in modulating and perpetuating the hypertensive response via renin-angiotensin system modulation.
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Validation of a medical record-based delirium risk assessment.
J Am Geriatr Soc
PUBLISHED: 11-19-2011
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To improve identification of patients at high risk for delirium, this study developed a chart abstraction tool for delirium risk and validated the tool against clinical expert diagnosis of delirium.
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Smoking withdrawal in smokers with and without posttraumatic stress disorder.
Nicotine Tob. Res.
PUBLISHED: 10-24-2011
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Previous research on smoking withdrawal in posttraumatic stress disorder (PTSD) has been limited by the use of retrospective and observational methods and has lacked repeated assessments on the first day of abstinence and evaluation of the conditioned effects of smoking.
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Updates on the antinociceptive mechanism hypothesis of botulinum toxin A.
Parkinsonism Relat. Disord.
PUBLISHED: 10-18-2011
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Botulinum toxin A has been traditionally viewed as a motor nerve specific treatment. However, clinical uses for botulinum toxin A have continued to expand, with increased use in conditions implicating sensory pain nerve dysfunction. Chronic pain is associated with excess pain fiber activity. When the site of this excess activity resides in the peripheral portion of the pain pathway, a condition of peripheral sensitization can establish. During this state, excess pain signaling reaches the central nervous system, which can then lead to a condition of central sensitization, manifesting as the symptoms associated with chronic pain (i.e. burning, electric pain, lowered pain threshold to normal stimuli, etc). Experimentally, botulinum toxin type A has been shown to reduce neuropeptides and neurotransmitter release from treated cells or nerve endings and to attenuate nociception in both neuropathic and non-neuropathic pain models. This review summarizes the literature to update the hypothesis for the mechanism by which botulinum toxin type A can modulate chronic pain.
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ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension.
Cardiovasc. Res.
PUBLISHED: 09-27-2011
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Angiotensin II (Ang II) has been shown to have both central and peripheral effects in mediating hypertension, for which the hypothalamic paraventricular nucleus (PVN) is an important brain cardio-regulatory centre. Angiotensin-converting enzyme 2 (ACE2) has been identified as a negative regulator of the pro-hypertensive actions of Ang II. Recent findings from our laboratory suggest that Ang II infusion decreases ACE2 expression in the PVN. In the present study, we hypothesized that ACE2 overexpression in the PVN will have beneficial effects in counteracting Ang II-induced hypertension.
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Chronic exercise preserves renal structure and hemodynamics in spontaneously hypertensive rats.
Antioxid. Redox Signal.
PUBLISHED: 09-22-2011
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Exercise training (ExT) is a recommended adjunct to many pharmaceutical antihypertensive therapies. The effects of chronic ExT on the development of hypertension-induced renal injury remain unknown. We examined whether ExT would preserve renal hemodynamics and structure in the spontaneously hypertensive rat (SHR), and whether these effects were mediated by improved redox status and decreased inflammation. Normotensive WKY rats and SHR underwent moderate-intensity ExT for 16 weeks. One group of SHR animals was treated with hydralazine to investigate the pressure-dependent/independent effects of ExT. Acute renal clearance experiments were performed prior to sacrifice. Tissue free radical production rates were measured by electron paramagnetic resonance; gene and protein expression were measured by real time RT-PCR and Western blot or immunofluorescence, respectively. Plasma angiotensin II levels and kidney antioxidants were assessed. Training efficacy was assessed by citrate synthase activity assay in hind-limb muscle.
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Reinforcement learning via kernel temporal difference.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 08-29-2011
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This paper introduces a kernel adaptive filter implemented with stochastic gradient on temporal differences, kernel Temporal Difference (TD)(?), to estimate the state-action value function in reinforcement learning. The case ?=0 will be studied in this paper. Experimental results show the methods applicability for learning motor state decoding during a center-out reaching task performed by a monkey. The results are compared to the implementation of a time delay neural network (TDNN) trained with backpropagation of the temporal difference error. From the experiments, it is observed that kernel TD(0) allows faster convergence and a better solution than the neural network.
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Optimizing microstimulation using a reinforcement learning framework.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 08-29-2011
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The ability to provide sensory feedback is desired to enhance the functionality of neuroprosthetics. Somatosensory feedback provides closed-loop control to the motor system, which is lacking in feedforward neuroprosthetics. In the case of existing somatosensory function, a template of the natural response can be used as a template of desired response elicited by electrical microstimulation. In the case of no initial training data, microstimulation parameters that produce responses close to the template must be selected in an online manner. We propose using reinforcement learning as a framework to balance the exploration of the parameter space and the continued selection of promising parameters for further stimulation. This approach avoids an explicit model of the neural response from stimulation. We explore a preliminary architecture--treating the task as a k-armed bandit--using offline data recorded for natural touch and thalamic microstimulation, and we examine the methods efficiency in exploring the parameter space while concentrating on promising parameter forms. The best matching stimulation parameters, from k = 68 different forms, are selected by the reinforcement learning algorithm consistently after 334 realizations.
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Chronic exercise modulates RAS components and improves balance between pro- and anti-inflammatory cytokines in the brain of SHR.
Basic Res. Cardiol.
PUBLISHED: 08-25-2011
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Recently, exercise has been recommended as a part of lifestyle modification for all hypertensive patients; however, the precise mechanisms of its effects on hypertension are largely unknown. Therefore, this study aimed to investigate the mechanisms within the brain that can influence exercise-induced effects in an animal model of human essential hypertension. Young normotensive WKY rats and SHR were given moderate-intensity exercise for 16 weeks. Blood pressure was measured bi-weekly by tail-cuff method. Animals were then euthanized; paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM), important cardiovascular regulatory centers in the brain, were collected and analyzed by real-time RT-PCR, Western blot, EIA, and fluorescent microscopy. Exercise of 16-week duration attenuated systolic, diastolic, and mean arterial pressure in SHR. Sedentary SHR exhibited increased pro-inflammatory cytokines (PICs) and decreased anti-inflammatory IL-10 levels in the PVN and RVLM. Furthermore, SHR(sed) rats exhibited elevated levels of ACE, AT1R, and decreased levels of ACE2 and receptor Mas in the PVN and RVLM. Chronic exercise not only prevented the increase in PICs (TNF-?, IL-1?), ACE, and AT1R protein expression in the brain of SHR, but also dramatically upregulated IL-10, ACE2, and Mas receptor expression in SHR. In addition, these changes were associated with reduced plasma AngII levels, reduced neuronal activity, reduced NADPH-oxidase subunit gp91(phox) and inducible NO synthase in trained SHRs indicating reduced oxidative stress. These results suggest that chronic exercise not only attenuates PICs and the vasoconstrictor axis of the RAS but also improves the anti-inflammatory defense mechanisms and vasoprotective axis of the RAS in the brain, which, at least in part, explains the blood pressure-lowering effects of exercise in hypertension.
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Neuroplasticity of the sensorimotor cortex during learning.
Neural Plast.
PUBLISHED: 05-24-2011
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We will discuss some of the current issues in understanding plasticity in the sensorimotor (SM) cortices on the behavioral, neurophysiological, and synaptic levels. We will focus our paper on reaching and grasping movements in the rat. In addition, we will discuss our preliminary work utilizing inhibition of protein kinase M? (PKM?), which has recently been shown necessary and sufficient for the maintenance of long-term potentiation (LTP) (Ling et al., 2002). With this new knowledge and inhibitors to this system, as well as the ability to overexpress this system, we can start to directly modulate LTP and determine its influence on behavior as well as network level processing dependent at least in part due to this form of LTP. We will also briefly introduce the use of brain machine interface (BMI) paradigms to ask questions about sensorimotor plasticity and discuss current analysis techniques that may help in our understanding of neuroplasticity.
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Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 05-17-2011
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As a part of aging there are known to be numerous alterations which occur in multiple tissues of the body, and the focus of this study was to determine the extent to which oxidative stress and hypoxia occur during adipose tissue aging. In our studies we demonstrate for the first time that aging is associated with both hypoxia (38% reduction in oxygen levels, Po(2) 21.7 mmHg) and increases reactive oxygen species in visceral fat depots of aging male C57Bl/6 mice. Interestingly, aging visceral fat depots were observed to have significantly less change in the expression of genes involved in redox regulation compared with aging subcutaneous fat tissue. Exposure of 3T3-L1 adipocytes to the levels of hypoxia observed in aging adipose tissue was sufficient to alter multiple aspects of adipose biology inducing increased levels of in insulin-stimulated glucose uptake and decreased lipid content. Taken together, these data demonstrate that hypoxia and increased levels of reactive oxygen species occur in aging adipose tissue, highlighting the potential for these two stressors as potential modulators of adipose dysfunction during aging.
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Cell wall damage-induced lignin biosynthesis is regulated by a reactive oxygen species- and jasmonic acid-dependent process in Arabidopsis.
Plant Physiol.
PUBLISHED: 05-05-2011
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The plant cell wall is a dynamic and complex structure whose functional integrity is constantly being monitored and maintained during development and interactions with the environment. In response to cell wall damage (CWD), putatively compensatory responses, such as lignin production, are initiated. In this context, lignin deposition could reinforce the cell wall to maintain functional integrity. Lignin is important for the plants response to environmental stress, for reinforcement during secondary cell wall formation, and for long-distance water transport. Here, we identify two stages and several components of a genetic network that regulate CWD-induced lignin production in Arabidopsis (Arabidopsis thaliana). During the early stage, calcium and diphenyleneiodonium-sensitive reactive oxygen species (ROS) production are required to induce a secondary ROS burst and jasmonic acid (JA) accumulation. During the second stage, ROS derived from the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D and JA-isoleucine generated by JASMONIC ACID RESISTANT1, form a negative feedback loop that can repress each others production. This feedback loop in turn seems to influence lignin accumulation. Our results characterize a genetic network enabling plants to regulate lignin biosynthesis in response to CWD through dynamic interactions between JA and ROS.
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A blueberry-enriched diet attenuates nephropathy in a rat model of hypertension via reduction in oxidative stress.
PLoS ONE
PUBLISHED: 04-13-2011
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To assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS) appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeutic potential of natural products as antioxidants. Blueberries (BB) have among the highest antioxidant capacities of fruits and vegetables.
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NF-?B in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure.
Basic Res. Cardiol.
PUBLISHED: 01-27-2011
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Findings from our laboratory indicate that proinflammatory cytokines and their transcription factor, nuclear factor-kappaB (NF-?B), are increased in the hypothalamic paraventricular nucleus (PVN) and contribute towards the progression of heart failure. In this study, we determined whether NF-?B activation within the PVN contributes to sympathoexcitation via interaction with neurotransmitters in the PVN during the pathogenesis of heart failure. Heart failure was induced in rats by left anterior descending coronary artery ligation. Sham-operated control (SHAM) or heart failure rats were treated for 4 weeks through bilateral PVN infusion with SN50, SN50M or vehicle via osmotic minipump. Rats with heart failure treated with PVN vehicle or SN50M (inactive peptide for SN50) had increased levels of glutamate, norepinephrine (NE), tyrosine hydroxylase (TH), superoxide, gp91(phox) (a subunit of NAD(P)H oxidase), phosphorylated IKK? and NF-?B p65 activity, and lower levels of gamma-aminobutyric acid (GABA) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN compared with those of SHAM rats. Plasma levels of cytokines, norepinephrine, epinephrine and angiotensin II, and renal sympathetic nerve activity (RSNA) were increased in heart failure rats. Bilateral PVN infusion of SN50 prevented the decreases in PVN GABA and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH, superoxide, gp91(phox), phosphorylated IKK? and NF-?B p65 activity observed in vehicle or SN50M-treated heart failure rats. A same dose of SN50 given intraperitoneally did not affect neurotransmitters concentration in the PVN and was similar to vehicle-treated heart failure rats. These findings suggest that NF-?B activation in the PVN modulates neurotransmitters and contributes to sympathoexcitation in rats with ischemia-induced heart failure.
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Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure.
Basic Res. Cardiol.
PUBLISHED: 01-21-2011
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Recent studies indicate that systemic administration of tumor necrosis factor (TNF)-? induces increases in corticotrophin releasing hormone (CRH) and CRH type 1 receptors in the hypothalamic paraventricular nucleus (PVN). In this study, we explored the hypothesis that CRH in the PVN contributes to sympathoexcitation via interaction with neurotransmitters in heart failure (HF). Sprague-Dawley rats with HF or sham-operated controls (SHAM) were treated for 4 weeks with a continuous bilateral PVN infusion of the selective CRH-R1 antagonist NBI-27914 or vehicle. Rats with HF had higher levels of glutamate, norepinephrine (NE) and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, NE, ACTH and renal sympathetic nerve activity (RSNA) were increased in HF rats. Bilateral PVN infusions of NBI-27914 attenuated the decreases in PVN GABA and GAD67, and the increases in RSNA, ACTH and PVN glutamate, NE and TH observed in HF rats. These findings suggest that CRH in the PVN modulates neurotransmitters and contributes to sympathoexcitation in rats with ischemia-induced HF.
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Central TNF inhibition results in attenuated neurohumoral excitation in heart failure: a role for superoxide and nitric oxide.
Basic Res. Cardiol.
PUBLISHED: 01-19-2011
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This study examined the effect of central tumor necrosis factor-alpha (TNF) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus (PVN) and ventrolateral medulla (VLM), key autonomic regulators, and their contribution to enhanced sympathetic drive in mice with congestive heart failure (CHF). We also used a TNF gene knockout (KO) mouse model to study the involvement of TNF in body fluid homeostasis and sympathoexcitation in CHF. After implantation of intracerebroventricular (ICV) cannulae, myocardial infarction (MI) was induced in wild-type (WT) and KO mice by coronary artery ligation. Osmotic mini-pumps were implanted into one set of WT + MI/Sham mice for continuous ICV infusion of Etanercept (ETN), a TNF receptor fusion protein, or vehicle (VEH). Gene expressions of neuronal nitric oxide synthase (NOS) and angiotensin receptor-type 2 were reduced, while those of inducible NOS, Nox2 homologs, superoxide, peroxynitrite and angiotensin receptor-type 1 were elevated in the brainstem and hypothalamus of MI + VEH. Plasma norepinephrine levels and the number of Fos-positive neurons were also increased in the PVN and VLM in MI + VEH. MI + ETN and KO + MI mice exhibited reduced oxidative stress, reduced sympathoexcitation and an improved cardiac function. These changes in WT + MI were associated with increased sodium and fluid retention. These results indicate that elevated TNF in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide, contributing to fluid imbalance and sympathoexcitation in CHF.
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TNF-? in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters.
Tohoku J. Exp. Med.
PUBLISHED: 12-08-2010
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Proinflammatory cytokines, including tumor necrosis factor (TNF)-?, augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-? in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-? blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-? blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-? in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.
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Comparison of force and power generation patterns and their predictions under different external dynamic environments.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 11-25-2010
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Use of neural activity to predict kinematic variables such as position, velocity and direction etc of movements has been implemented in real-time control of robotic systems and computer cursors. In everyday life, however, we generate variable amounts of force to manipulate objects of different inertial properties or to follow the same trajectory under different external dynamic environments like air or water. The resultant work during such movements, and its time derivative power, should depend on the dynamics of the movement. In order to give the users of a brain-machine interface (BMI) comprehensive control of a prosthetic limb under different dynamic conditions, it is imperative to consider the dynamics-related parameters like end-effector forces, joint torques or power. In this paper, we show distribution patterns of two such dynamics parameters - force and power - and their predictive efficiency under different dynamic environmental conditions. We intend to find the force-related parameter, which has optimal predictive efficiency across different dynamic environments that is generalization. Our ultimate goal is to materialize a force-based brain-machine interface (fBMI).
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HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats.
Hypertension
PUBLISHED: 08-02-2010
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Reactive oxygen species and proinflammatory cytokines contribute to cardiovascular diseases. Inhibition of downstream transcription factors and gene modifiers of these components are key mediators of hypertensive response. Histone acetylases/deacetylases can modulate the gene expression of these hypertrophic and hypertensive components. Therefore, we hypothesized that long-term inhibition of histone deacetylase with valproic acid might attenuate hypertrophic and hypertensive responses by modulating reactive oxygen species and proinflammatory cytokines in SHR rats. Seven-week-old SHR and WKY rats were used in this study. Following baseline blood pressure measurement, rats were administered valproic acid in drinking water (0.71% wt/vol) or vehicle, with pressure measured weekly thereafter. Another set of rats were treated with hydralazine (25 mg/kg per day orally) to determine the pressure-independent effects of HDAC inhibition on hypertension. Following 20 weeks of treatment, heart function was measured using echocardiography, rats were euthanized, and heart tissue was collected for measurement of total reactive oxygen species, as well as proinflammatory cytokine, cardiac hypertrophic, and oxidative stress gene and protein expressions. Blood pressure, proinflammatory cytokines, hypertrophic markers, and reactive oxygen species were increased in SHR versus WKY rats. These changes were decreased in valproic acid-treated SHR rats, whereas hydralazine treatment only reduced blood pressure. These data indicate that long-term histone deacetylase inhibition, independent of the blood pressure response, reduces hypertrophic, proinflammatory, and hypertensive responses by decreasing reactive oxygen species and angiotensin II type1 receptor expression in the heart, demonstrating the importance of uncontrolled histone deacetylase activity in hypertension.
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The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 06-25-2010
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An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/AngII type 1 receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin angiotensin system composed of ACE2/Ang-(1-7)/Mas has led us to examine the role of this vasoprotective axis on such disorders.
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Understanding the psychological motives behind microblogging.
Stud Health Technol Inform
PUBLISHED: 06-15-2010
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This research aims to understand the psychological motives behind microblogging. We conducted two studies to investigate if social exclusion and existential anxiety would lead to a high tendency to microblog. Our results show that participants did not use microblogging to satisfy their needs for social connection and affiliation, but highly extraverted participants did use it to relieve their existential anxiety.
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Brain microglial cytokines in neurogenic hypertension.
Hypertension
PUBLISHED: 06-14-2010
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Accumulating evidence indicates a key role of inflammation in hypertension and cardiovascular disorders. However, the role of inflammatory processes in neurogenic hypertension remains to be determined. Thus, our objective in the present study was to test the hypothesis that activation of microglial cells and the generation of proinflammatory cytokines in the paraventricular nucleus (PVN) contribute to neurogenic hypertension. Intracerebroventricular infusion of minocycline, an anti-inflammatory antibiotic, caused a significant attenuation of mean arterial pressure, cardiac hypertrophy, and plasma norepinephrine induced by chronic angiotensin II infusion. This was associated with decreases in the numbers of activated microglia and mRNAs for interleukin (IL) 1beta, IL-6, and tumor necrosis factor-alpha, and an increase in the mRNA for IL-10 in the PVN. Overexpression of IL-10 induced by recombinant adenoassociated virus-mediated gene transfer in the PVN mimicked the antihypertensive effects of minocycline. Furthermore, acute application of a proinflammatory cytokine, IL-1beta, into the left ventricle or the PVN in normal rats resulted in a significant increase in mean arterial pressure. Collectively, this indicates that angiotensin II induced hypertension involves activation of microglia and increases in proinflammatory cytokines in the PVN. These data have significant implications on the development of innovative therapeutic strategies for the control of neurogenic hypertension.
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Central adiposity, systemic inflammation, and the metabolic syndrome.
Curr. Hypertens. Rep.
PUBLISHED: 04-29-2010
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Metabolic syndrome (MetS) is a constellation of metabolic derangements and underlying factors that significantly increases the risk for developing type 2 diabetes and cardiovascular diseases. MetS is a low-grade inflammatory condition, with systemic inflammation and inflammation of central abdominal fat as contributors. Systemic inflammation in MetS is thought to involve C-reactive protein and some proinflammatory cytokines; the nuclear factor-kappaB pathway also is believed to play a role. Inflammation of central adipose tissue leads to adipokine production, followed by secretion of adipokines into the general circulation to contribute to the overall inflammatory condition. The molecular mechanisms that contribute to this inflammation are still somewhat unclear, but several serine/threonine kinases are known to be involved. Dietary components may also contribute to central adiposity and the inflammation seen in MetS.
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Involvement of tumor necrosis factor-alpha in natriuretic response to systemic infusion of nitric oxide synthase inhibitor in anesthetized mice.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 04-21-2010
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Systemic infusion of TNF-alpha exerts renal vasoconstriction but caused marked natriuresis in mice. Similar renal responses were also observed during systemic infusion of nitric oxide (NO) synthase inhibitors as opposed to their usual antinatriuretic responses when administered intrarenally. In the present study, we examined the hypothesis that acute NO blockade systemically induces TNF-alpha generation. which induces this natriuretic response. Renal responses to intravenous infusion of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 0.2 microg x min(-1) x g body wt(-1) for 85 min) and its impact on the plasma level of TNF-alpha were evaluated in anesthetized mice. Plasma TNF-alpha was undetected in untreated mice (n = 7) but was elevated in L-NAME-treated mice (109 +/- 22 pg/ml; P < 0.01 vs. untreated group; n = 7) along with an increase in TNF-alpha protein expression in kidney tissue. L-NAME infusion caused a usual increase in mean arterial pressure (MAP; 98 +/- 3 to 122 +/- 3 mmHg; P < 0.01) and decreases in renal blood flow (RBF; 8.6 +/- 0.3 to 4.4 +/- 0.2 ml x min(-1) x g(-1); P < 0.01) and glomerular filtration rate (GFR; 1.14 +/- 0.07 to 0.77 +/- 0.04 ml x min(-1) x g(-1); P < 0.01) with a marked increase in sodium excretion (U(Na)V; 0.48 +/- 0.10 to 3.52 +/- 0.85 micromol x min(-1) x g(-1); P < 0.01). Interestingly, in mice (n = 7) pretreated with the TNF-alpha blocker etanercept (5 mg/kg sc), the U(Na)V response to l-NAME infusion was markedly blunted (0.58 +/- 0.08 to 1.22 +/- 0.28 micromol x min(-1) x g(-1); P = NS) although responses for MAP, RBF, and GFR were mostly unchanged. However, pretreatment with the superoxide scavenger tempol in mice (n = 7) did not alter the U(Na)V response to L-NAME. These data demonstrate that L-NAME-induced natriuresis is mediated, at least in part, by concomitant generation of TNF-alpha during NO blockade.
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Erasing sensorimotor memories via PKMzeta inhibition.
PLoS ONE
PUBLISHED: 04-09-2010
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Sensorimotor cortex has a role in procedural learning. Previous studies suggested that this learning is subserved by long-term potentiation (LTP), which is in turn maintained by the persistently active kinase, protein kinase Mzeta (PKMzeta). Whereas the role of PKMzeta in animal models of declarative knowledge is established, its effect on procedural knowledge is not well understood. Here we show that PKMzeta inhibition, via injection of zeta inhibitory peptide (ZIP) into the rat sensorimotor cortex, disrupts sensorimotor memories for a skilled reaching task even after several weeks of training. The rate of relearning the task after the memory disruption by ZIP was indistinguishable from the rate of initial learning, suggesting no significant savings after the memory loss. These results indicate a shared molecular mechanism of storage for declarative and procedural forms of memory.
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A bio-friendly and economical technique for chronic implantation of multiple microelectrode arrays.
J. Neurosci. Methods
PUBLISHED: 02-03-2010
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Many neurophysiological experiments on rodents and non-human primates involve the implantation of more than one multi-electrode array to record from many regions of the brain. So called floating microelectrode arrays are implanted in cortical regions of interest and are coupled via a flexible cable to their connectors which are fixed to the skull by a cement cap or a titanium pedestal, such as the Cereport system, which has been approved for human use. The use of bone cement has several disadvantages including the creation of infection prone areas at the interface with the skull and surrounding skin. Alternatively, the more biocompatible Cereport has a limited carrying capacity and is far more expensive. In this paper, we describe a new implantation technique, which combines the biocompatibility of titanium, a high carrying capacity with a minimal skull footprint, and a decreased chance of infection, all in a relatively inexpensive package. This technique utilizes an in-house fabricated Nesting Platform (NP), mounted on a titanium headpost to hold multiple connectors above the skin, making the headpost the only transcutaneous object. The use of delrin, a durable, lightweight and easily machinable material, allows easy customization of the NP for a wide variety of floating electrodes and their connectors. The ultimate result is a longer survival time with superior neural recordings that can potentially last longer than with traditional implantation techniques.
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Use of health information technology to advance evidence-based care: lessons from the VA QUERI program.
J Gen Intern Med
PUBLISHED: 01-16-2010
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As the Department of Veterans Affairs (VA) Health Services Research and Development Services Quality Enhancement Research Initiative (QUERI) has progressed, health information technology (HIT) has occupied a crucial role in implementation research projects.
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Developing and sustaining quality improvement partnerships in the VA: the Colorectal Cancer Care Collaborative.
J Gen Intern Med
PUBLISHED: 01-16-2010
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The Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) seeks to develop partnerships between VA health services researchers and clinical managers, with the goal of designing and evaluating interventions to improve the quality of VA health care.
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TNF-induced mitochondrial damage: a link between mitochondrial complex I activity and left ventricular dysfunction.
Free Radic. Biol. Med.
PUBLISHED: 12-16-2009
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Mitochondrial damage is implicated in the progression of cardiac disease. Considerable evidence suggests that proinflammatory cytokines induce oxidative stress and contribute to cardiac dysfunction. This study was conducted to determine whether a TNF-induced increase in superoxide (O(2)(*)(-)) contributes to mitochondrial damage in the left ventricle (LV) by impairing respiratory complex I activity. We employed an electron paramagnetic resonance (EPR) method to measure O(2)(*)(-) and oxygen consumption in mitochondrial respiratory complexes, using an oxygen label. Adult male Sprague-Dawley rats were divided into four groups: control, TNF treatment (ip), TNF+ apocynin (APO; 200 micromol/kg bw, orally), and TNF+ Tempol (Temp; 300 micromol/kg bw, orally). TNF was injected daily for 5 days. Rats were sacrificed, LV tissue was collected, and mitochondria were isolated for EPR studies. Total LV ROS production was significantly higher in TNF animals than in controls; APO or Temp treatment ameliorated TNF-induced LV ROS production. Total mitochondrial ROS production was significantly higher in the TNF and TNF+ APO groups than in the control and TNF+ Temp groups. These findings suggest that TNF alters the cellular redox state, reduces the expression of four complex I subunits by increasing mitochondrial O(2)(*)(-) production and depleting ATP synthesis, and decreases oxygen consumption, thereby resulting in mitochondrial damage and leading to LV dysfunction.
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Autonomic cardiovascular modulation.
IEEE Eng Med Biol Mag
PUBLISHED: 11-17-2009
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We validated a symbolic approach to assess autonomic modulation from pulse interval (PI) and systolic arterial pressure (SAP) series obtained from an animal model of chronic heart failure (CHF). We studied three groups of rats: controls; CHF animals; CHF animals treated with spironolactone (CHF-SP), reducing sympathetic activity in CHF. Simulations confirmed that symbolic analysis captures modifications of cardiovascular regulation in the case of fast dynamics and negligible variance. While spectral indexes did not reveal any significant difference among groups, symbolic analysis pointed out that sympathetic modulation is reduced in CHF group and restored to basal values in CHF-SP one.
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Role of proinflammatory cytokines and redox homeostasis in exercise-induced delayed progression of hypertension in spontaneously hypertensive rats.
Hypertension
PUBLISHED: 10-19-2009
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Hypertension is a well-known risk factor for various cardiovascular diseases. Recently, exercise has been recommended as a part of lifestyle modification for all hypertensive patients. However, the precise mechanisms of exercise training (ExT)-induced effects on the development of hypertension are poorly understood. Therefore, we hypothesized that chronic ExT would delay the progression of hypertension in young spontaneously hypertensive rats (SHRs). In addition, we explored whether the beneficial effects of chronic ExT were mediated by reduced proinflammatory cytokines and improved redox status. We also investigated the involvement of nuclear factor-kappaB in exercise-induced effects. To test our hypotheses, young normotensive (Wistar-Kyoto) and SHRs were given moderate-intensity ExT for 16 weeks. Blood pressure was determined by the tail-cuff method, and cardiac function was assessed by echocardiography. Myocardial total reactive oxygen species and superoxide production were measured by electron paramagnetic resonance spectroscopy; tumor necrosis factor-alpha, interleukin-1beta, gp91(phox), and inducible NO synthase by real-time PCR; and nuclear factor kappaB activity by electrophoretic mobility shift assay. Chronic ExT in hypertensive rats resulted in significantly reduced blood pressure, reduced concentric hypertrophy, and improved diastolic function. ExT significantly reduced proinflammatory cytokines and inducible NO synthase, attenuated total reactive oxygen species and superoxide production, and increased antioxidants in SHRs. ExT also resulted in increased NO production and decreased nuclear factor kappaB activity in SHRs. In summary, chronic ExT delays the progression of hypertension and improves cardiac function in young SHRs; these ExT-induced beneficial effects are mediated by reduced proinflammatory cytokines and improved redox homeostasis via downregulation of nuclear factor-kappaB.
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Effect of the HMG-CoA reductase inhibitor rosuvastatin on early chronic kidney injury in obese zucker rats fed with an atherogenic diet.
Am. J. Med. Sci.
PUBLISHED: 10-15-2009
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The obese Zucker rat (OZR) spontaneously develops hyperlipidemia, insulin resistance, and microalbuminuria. In this study, the initial metabolic, functional, and glomerular pathology in young OZR fed with an atherogenic diet resembles the characteristics of metabolic syndrome. Hyperlipidemia and other metabolic derangement cause early glomerular damage in OZR by 10 weeks of age, before overt diabetes is developed. Consequently, the effects of potential interventions should also be evaluated at the young age. In OZR fed with an atherogenic high-fat diet, low (5 mg/kg) and high (20 mg/kg) dosages of rosuvastatin started at 5 weeks and maintained for 10 weeks induced a significant improvement in metabolic abnormalities, blood pressure, and renal function, including microalbuminuria. The low dose of rosuvastatin significantly decreased mesangial expansion, and the high dose exerted a marked protective effect on the development of both glomerular hypertrophy and mesangial expansion. The statin also attenuated the inflammatory expression in the kidney cortex.
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NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes.
Cardiovasc. Res.
PUBLISHED: 09-03-2009
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Inflammatory molecules and their transcription factor, nuclear factor kappa-B (NF-kappaB), are thought to play important roles in diabetes-induced cardiac dysfunction. Here, we investigated the effects of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, in diabetic mice.
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Prevention of pulmonary hypertension by Angiotensin-converting enzyme 2 gene transfer.
Hypertension
PUBLISHED: 06-29-2009
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In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline (MCT) treatment of mice for 8 weeks resulted in significant increases in right ventricular systolic pressure, right ventricle:left ventricle plus septal weight ratio, and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2, 7 days before MCT treatment prevented the increases in right ventricular systolic pressure (control: 25+/-1 mm Hg; MCT: 44+/-5 mm Hg; MCT+ACE2: 26+/-1 mm Hg; n=6; P<0.05) and right ventricle:left ventricle plus septal weight ratio (control: 0.25+/-0.01; MCT: 0.31+/-0.01; MCT+ACE2: 0.26+/-0.01; n=8; P<0.05). A significant attenuation in muscularization of pulmonary vessels induced by MCT was also observed in animals overexpressing ACE2. These beneficial effects were associated with an increase in the angiotensin II type 2 receptor:angiotensin II type 1 receptor mRNA ratio. Also, pulmonary hypertension-induced increases in proinflammatory cytokines were significantly attenuated by lentiviral vector-containing ACE2 treatment. Furthermore, ACE2 gene transfer in mice after 6 weeks of MCT treatment resulted in a significant reversal of right ventricular systolic pressure. These observations demonstrate that ACE2 overexpression prevents and reverses right ventricular systolic pressure and associated pathophysiology in MCT-induced pulmonary hypertension by a mechanism involving a shift from the vasoconstrictive, proliferative, and fibrotic axes to the vasoprotective axis of the renin-angiotensin system and inhibition of proinflammatory cytokines.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.