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Find video protocols related to scientific articles indexed in Pubmed.
IL12R?1?TM is a secreted product of il12rb1 that promotes control of extra-pulmonary tuberculosis.
Infect. Immun.
PUBLISHED: 11-19-2014
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IL12RB1 is a human gene that is important for resistance to Mycobacterium tuberculosis (Mtb) infection. IL12RB1 is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12R?1) that associates with IL12p40 and promotes the development host-protective TH1cells. Recently, we observed that il12rb1 - the mouse homolog of IL12RB1 - is alternatively spliced by leukocytes to produce a second isoform (IL12R?1?TM) that has biological properties distinct from IL12R?1. While expression of IL12R?1?TM is elicited by Mtb in vivo, and its overexpression enhances IL12p40-responsiveness in vitro, the contribution of IL12R?1?TM to controlling Mtb infection has not been tested. Here, we demonstrate that IL12R?1?TM represents a secreted product of il12rb1 that, when absent in mice, compromises their ability to control M. tuberculosis infection in extra-pulmonary organs. Furthermore, elevated Mtb burdens in Isoform 2-deficient animals are associated with decreased lymph node cellularity and a decline in TH1 development. Collectively, these data support a model wherein IL12R?1?TM is a secreted product of il12rb1 that promotes resistance to Mtb-infection by potentiating TH cells response to IL12.
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Selective binding of zn(2+) complexes to human telomeric g-quadruplex DNA.
Inorg Chem
PUBLISHED: 10-13-2014
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The Zn(2+) complex of 5-(1,4,7,10-tetraazacyclododecan-1-ylsulfonyl)-N,N-dimethylnaphthalen-1-amine, Zn(DSC), binds selectively to the biologically relevant human telomeric (H-Telo) G-quadruplex. An increase in the Zn(DSC) dansyl group fluorescence with a simultaneous shift in emission is consistent with the complex binding to H-Telo. The H-Telo G-quadruplex has two binding sites for Zn(DSC) with binding constants in the low micromolar range (2.5 ?M). Isothermal calorimetric titrations confirm low micromolar dissociation constants with a 2:1 stoichiometry. The interaction between H-Telo and Zn(DSC) is highly pH-dependent, consistent with binding to the unpaired thymines in the G-quadruplex loops. As a result, Zn(DSC) selectively binds to H-Telo over duplex DNA. In contrast to Zn(2+), Fe(2+) and Co(2+) do not complex to the DSC macrocycle appreciably under the conditions of the experiment. The Cu(2+) complex of DSC does not interact measurably with the H-Telo G-quadruplex. Interestingly, the H-Telo-Zn(DSC) adduct self-assembles from its individual components at physiological pH and 100 mM KCl. The self-assembly feature, which is specific for the Zn(2+) ion, suggests that this system may be viable as a Zn(2+) sensor. Pentanucleotides were studied in order to better describe the binding of Zn(DSC) to thymine sequences. NMR studies were consistent with the binding of Zn(DSC) to thymine-containing oligonucleotides including CCTCC, CTTCC, and CTCTC. Studies showed that the dansyl group of Zn(DSC) interacts with thymines in CTTCC. Fluorescence spectroscopy and ITC data indicate that Zn(DSC) forms 2:1 adducts with thymines that are spaced (CTCTC) but not tandem thymines (CTTCC). These data are consistent with one Zn(DSC) complex binding to two separate loops in the G-quadruplex. A second Zn(2+) complex containing an acridine pendent, Zn(ACR), binds tightly to pentanucleotides with both tandem and spaced thymines. Zn(ACR) indiscriminately binds to both H-Telo and duplex DNA.
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Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material.
Hum. Gene Ther.
PUBLISHED: 10-03-2014
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Abstract Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50×10(11) pt/ml; CI, 4.26×10(11) to 6.75×10(11) pt/ml), vector genomes (mean, 5.75×10(11) vg/ml; CI, 3.05×10(11) to 1.09×10(12) vg/ml), and infectious units (mean, 1.26×10(9) IU/ml; CI, 6.46×10(8) to 2.51×10(9) IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community.
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P2Y6 receptor inhibition perturbs CCL2-evoked signalling in human monocytic and peripheral blood mononuclear cells.
J. Cell. Sci.
PUBLISHED: 09-30-2014
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The chemokine CCL2 serves to target circulating monocytes and other leukocytes to tissue during innate immune responses, and modulates the progression of chronic inflammatory disease through activation of the receptor CCR2. Here, we show that co-activation of the P2Y6 purinergic receptor (encoded by P2RY6) occurs when THP-1 cells and human peripheral blood mononuclear cells sense CCL2 through CCR2. Furthermore, P2Y6 receptor activation accounts for ?80% of the intracellular Ca(2+) signal evoked by CCL2. Scavenging extracellular nucleotides with apyrase caused a fourfold reduction in THP-1 sensitivity to CCL2, whereas inhibition of CD39-like ectonucleotidases potentiated CCL2-evoked Ca(2+) responses. Pharmacological inhibition of P2Y6 impaired CCL2-evoked Ca(2+) signalling and chemotaxis in peripheral blood mononuclear cells and THP-1 cells. Furthermore, stable P2Y6 receptor knockdown (of twofold) in THP-1 cells impaired CCL2-evoked Ca(2+) signalling, chemotaxis and adhesion to TNF?-treated HUVECs. We demonstrate that THP-1 cells rapidly secrete ATP during signalling downstream of the CCL2-CCR2 axis and suggest this might act as a mechanism for P2Y6 receptor co-activation following CCL2 activation of the CCR2 receptor. The discovery that P2Y6 receptor mediates leukocyte responsiveness to CCL2 represents a new mechanism by which to modulate CCL2 signals.
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Executive functions and theory of mind as predictors of social adjustment in childhood traumatic brain injury.
J. Neurotrauma
PUBLISHED: 09-24-2014
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Abstract This study examined whether executive function and theory of mind mediate the effects of pediatric traumatic brain injury (TBI) on social adjustment, relative to children with orthopedic injury (OI). Participants included 19 children with severe TBI, 41 children with complicated mild/moderate TBI, and 57 children with OI. They completed measures of executive function, as well as cognitive, affective, and conative theory of mind. Parents provided ratings of children's social adjustment. Children with severe TBI performed more poorly than children with OI on executive function and theory of mind tasks and were rated by parents as having more behavioral symptoms and worse communication and social skills. Executive function and theory of mind were positively correlated with social skills and communication skills, and negatively correlated with behavioral symptoms. In multiple mediator models, theory of mind and executive function were not significant direct predictors of any measure of social adjustment, but mediated the association between injury and adjustment for children with severe TBI. Theory of mind was a significant independent mediator when predicting social skills, but executive function was not. TBI in children, particularly severe injury, is associated with poor social adjustment. The impact of TBI on children's social adjustment is likely mediated by its effects on executive function and theory of mind.
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Awareness, acceptability and application of paracetamol overdose management guidelines in a New Zealand emergency department.
N. Z. Med. J.
PUBLISHED: 09-18-2014
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To measure emergency physicians' awareness, acceptance, access to and application of the Australasian Paracetamol Overdose Guidelines.
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We Never See Children in Parks: A Qualitative Examination of the Role of Safety Concerns on Physical Activity Among Children.
J Phys Act Health
PUBLISHED: 08-22-2014
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Previous literature indicates physical activity and obesity are interrelated problems, especially among children in disorganized environments.
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Use of poisons information resources and satisfaction with electronic products by Victorian emergency department staff.
Emerg Med Australas
PUBLISHED: 08-04-2014
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ED staff use a range of poisons information resources of varying type and quality. The present study aims to identify those resources utilised in the state of Victoria, Australia, and assess opinion of the most used electronic products.
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Recent advances and remaining challenges for the spectroscopic detection of explosive threats.
Appl Spectrosc
PUBLISHED: 07-26-2014
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In 2010, the U.S. Army initiated a program through the Edgewood Chemical Biological Center to identify viable spectroscopic signatures of explosives and initiate environmental persistence, fate, and transport studies for trace residues. These studies were ultimately designed to integrate these signatures into algorithms and experimentally evaluate sensor performance for explosives and precursor materials in existing chemical point and standoff detection systems. Accurate and validated optical cross sections and signatures are critical in benchmarking spectroscopic-based sensors. This program has provided important information for the scientists and engineers currently developing trace-detection solutions to the homemade explosive problem. With this information, the sensitivity of spectroscopic methods for explosives detection can now be quantitatively evaluated before the sensor is deployed and tested.
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Race and gender disparities in nutrient intake are not related to metabolic syndrome in 20- to 59-year-old US adults.
Metab Syndr Relat Disord
PUBLISHED: 07-21-2014
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The goal of this study was to examine the relationship between macronutrient and micronutrient intake and metabolic syndrome within race and gender cohorts of young US adults.
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Protein profiles reveal diverse responsive signaling pathways in kernels of two maize inbred lines with contrasting drought sensitivity.
Int J Mol Sci
PUBLISHED: 06-23-2014
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Drought stress is a major factor that contributes to disease susceptibility and yield loss in agricultural crops. To identify drought responsive proteins and explore metabolic pathways involved in maize tolerance to drought stress, two maize lines (B73 and Lo964) with contrasting drought sensitivity were examined. The treatments of drought and well water were applied at 14 days after pollination (DAP), and protein profiles were investigated in developing kernels (35 DAP) using iTRAQ (isobaric tags for relative and absolute quantitation). Proteomic analysis showed that 70 and 36 proteins were significantly altered in their expression under drought treatments in B73 and Lo964, respectively. The numbers and levels of differentially expressed proteins were generally higher in the sensitive genotype, B73, implying an increased sensitivity to drought given the function of the observed differentially expressed proteins, such as redox homeostasis, cell rescue/defense, hormone regulation and protein biosynthesis and degradation. Lo964 possessed a more stable status with fewer differentially expressed proteins. However, B73 seems to rapidly initiate signaling pathways in response to drought through adjusting diverse defense pathways. These changes in protein expression allow for the production of a drought stress-responsive network in maize kernels.
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Can we maximize both value and quality in gynecologic cancer care? A work in progress.
Am Soc Clin Oncol Educ Book
PUBLISHED: 05-27-2014
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Value is defined as desirable health outcomes achieved per monetary unit spent. Comparative effectiveness research and cost-effectiveness research are methods that have been developed to quantify effectiveness and value to inform management decisions. In this article we review the comparative and cost-effectiveness literature in the field of ovarian cancer treatment. Studies have shown that improved ovarian cancer survival is associated with complete primary surgical cytoreduction, with treatment at high volume facilities by subspecialist providers (gynecologic oncologists) and with National Comprehensive Cancer Network (NCCN) guideline-adherent care in both surgical staging and chemotherapy regimens. Intraperitoneal/intravenous chemotherapy (compared with intravenous alone) has been associated with improved survival and cost-effectiveness. Bevacizumab for primary and maintenance therapy has been found to not be cost-effective (even in selective subsets) despite a small progression-free survival (PFS) advantage. For platinum-sensitive recurrent ovarian cancer, secondary cytoreduction and platinum-based combinations are associated with improved overall survival (OS); several platinum-based combinations have also been found cost-effective. For platinum-resistant recurrence, single agent therapy and supportive care are cost-effective compared with combination therapies. Although little prospective clinical research has been done around end-of-life care, one study reported that for platinum-resistant ovarian cancer, palliative intervention would potentially reduce costs and increase quality adjusted life years compared with usual care (based on improvement in quality of life [QOL]). Overall, cost comparisons of individual chemotherapy regimens are highly dependent on market prices of novel therapeutic agents.
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New insights into the bacterial RNA polymerase inhibitor CBR703 as a starting point for optimization as an anti-infective agent.
Antimicrob. Agents Chemother.
PUBLISHED: 05-12-2014
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CBR703 was reported to inhibit bacterial RNA polymerase (RNAP) and biofilm formation, considering it to be a good candidate for further optimization. While synthesized derivatives of CBR703 did not result in more-active RNAP inhibitors, we observed promising antibacterial activities. These again correlated with a significant cytotoxicity toward mammalian cells. Furthermore, we suspect the promising effects on biofilm formation to be artifacts. Consequently, this class of compounds can be considered unattractive as antibacterial agents.
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Matrix effects in metabolite quantification for MIST assessment: the impact of phospholipid removal and HPLC column particle size.
Bioanalysis
PUBLISHED: 04-08-2014
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This Research article investigates the impact of phospholipid removal and high-performance liquid chromatography column particle size on the accuracy of determining the relative abundance of human metabolites using mass spectrometry peak areas in the context of assessing metabolite abundance for Metabolites in Safety Testing assessment. RESULTS/METHODOLOGY: Plasma samples spiked with 20 compounds, representing ten pairs of drugs and metabolites, were prepared using phospholipid removal plates (Ostro™) or standard protein precipitation techniques and analyzed by liquid chromatography-tandem mass spectrometry using high-performance liquid chromatography columns containing either 2.5 or 3.5 µm particles. Removal of phospholipids significantly reduced matrix effects for samples analyzed on the larger particle size columns while preventing phospholipid build up on the analytical columns. In addition, quantitative accuracy and linearity were not affected by phospholipid removal.
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Salmonella berta meningitis in a term neonate.
J Perinatol
PUBLISHED: 03-24-2014
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We report the case of a 37-week male infant born via spontaneous vaginal delivery who developed Salmonella berta sepsis and meningitis. The infant was born to a mother with active diarrhea and stool cultures growing S. berta. On day 3, the infant developed poor feeding, lethargy, apnea and bradycardia prompting a sepsis evaluation. Blood, stool and cerebrospinal fluid cultures were positive for S. berta. An electroencephalogram performed for posturing revealed neonatal status epilepticus. Extensive bilateral periventricular venous hemorrhagic infarctions with multiple herniations were seen on brain magnetic resonance imaging. The infant's condition continued to deteriorate despite maximal support and care was redirected towards comfort measures.
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A retrospective observational study of current treatment for generalized convulsive status epilepticus.
Epilepsy Behav
PUBLISHED: 03-07-2014
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This study aimed at determining the current state of practice of treatment for acute generalized convulsive status epilepticus (GCSE) and responsiveness to therapy.
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A scaling rule in supercritical fluid chromatography. I. Theory for isocratic systems.
J Chromatogr A
PUBLISHED: 02-25-2014
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Scaling is regularly done in chromatography either to transfer a successfully designed method of analysis developed in one system to another system, or to scale-up a separation method developed in analytical scale to preparative scale. For liquid chromatography there are well-tested guidelines for scaling, which makes it a routine job. For supercritical fluid chromatography (SFC), on the other hand, neither do we have any well-understood principles behind scaling nor do we know how far the strategies applied in LC could be applicable to SFC. In this article, we have addressed these issues and proposed a rule applicable for scaling isocratic methods between different SFC systems and column dimensions under commonly used operating temperatures and pressures. We have shown that the scale-up and method transfer techniques used in LC can be applied to SFC, provided we ensure that both the original and the target systems in SFC operate at the same average density. The current article will present the theory, discuss the extents of applicability of this rule, and outline its limitations. In an accompanying article implementation of this rule in various practical situations will be presented.
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Sports medicine in children: common overuse injuries.
FP Essent
PUBLISHED: 02-22-2014
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With millions of children participating in high-intensity sports activities at a young age, overuse injuries are seen commonly by family physicians. Little Leaguer's shoulder, swimmer's shoulder, Little Leaguer's elbow, snapping hip, and shin splints are 5 overuse injuries frequently sustained by pediatric athletes. Physicians managing these injuries require a basic understanding of the underlying sport-related strain on the body. Diagnosis is clinical for most patients, and management typically is conservative. The physician must be able to differentiate these conditions from more significant injuries that necessitate further imaging and referral. For most patients, monitoring and limiting the repetitive activity can prevent the occurrence of these injuries.
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Neuro-Behçet's disease: an unusual cause of headache.
J Gen Intern Med
PUBLISHED: 01-10-2014
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Neuro-Behçet's disease (NBD) is a potentially fatal complication of Behçet's disease (BD) that can sometimes masquerade as a primary neoplasm, aseptic meningitis or multiple sclerosis. Headache in patients with BD may portend onset of NBD, but the majority of headache in BD is benign. Clinicians who are unaware of the specific neurological manifestations of systemic inflammatory disorders like BD may fail to consider the possibility of serious intracranial pathology. We illustrate these challenges with the case of a 50-year-old woman with a history of BD who presented with headache in the absence of initial focal neurological deficits. The diagnosis of NBD was missed on multiple occasions before the correct diagnosis was made. We describe the etiology of headache in BD, the specific neurological manifestations of BD that suggest NBD, and the utility of routine neurological exams for BD patients with chronic headache. We further discuss the appropriate use of neuroimaging for headache in BD, and we recommend consideration of NBD as a diagnosis for headache in patients suspected of having an underlying systemic disease.
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Congenital heart disease is associated with reduced cortical and hippocampal volume in patients with 22q11.2 deletion syndrome.
Cortex
PUBLISHED: 01-08-2014
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There is increasing evidence that congenital heart disease (CHD) affects brain structure, but little is known about the long-term trajectory of brain maturation and its impact on the cognitive development of patients with CHD. We proposed to address this question in a longitudinally-followed cohort of individuals with 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome in humans.
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Human-facilitated metapopulation dynamics in an emerging pest species, Cimex lectularius.
Mol. Ecol.
PUBLISHED: 01-06-2014
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The number and demographic history of colonists can have dramatic consequences for the way in which genetic diversity is distributed and maintained in a metapopulation. The bed bug (Cimex lectularius) is a re-emerging pest species whose close association with humans has led to frequent local extinction and colonization, that is, to metapopulation dynamics. Pest control limits the lifespan of subpopulations, causing frequent local extinctions, and human-facilitated dispersal allows the colonization of empty patches. Founder events often result in drastic reductions in diversity and an increased influence of genetic drift. Coupled with restricted migration, this can lead to rapid population differentiation. We therefore predicted strong population structuring. Here, using 21 newly characterized microsatellite markers and approximate Bayesian computation (ABC), we investigate simplified versions of two classical models of metapopulation dynamics, in a coalescent framework, to estimate the number and genetic composition of founders in the common bed bug. We found very limited diversity within infestations but high degrees of structuring across the city of London, with extreme levels of genetic differentiation between infestations (FST  = 0.59). ABC results suggest a common origin of all founders of a given subpopulation and that the numbers of colonists were low, implying that even a single mated female is enough to found a new infestation successfully. These patterns of colonization are close to the predictions of the propagule pool model, where all founders originate from the same parental infestation. These results show that aspects of metapopulation dynamics can be captured in simple models and provide insights that are valuable for the future targeted control of bed bug infestations.
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Further studies on sex pheromones of female Lygus and related bugs: development of effective lures and investigation of species-specificity.
J. Chem. Ecol.
PUBLISHED: 01-04-2014
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Mirid bugs (Heteroptera: Miridae) are important pests of many crops worldwide. In previous work by others and ourselves, several species of Lygus bugs were shown to produce blends of three compounds, hexyl butyrate, (E)-2-hexenyl butyrate, and (E)-4-oxo-2-hexenal. These have been proposed as components of the female-produced sex pheromones, but attraction of males to synthetic lures has been difficult to demonstrate. We studied the volatiles released by females of four species: Lygus rugulipennis, Lygus pratensis, Lygocoris pabulinus, and Liocoris tripustulatus. Analyses of volatiles from individual, undisturbed insects showed that the three compounds were produced in species-specific blends, by females only, or in greater quantities by females than by males. The three compounds were loaded into pipette tips, which released the defined blends over at least 30 days. Traps baited with the blend for L. rugulipennis caught more males than traps baited with virgin females, with all three compounds required for maximum attractiveness. Traps baited with the specific blends for each of the four species caught males of three of the species, indicating considerable cross-attraction. There is evidence that other, non-chemical factors, such as time-of-day of production of pheromone, contribute to species-specificity of attraction. This is the first report of consistent attraction of Lygus bugs to synthetic lures in the field.
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The unfinished body: The medical and social reshaping of disabled young bodies.
Soc Sci Med
PUBLISHED: 01-02-2014
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Stories about disability are heavily shaped by the narratives offered by medicine and society. Those narratives enact an 'anomalous' body that is constructed as distant from the norm and therefore 'damaged' but also fixable. In this paper we explore how such narratives, and the practices they encompass, influence the stories disabled young people tell about their bodies and impairment. We do so by drawing on narrative qualitative interviews and visual practices carried out with seventeen disabled young people in a project funded by the Economic and Social Research Council that took place between 2011 and 2012 in the North East of England. The findings discussed here focus on how medical and societal responses to bodily difference become part of the stories disabled young people tell about their bodies, and influence the way they work with the body as something which remains 'unfinished' and therefore both fixable and flawed. Our conclusion is that a narrative of an unfinished body is produced, as young people manage their bodies as something that is integral to their emerging identity, but also as a potential threat that could undermine and give away their labour in making an 'ordinary' functioning body and life. The paper contributes to medical sociology and sociology of the body by producing new knowledge about how disabled embodiment is lived and framed by disabled young people in the context of ongoing attempts to change the body.
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Out-of-body experiences associated with seizures.
Front Hum Neurosci
PUBLISHED: 01-01-2014
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Alterations of consciousness are critical factors in the diagnosis of epileptic seizures. With these alterations in consciousness, some persons report sensations of separating from the physical body, experiences that may in rare cases resemble spontaneous out-of-body experiences. This study was designed to identify and characterize these out-of-body-like subjective experiences associated with seizure activity. Fifty-five percent of the patients in this study recalled some subjective experience in association with their seizures. Among our sample of 100 patients, 7 reported out-of-body experiences associated with their seizures. We found no differentiating traits that were associated with patients' reports of out-of-body experiences, in terms of either demographics; medical history, including age of onset and duration of seizure disorder, and seizure frequency; seizure characteristics, including localization, lateralization, etiology, and type of seizure, and epilepsy syndrome; or ability to recall any subjective experiences associated with their seizures. Reporting out-of-body experiences in association with seizures did not affect epilepsy-related quality of life. It should be noted that even in those patients who report out-of-body experiences, such sensations are extremely rare events that do not occur routinely with their seizures. Most patients who reported out-of-body experiences described one or two experiences that occurred an indeterminate number of years ago, which precludes the possibility of associating the experience with the particular characteristics of that one seizure or with medications taken or other conditions at the time.
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Environmental influences on maize-Aspergillus flavus interactions and aflatoxin production.
Front Microbiol
PUBLISHED: 01-01-2014
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Since the early 1960s, the fungal pathogen Aspergillus flavus (Link ex Fr.) has been the focus of intensive research due to the production of carcinogenic and highly toxic secondary metabolites collectively known as aflatoxins following pre-harvest colonization of crops. Given this recurrent problem and the occurrence of a severe aflatoxin outbreak in maize (Zea mays L.), particularly in the Southeast U.S. in the 1977 growing season, a significant research effort has been put forth to determine the nature of the interaction occurring between aflatoxin production, A. flavus, environment and its various hosts before harvest. Many studies have investigated this interaction at the genetic, transcript, and protein levels, and in terms of fungal biology at either pre- or post-harvest time points. Later experiments have indicated that the interaction and overall resistance phenotype of the host is a quantitative trait with a relatively low heritability. In addition, a high degree of environmental interaction has been noted, particularly with sources of abiotic stress for either the host or the fungus such as drought or heat stresses. Here, we review the history of research into this complex interaction and propose future directions for elucidating the relationship between resistance and susceptibility to A. flavus colonization, abiotic stress, and its relationship to oxidative stress in which aflatoxin production may function as a form of antioxidant protection to the producing fungus.
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Multidimensional LC-MS/MS Enables Simultaneous Quantification of Intact Human Insulin and Five Recombinant Analogs in Human Plasma.
Anal. Chem.
PUBLISHED: 12-17-2013
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This work provides a multidimensional method for the simultaneous, direct quantification of intact human insulin and five insulin analogs in human plasma. This investigation solves both the selectivity and sensitivity problems encountered for accurate quantification of insulins in plasma since the former is not possible with conventional assays and the latter with conventional LC-MS/MS. The method uses a mixed-mode SPE and a multidimensional LC method including a solid-core particle column containing an anion exchange stationary phase. Matrix factors for all analogs were calculated in 6 sources of human plasma and CVs of the matrix factors were <15% in all cases supporting the selectivity of the method, while achieving LLOQs of 50-200 pg/mL (1.4-5.6 ?IU/mL) for each insulin from 250 ?L of human plasma. The average accuracy for the standard curve points in extracted human plasma was 99-100%. Average inter- and intraday accuracies for QC samples were 98% and 94%, respectively. Average inter- and intraday precisions for QC samples were 7.5 and 5.3%, respectively. Patient samples were analyzed in a blind study and results concurred with their diabetes multidosing regimes. The study also demonstrated that the presence of high levels of human insulin and bovine insulin does not interfere with quantification of any of the analyzed analogs. We propose this method for the accurate pharmacokinetic monitoring of diabetic patients, for sport antidoping and forensic toxicology analysis.
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Refractory status epilepticus: What to put down: The anesthetics or the patient?
Neurology
PUBLISHED: 12-06-2013
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Status epilepticus is a well-recognized medical emergency that must be treated urgently to prevent permanent neuronal injury, prolonged unconsciousness, and even mortality. There is a high level of evidence that first-line treatment with benzodiazepines is indicated over other treatments based on a seminal double-blind randomized controlled trial of then-common treatments.(1) Second-line treatment is typically with IV antiepileptic drugs (AED), and while any drug might be used, the most common in clinical practice in the United States are phenytoin, levetiracetam, and valproate. At this stage of management, there are a few comparative studies, but a double-blind randomized controlled trial is needed.(2) The definition of refractory status epilepticus (RSE) is variable, but most would agree that patients who fail first- and second-line therapy have RSE. Standard third-line therapy consists of IV anesthetics; pentobarbital was historically favored but now midazolam or propofol are more often preferred. IV anesthesia is considered so effective that some have suggested moving directly to IV anesthesia and skipping second-line therapy to avoid major time delays that could contribute to ongoing excitotoxicity and neuronal injury.
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Development of a fast method for direct analysis of intact synthetic insulins in human plasma: the large peptide challenge.
Bioanalysis
PUBLISHED: 10-01-2013
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Intact insulins are difficult to analyze by LC-MS/MS due to nonspecific binding and poor sensitivity, solubility and fragmentation. This work aims to provide a simpler, faster LC-MS method and focuses on solving the above issues.
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Relationships between depression, anxiety, and pain in a group of university music students.
Med Probl Perform Art
PUBLISHED: 09-10-2013
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There is emerging interest in studying the incidence of music-related injuries and problems among students. The current study drew on a data set collected from 287 music majors and minors at a large US midwestern university school of music in order to determine if correlations existed between anxiety and/or depression and the reported presence of physical pain, and to understand the nature of any such relationships. Physical pain symptoms were scored on a scale of 0 (none) to 10 (excruciating) and summed across 21 body regions. Depression and anxiety symptoms were scored as none (0), mild (1), moderate (2), or severe (3), and each summed across either 13 symptoms for depression or 8 symptoms for anxiety. The potential linear relationship among these variables was evaluated using F-tests (as part of ANOVAs) and linear regression parameter estimation techniques. The explanatory value of these relationships was evaluated using R² values. Results indicate a clear positive linear relationship between both depression and pain, and anxiety and pain. However, the presence of depression and/or anxiety symptoms was insufficient to explain variability in pain scores of these participants.
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The established status epilepticus trial 2013.
Epilepsia
PUBLISHED: 09-05-2013
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Benzodiazepine-refractory status epilepticus (established status epilepticus, ESE) is a relatively common emergency condition with several widely used treatments. There are no controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently available treatments for ESE. The ESE treatment trial is designed to determine the most effective and/or the least effective treatment of ESE among patients older than 2 years by comparing three arms: fosphenytoin (fPHT) levetiracetam (LVT), and valproic acid (VPA). This is a multicenter, randomized, double-blind, Bayesian adaptive, phase III comparative effectiveness trial. Up to 795 patients will be randomized initially 1:1:1, and response-adaptive randomization will occur after 300 patients have been recruited. Randomization will be stratified by three age groups, 2-18, 19-65, and 66 and older. The primary outcome measure is cessation of clinical seizure activity and improving mental status, without serious adverse effects or further intervention at 60 min after administration of study drug. Each subject will be followed until discharge or 30 days from enrollment. This trial will include interim analyses for early success and futility. This trial will be considered a success if the probability that a treatment is the most effective is >0.975 or the probability that a treatment is the least effective is >0.975 for any treatment. Proposed total sample size is 795, which provides 90% power to identify the most effective and/or the least effective treatment when one treatment arm has a true response rate of 65% and the true response rate is 50% in the other two arms.
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The epilepsy phenome/genome project.
Clin Trials
PUBLISHED: 07-01-2013
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Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy.
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High-resolution peptide mapping separations with MS-friendly mobile phases and charge-surface-modified C18.
Anal. Chem.
PUBLISHED: 07-01-2013
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Ionic analytes, such as peptides, can be challenging to separate by reverse-phase chromatography with optimal efficiency. They tend, for instance, to exhibit poor peak shapes, particularly when eluted with mobile phases preferred for electrospray ionization mass spectrometry. We demonstrate that a novel charged-surface C18 stationary phase alleviates some of the challenges associated with reverse-phase peptide separations. This column chemistry, known as CSH (charged-surface hybrid) C18, improves upon an already robust organosilica hybrid stationary phase, BEH (ethylene-bridged hybrid) C18. Based on separations of a nine-peptide standard, CSH C18 was found to exhibit improved loadability, greater peak capacities, and unique selectivity compared to BEH C18. Its performance was also seen to be significantly less dependent on TFA-ion pairing, making it ideal for MS applications where high sensitivity is desired. These performance advantages were evaluated through application to peptide mapping, wherein CSH C18 was found to aid the development of a high-resolution, high-sensitivity LC-UV-MS peptide mapping method for the therapeutic antibody, trastuzumab. From these results, the use of a C18 stationary phase with a charged surface, such as CSH C18, holds significant promise for facilitating challenging peptide analyses.
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Infection versus ALVAL: acute presentation with abdominal pain.
BMJ Case Rep
PUBLISHED: 06-14-2013
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A 52-year-old man underwent bilateral articular surface replacement (ASR) DePuy in June 2006. Following a right femoral neck fracture 4 days postoperatively, he underwent revision to a cemented C-stem DePuy, a taper sleeve adaptor and a 47 mm diameter cobalt chromium femoral head. The patient recovered well with satisfactory 5-year follow-up. In September 2011 the patient presented to the accident and emergency department with a 5-day history of feeling unwell with right lower quadrant pain. Examination of the right hip was unremarkable apart from painful adduction. Blood tests showed raised inflammatory markers and white cell count. MRI scan showed a right iliopsoas collection which appeared to communicate with the hip joint. The patient underwent a direct exchange of the right hip prosthesis. The intraoperative clinical picture was suggestive of atypical lymphocytic vasculitis and associated lesions. The patient recovered well and was discharged home. At his last clinic visit he was well and pain free.
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High sensitivity LC-MS/MS method for direct quantification of human parathyroid 1-34 (teriparatide) in human plasma.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 06-10-2013
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Teriparatide, the 1-34 fragment of human parathyroid hormone, is used to treat osteoporosis patients with a high risk of fracture by stimulating new bone formation. Routinely teriparatide is quantified using radioimmunoassay however the LC-MS/MS described here has the potential to achieve greater accuracy and precision, higher specificity, and is readily implemented in routine bioanalytical laboratories. Hence a complete method combining effective sample prep with appropriate LC separation and selected reaction monitoring (SRM) MS detection was developed to selectively separate teriparatide from closely related endogenous peptides and to reduce interferences. Samples were concentrated without evaporation, minimizing the risk of adsorptive losses. Chromatography was performed on a sub 2?m particle charged surface hybrid column, which provided significantly higher peak capacity than a traditional C18 column when formic acid was used as the mobile phase modifier. Total LC cycle time was 6min. An LOD of 15pg/mL (3.6fmol/mL) from 200?L of human plasma was readily achieved and standard curves were accurate and precise from 15pg/mL to 500pg/mL. Mean QC accuracies ranged from 90% to 106%. Mean QC precision was better than 7%. The CV of matrix factors across 6 sources of human plasma was 5%. The assay presented here is the first LC-MS method which reaches clinically relevant detection limits for teriparatide.
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Ultraviolet resonance Raman spectroscopy of explosives in solution and the solid state.
J Phys Chem A
PUBLISHED: 05-14-2013
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Resonance Raman cross sections of common explosives have been measured by use of excitation wavelengths in the deep-UV from 229 to 262 nm. These measurements were performed both in solution and in the native solid state for comparison. While measurements of UV Raman cross sections in solution with an internal standard are straightforward and commonly found in the literature, measurements on the solid phase are rare. This is due to the difficulty in preparing a solid sample in which the molecules of the internal standard and absorbing analyte/explosive experience the same laser intensity. This requires producing solid samples that are mixtures of strongly absorbing explosives and an internal standard transparent at the UV wavelengths used. For the solid-state measurements, it is necessary to use nanostructured mixtures of the explosive and the internal standard in order to avoid this bias due to the strong UV absorption of the explosive. In this study we used a facile spray-drying technique where the analyte of interest was codeposited with the nonresonant standard onto an aluminum-coated microscope slide. The generated resonance enhancement profiles and quantitative UV-vis absorption spectra were then used to plot the relative Raman return as a function of excitation wavelength and particle size.
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Characterization and treatment of patients with chronic rhinosinusitis and nasal polyps.
Ann. Allergy Asthma Immunol.
PUBLISHED: 04-30-2013
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Patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs) may be subdivided into aspirin-sensitive (AS) and aspirin-tolerant (AT) populations. These cohorts are not well characterized.
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Sex differences in adult cognitive deficits after adolescent nicotine exposure in rats.
Neurotoxicol Teratol
PUBLISHED: 04-30-2013
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This study was designed to determine whether deficits in adult serial pattern learning caused by adolescent nicotine exposure persist as impairments in asymptotic performance, whether adolescent nicotine exposure differentially retards learning about pattern elements that are inconsistent with "perfect" pattern structure, and whether there are sex differences in rats response to adolescent nicotine exposure as assessed by a serial multiple choice task. The current study replicated the results of our initial report (Fountain et al., 2008) using this task by showing that adolescent nicotine exposure (1.0mg/kg/day nicotine for 35days) produced a specific cognitive impairment in male rats that persisted into adulthood at least a month after adolescent nicotine exposure ended. In addition, sex differences were observed even in controls, with additional evidence that adolescent nicotine exposure significantly impaired learning relative to same-sex controls for chunk boundary elements in males and for violation elements in females. All nicotine-induced impairments were overcome by additional training so that groups did not differ at asymptote. An examination of the types of errors rats made indicated that adolescent nicotine exposure slowed learning without affecting rats cognitive strategy in the task. This data pattern suggests that exposure to nicotine in adolescence may have impaired different aspects of adult stimulus-response discrimination learning processes in males and females, but left abstract rule learning processes relatively spared in both sexes. These effects converge with other findings in the field and reinforce the concern that adolescent nicotine exposure poses an important threat to cognitive capacity in adulthood.
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Surface-enhanced Raman scattering (SERS) evaluation protocol for nanometallic surfaces.
Appl Spectrosc
PUBLISHED: 04-23-2013
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We present the results of a three-year collaboration between the U.S. Army Edgewood Chemical Biological Center and the U.S. Army Research Laboratory-Aldelphi Laboratory Center on the evaluation of selected nanometallic surfaces developed for the Defense Advanced Research Projects Agency Surface-Enhanced Raman Scattering (SERS) Science and Technology Fundamentals program. The primary role of the two Army labs was to develop the analytical and spectroscopic figures of merit to unambiguously compare the sensitivity and reproducibility of various SERS substrates submitted by the program participants. We present the design and implementation of an evaluation protocol for SERS active surfaces enabling an enhancement value calculation from which different substrates can be directly compared. This method was established to: (1) collect physical and spectral characterization data from the small number of substrates (performer supplied) typically encountered, and (2) account for the complex fabrication technique and varying nature of the substrate platforms encountered within this program.
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Accelerated thermokarst formation in the McMurdo Dry Valleys, Antarctica.
Sci Rep
PUBLISHED: 04-11-2013
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Thermokarst is a land surface lowered and disrupted by melting ground ice. Thermokarst is a major driver of landscape change in the Arctic, but has been considered to be a minor process in Antarctica. Here, we use ground-based and airborne LiDAR coupled with timelapse imaging and meteorological data to show that 1) thermokarst formation has accelerated in Garwood Valley, Antarctica; 2) the rate of thermokarst erosion is presently ~ 10 times the average Holocene rate; and 3) the increased rate of thermokarst formation is driven most strongly by increasing insolation and sediment/albedo feedbacks. This suggests that sediment enhancement of insolation-driven melting may act similarly to expected increases in Antarctic air temperature (presently occurring along the Antarctic Peninsula), and may serve as a leading indicator of imminent landscape change in Antarctica that will generate thermokarst landforms similar to those in Arctic periglacial terrains.
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Multiple births following in vitro fertilization treatment: redefining success.
Eur. J. Obstet. Gynecol. Reprod. Biol.
PUBLISHED: 03-13-2013
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The focus of this article is to review the definition of success following in vitro fertilization (IVF) treatment. Pregnancy rates after IVF have been increasing, but the problem of multiple births with its associated morbidity and mortality has been considerable. This has led to rethinking of assisted reproductive technology (ART) success not only in terms of live birth rates, but also in terms of reduction of multiple births to singleton babies. Single embryo transfer using blastocysts and such other measures are being encouraged. Financial factors and patient satisfaction are key issues. IVF success is thus being redefined.
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De novo mutations in epileptic encephalopathies.
Nature
PUBLISHED: 03-03-2013
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Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ?4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9?×?10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1?×?10(-10) and P = 7.8?×?10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P?
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Flipping the classroom to improve student performance and satisfaction.
J Nurs Educ
PUBLISHED: 03-01-2013
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This study aimed to determine the effects of a flipped classroom (i.e., reversal of time allotment for lecture and homework) and innovative learning activities on academic success and the satisfaction of nursing students. A quasi-experimental design was used to compare three approaches to learning: traditional lecture only (LO), lecture and lecture capture back-up (LLC), and the flipped classroom approach of lecture capture with innovative classroom activities (LCI). Examination scores were higher for the flipped classroom LCI group (M = 81.89, SD = 5.02) than for both the LLC group (M = 80.70, SD = 4.25), p = 0.003, and the LO group (M = 79.79, SD = 4.51), p < 0.001. Students were less satisfied with the flipped classroom method than with either of the other methods (p < 0.001). Blending new teaching technologies with interactive classroom activities can result in improved learning but not necessarily improved student satisfaction.
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Attentional biases for betel nut cues in heavy and light chewers.
Psychol Addict Behav
PUBLISHED: 02-25-2013
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The betel nut (Areca catecu) is regarded by the World Health Organization as the fourth most prevalent human carcinogen. Our study aims to investigate whether habitual chewers show bias in their attention toward betel nut usage. In the current study, heavy and light betel nut chewers were instructed to respond to a probe presented immediately after either one of a pair of areca-related picture and non-areca-matched picture. The presentation durations of these pictures were manipulated to investigate attentional biases under awareness threshold (17 ms), in initial orienting (200 ms), and maintenance of attention (2,000 ms). Faster response to the probe replacing the areca-related picture, in comparison with a matched picture, indicated attentional bias. The results showed that neither group showed subliminal attentional biases. Further, heavy chewers, but not light chewers, exhibited supraliminal biases toward betel nut cues in initial orienting of attention and maintained attention. Moreover, attentional bias scores at 2,000 ms were also shown to be positively associated with betel nut craving and dependence. Implications of the current findings are thoroughly discussed in the article. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
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Delivering quality care in epilepsy.
Curr. Opin. Neurol.
PUBLISHED: 02-22-2013
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The science of quality of care in medicine has been emerging for the past decade, but it has only recently addressed epilepsy care. Quality of care in this sense refers to implementation of policies in large populations to improve care. This can have a large impact on epilepsy patients, as much of their care is delivered by generalists who can improve their care through the explicit direct requirements of quality measures.
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Acute Transverse Myelitis Associated with Buserelin Use during IVF.
Case Rep Obstet Gynecol
PUBLISHED: 02-21-2013
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A healthy woman undergoing in vitro fertilization (IVF) developed acute transverse myelitis (ATM) following the use of Buserelin. ATM has a multifactorial etiology and may develop as a result of the activation of immune responses. Infectious agents have been postulated as possible triggers of an immune response (Sá, 2009). Gonadotropin-releasing agonists may have a similar role and trigger the acceleration of preexisting disease by the activation of immune responses (Ho et al., 1995, and Umesaki et al., 1999).
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Central cholinergic involvement in sequential behavior: Impairments of performance by atropine in a serial multiple choice task for rats.
Neurobiol Learn Mem
PUBLISHED: 02-04-2013
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Two experiments examined whether muscarinic cholinergic systems play a role in rats ability to perform well-learned highly-structured serial response patterns, particularly focusing on rats performance on pattern elements learned by encoding rules versus by acquisition of stimulus-response (S-R) associations. Rats performed serial patterns of responses in a serial multiple choice task in an 8-lever circular array for hypothalamic brain-stimulation reward. Two experiments examined the effects of atropine, a centrally-acting muscarinic cholinergic receptor antagonist, on rats ability to perform pattern elements where responses were controlled by rules versus elements, such as rule-inconsistent "violation elements" and elements following "phrasing cues," where responses were controlled by associative cues. In Experiment 1, 3-element chunks of both patterns were signaled by pauses that served as phrasing cues before chunk-boundary elements, but one pattern also included a violation element that was inconsistent with pattern structure. Once rats reached a high criterion of performance, the drug challenge was intraperitoneal injection of a single dose of 50mg/kg atropine sulfate. Atropine impaired performance on elements learned by S-R learning, namely, chunk-boundary elements and the violation element, but had no effect on performance of rule-based within-chunk elements. In Experiment 2, patterns were phrased and unphrased perfect patterns (i.e., without violation elements). To control for peripheral effects of atropine, rats were treated with a series of doses of either centrally-acting atropine or peripherally-acting atropine methyl nitrate (AMN), which does not cross the blood-brain barrier. Once rats reached a high criterion, the drug challenges were on alternate days in the order 50, 25, and 100mg/kg of either atropine sulfate or AMN. Atropine, but not AMN, impaired performance in the phrased perfect pattern for pattern elements where S-R associations were important for performance, namely, chunk-boundary elements. However, in the structurally more ambiguous unphrased perfect pattern where rats had fewer cues and presumably relied more on S-R associations throughout, atropine impaired performance on all pattern elements. Thus, intact muscarinic cholinergic systems were shown to be necessary for discriminative control previously established by S-R learning, but were not necessary for rule-based serial pattern performance.
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Many young men with prostate-specific antigen (PSA) screen-detected prostate cancers may be candidates for active surveillance.
BJU Int.
PUBLISHED: 01-25-2013
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WHATS KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Little is known as to the potential for over-treatment of young men diagnosed with prostate cancer. We show that for men aged ?55 years with PSA screen-detected disease, 45% of the tumours are classified as very low risk and 85% of these have favourable pathology, yet most are actively treated. These findings raise the spectre of over-treatment for a group of men likely to be affected by treatment side-effects.
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The utilization of poisons information resources in Australasia.
Int J Med Inform
PUBLISHED: 01-21-2013
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To identify poisons information resources most commonly utilized by Australasian Emergency Department staff, and examine attitudes regarding the benefits and user experience of the electronic products used.
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Constitutive and agonist stimulated ATP secretion in leukocytes.
Commun Integr Biol
PUBLISHED: 01-14-2013
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Release and reception of extracellular ATP by leukocytes plays a critical role in immune responses to infection, injury and cardiovascular disease. Leukocytes of both the innate, adaptive immune and central nervous system express a repertoire of cell surface receptors for ATP (P2X and P2Y receptors) and its metabolites. ATP acts as a damage-associated molecule pattern (DAMP) released by injured or dying cells. Detection of released ATP by neighboring leukocytes initiates inflammation and wound healing. However, recent evidence from our group and others suggests ATP release by leukocytes themselves serves to regulate homeostatic mechanisms and coordinate responses to external pro-inflammatory cues. Examples include the homeostatic control of intracellular calcium and regulation of migratory guidance during chemotactic response to external cues. Though there has been some progress in elucidating ATP release mechanisms of some mammalian cells types, release conduits and coupling signal transduction machinery remain larger elusive for leukocytes. Our recent studies suggest a role for secretory lysosomes in releasing ATP in monocytes. Though poorly defined, targeting ATP release mechanisms in leukocytes have great anti-inflammatory potential.
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Primitive ATP-activated P2X receptors: discovery, function and pharmacology.
Front Cell Neurosci
PUBLISHED: 01-01-2013
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Adenosine 5-triphosphate (ATP) is omnipresent in biology. It is therefore no surprise that organisms have evolved multifaceted roles for ATP, exploiting its abundance and restriction of passive diffusion across biological membranes. A striking role is the emergence of ATP as a bona fide transmitter molecule, whereby the movement of ATP across membranes serves as a chemical message through a direct ligand-receptor interaction. P2X receptors are ligand-gated ion channels that mediate fast responses to the transmitter ATP in mammalian cells including central and sensory neurons, vascular smooth muscle, endothelium, and leukocytes. Molecular cloning of P2X receptors and our understanding of structure-function relationships has provided sequence information with which to query an exponentially expanding wealth of genome sequence information including protist, early animal and human pathogen genomes. P2X receptors have now been cloned and characterized from a number of simple organisms. Such work has led to surprising new cellular roles for the P2X receptors family and an unusual phylogeny, with organisms such as Drosophila and C. elegans notably lacking P2X receptors despite retaining ionotropic receptors for other common transmitters that are present in mammals. This review will summarize current work on the evolutionary biology of P2X receptors and ATP as a signaling molecule, discuss what can be drawn from such studies when considering the action of ATP in higher animals and plants, and outline how simple organisms may be exploited experimentally to inform P2X receptor function in a wider context.
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Differential and site specific impact of B cells in the protective immune response to Mycobacterium tuberculosis in the mouse.
PLoS ONE
PUBLISHED: 01-01-2013
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Cell-mediated immune responses are known to be critical for control of mycobacterial infections whereas the role of B cells and humoral immunity is unclear. B cells can modulate immune responses by secretion of immunoglobulin, production of cytokines and antigen-presentation. To define the impact of B cells in the absence of secreted immunoglobulin, we analyzed the progression of Mycobacterium tuberculosis (Mtb) infection in mice that have B cells but which lack secretory immunoglobulin (AID(-/-)µS(-/-)mice). AID(-/-)µS(-/-) mice accumulated a population of activated B cells in the lungs when infected and were more susceptible to aerosol Mtb when compared to wild type (C57BL/6) mice or indeed mice that totally lack B cells. The enhanced susceptibility of AID(-/-)µS(-/-) mice was not associated with defective T cell activation or expression of a type 1 immune response. While delivery of normal serum to AID(-/-)µS(-/-) mice did not reverse susceptibility, susceptibility in the spleen was dependent upon the presence of B cells and susceptibility in the lungs of AID(-/-)µS(-/-)mice was associated with elevated expression of the cytokines IL-6, GM-CSF, IL-10 and molecules made by alternatively activated macrophages. Blocking of IL-10 signaling resulted in reversal of susceptibility in the spleens and lungs of AID(-/-)µS(-/-) mice. These data support the hypothesis that B cells can modulate immunity to Mtb in an organ specific manner via the modulation of cytokine production and macrophage activation.
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Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California.
Int J Epidemiol
PUBLISHED: 12-07-2011
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The incidence and prevalence of autism have dramatically increased over the last 20 years. Decomposition of autism incidence rates into age, period and cohort effects disentangle underlying domains of causal factors linked to time trends. We estimate an age-period-cohort effect model for autism diagnostic incidence overall and by level of functioning.
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Pathophysiology and definitions of seizures and status epilepticus.
Emerg. Med. Clin. North Am.
PUBLISHED: 11-08-2011
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The pathophysiology of seizures is multifactorial and incompletely understood. Experimental work demonstrates that prolonged, abnormal, and excessive neuronal electrical activity in itself is injurious through several mechanisms independent of systemic acidosis and hypoxia. Population survival studies and laboratory investigations support the idea that brain injury and epileptogenesis result from status epilepticus. The basic distinction in seizure types is that of generalized and partial seizures. Correct classification of seizure types will aid in clinical communications and guide correct therapies. Revised definitions of generalized convulsive status epilepticus suggest making this diagnosis with as few as 5 minutes of continuous seizure activity.
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Advanced practice nurse outcomes 1990-2008: a systematic review.
Nurs Econ
PUBLISHED: 10-25-2011
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Advanced practice registered nurses have assumed an increasing role as providers in the health care system, particularly for underserved populations. The aim of this systematic review was to answer the following question: Compared to other providers (physicians or teams without APRNs) are APRN patient outcomes of care similar? This systematic review of published literature between 1990 and 2008 on care provided by APRNs indicates patient outcomes of care provided by nurse practitioners and certified nurse midwives in collaboration with physicians are similar to and in some ways better than care provided by physicians alone for the populations and in the settings included. Use of clinical nurse specialists in acute care settings can reduce length of stay and cost of care for hospitalized patients. These results extend what is known about APRN outcomes from previous reviews by assessing all types of APRNs over a span of 18 years, using a systematic process with intentionally broad inclusion of outcomes, patient populations, and settings. The results indicate APRNs provide effective and high-quality patient care, have an important role in improving the quality of patient care in the United States, and could help to address concerns about whether care provided by APRNs can safely augment the physician supply to support reform efforts aimed at expanding access to care.
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IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the infected lung.
J. Immunol.
PUBLISHED: 10-14-2011
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IL-23 is required for the IL-17 response to infection with Mycobacterium tuberculosis, but is not required for the early control of bacterial growth. However, mice deficient for the p19 component of IL-23 (Il23a(-/-)) exhibit increased bacterial growth late in infection that is temporally associated with smaller B cell follicles in the lungs. Cxcl13 is required for B cell follicle formation and immunity during tuberculosis. The absence of IL-23 results in decreased expression of Cxcl13 within M. tuberculosis-induced lymphocyte follicles in the lungs, and this deficiency was associated with increased cuffing of T cells around the vessels in the lungs of these mice. Il23a(-/-) mice also poorly expressed IL-17A and IL-22 mRNA. These cytokines were able to induce Cxcl13 in mouse primary lung fibroblasts, suggesting that these cytokines are likely involved in B cell follicle formation. Indeed, IL-17RA-deficient mice generated smaller B cell follicles early in the response, whereas IL-22-deficient mice had smaller B cell follicles at an intermediate time postinfection; however, only Il23a(-/-) mice had a sustained deficiency in B cell follicle formation and reduced immunity. We propose that in the absence of IL-23, expression of long-term immunity to tuberculosis is compromised due to reduced expression of Cxcl13 in B cell follicles and reduced ability of T cells to migrate from the vessels and into the lesion. Further, although IL-17 and IL-22 can both contribute to Cxcl13 production and B cell follicle formation, it is IL-23 that is critical in this regard.
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Improving clinician-patient communication of health risks when diagnostic test information is imprecise.
N. Z. Med. J.
PUBLISHED: 10-04-2011
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Both clinicians and patients experience difficulty with the statistical reasoning required to make inferences about health states on the basis of information derived from diagnostic tests. This problem will grow in importance as we move into the era of personalised medicine where an increasing supply of imprecise diagnostic tests meets an increasing demand to use such tests on the part of intelligent but statistically innumerate clinicians and patients. We describe a user-friendly, interactive, graphical interface for calculating, visualising, and communicating accurate inferences about uncertain health states when diagnostic information (test sensitivity and specificity, and health state prevalence) is imprecise and ambiguous in its application to a specific patient. The software is free, open-source, and runs on all popular PC operating systems (Windows, Mac, Linux).
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How current understanding of clearance mechanisms and pharmacodynamics of therapeutic proteins can be applied for evaluation of their drug-drug interaction potential.
Drug Metab. Dispos.
PUBLISHED: 07-18-2011
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Increasing use of therapeutic proteins (TPs) in polypharmacy settings calls for more in-depth understanding of the biological interactions that can lead to increased toxicity or loss of pharmacological effect. Factors such as patient population, medications that are likely to be coadministered in that population, clearance mechanisms of a TP, and concomitant drugs have to be taken into account to determine the potential for drug-drug interactions (DDIs). The most well documented TP DDI mechanism involves cytokine-mediated changes in drug-metabolizing enzymes. Because of the limitations of the current preclinical models for addressing this type of DDI, clinical evaluation is currently the most reliable approach. Other DDI mechanisms need to be addressed on a case-by-case basis. These include altered clearance of TPs resulting from the changes in the target protein levels by the concomitant medication, displacement of TPs from binding proteins, modulation of Fc? receptor expression, and others. The purpose of this review is to introduce the approach used by Pfizer scientists for evaluation of the DDI potential of novel TP products during drug discovery and development.
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Eyelid eversion for visualisation of the upper eyelid lamellae: an anatomical cadaver study.
Br J Ophthalmol
PUBLISHED: 07-11-2011
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Controversy persists in surgical eyelid anatomy despite the routine use of microanatomical examination in modern eyelid research. The aim of our study was to facilitate visualisation of upper eyelid anatomy by optimising the orientation of cadaveric specimens. We studied the anatomy of everted eyelids, providing an excellent histological view of the posterior approach to the eyelid commonly used in surgery. Non-traumatic separation of the eyelid lamellae provides a new view of the eyelids lamellar nature. Further application of this model may enhance understanding of the multilayered aspect of the levator aponeurosis. The technique may improve intraoperative understanding of critical eyelid anatomy and promote safer and more effective eyelid surgery.
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Recognition of thymine in DNA bulges by a Zn(II) macrocyclic complex.
Chem. Commun. (Camb.)
PUBLISHED: 06-27-2011
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A Zn(II) macrocyclic complex with appended quinoline is a bifunctional recognition agent that uses both the Zn(II) center and the pendent aromatic group to bind to thymine in bulges with good selectivity over DNA containing G, C or A bulges. Spectroscopic studies show that the stem containing the bulge stays largely intact in a DNA hairpin with the Zn(II) complex bound to the thymine bulge.
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Risk as Social Context: Immigration Policy and Autism in California.
Sociol Forum (Randolph N J)
PUBLISHED: 06-07-2011
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Motivated by the dramatic increase in autism diagnoses in recent years, research into risk factors has uncovered substantial variation in autism prevalence by race/ethnicity, SES, and geography. Less studied is the connection between autism diagnosis rates and the social and political context. In this article, we link the temporal pattern of autism diagnosis for Hispanic children in California to state and federal anti-immigrant policy, particularly ballot initiative Proposition 187, limiting access to public services for undocumented immigrants and their families. Using a population-level dataset of 1992-2003 California births linked to 1992-2006 autism case records, we show that the effects of state and federal policies toward immigrants are visible in the rise and fall of autism risk over time. The common epidemiological practice of estimating risk on pooled samples is thereby shown to obscure patterns and mis-estimate effect sizes. Finally, we illustrate how spatial variation in Hispanic autism rates reflects differential vulnerability to these policies. This study reveals not only the spillover effects of immigration policy on childrens health, but also the hazards of treating individual attributes like ethnicity as risk factors without regard to the social and political environments that give them salience.
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Semi-automated detection of trace explosives in fingerprints on strongly interfering surfaces with Raman chemical imaging.
Appl Spectrosc
PUBLISHED: 06-07-2011
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We have previously demonstrated the use of wide-field Raman chemical imaging (RCI) to detect and identify the presence of trace explosives in contaminated fingerprints. In this current work we demonstrate the detection of trace explosives in contaminated fingerprints on strongly Raman scattering surfaces such as plastics and painted metals using an automated background subtraction routine. We demonstrate the use of partial least squares subtraction to minimize the interfering surface spectral signatures, allowing the detection and identification of explosive materials in the corrected Raman images. The resulting analyses are then visually superimposed on the corresponding bright field images to physically locate traces of explosives. Additionally, we attempt to address the question of whether a complete RCI of a fingerprint is required for trace explosive detection or whether a simple non-imaging Raman spectrum is sufficient. This investigation further demonstrates the ability to nondestructively identify explosives on fingerprints present on commonly found surfaces such that the fingerprint remains intact for further biometric analysis.
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The validation of a simple LC/MS/MS method for determining the level of mevalonic acid in human plasma.
Biomed. Chromatogr.
PUBLISHED: 06-04-2011
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A simple plasma extraction method coupled with liquid chromatography-tandem mass spectrometry (LC/MS/MS) detection was developed and validated for the analysis of endogenous mevalonic acid (MVA), a biomarker indicative of the rate of cholesterol biosynthesis, in human plasma samples. The analyte was extracted from the plasma matrix using a straightforward liquid-liquid sample preparation procedure. The extract supernatants were evaporated, reconstituted in aqueous solvent and injected into the LC/MS/MS system without further processing. The chromatographic separation was achieved on a reverse-phase high-performance liquid chromatography column. The accuracy and precision of the method was determined over the concentration range 0.25-25?ng/mL MVA from human plasma extracts in three validation batch runs. Inter-assay precision (%CV) and accuracy (%RE) of the quality control samples were ?7.00% (at lower limit quality control) and ?6.10%, respectively. The sensitivity and throughput of this assay was significantly improved relative to previously published methods, resulting in smaller sample requirements and shorter analysis time. Assay results from a clinical study following the oral administration of an exploratory statin demonstrate that this procedure could potentially be used in the investigation of therapies associated with hypercholesterolemia.
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When should clinicians order genetic testing for Dravet syndrome?
Pediatr. Neurol.
PUBLISHED: 05-06-2011
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The role of neuronal voltage-gated sodium channel, ?-1 subunit (SCN1A) gene mutations in Dravet syndrome is well-established. With a broader phenotype than initially described, some patients lack features of Dravet syndrome as defined by the International League Against Epilepsy. We evaluated the predictive value of International League Against Epilepsy criteria for a positive mutation in a cohort of consecutively tested children. Mutations of SCN1A were evident in 16 of 69 children. Exhibiting ?4 International League Against Epilepsy criteria demonstrated 100% sensitivity. Seven criteria (resistance to multiple antiepileptic drugs, multiple seizure types, abnormal electroencephalogram features, exacerbation with hyperthermia, normal development before seizure onset, seizures beginning before age 1 year, and psychomotor retardation) were present in ?85% of mutation-positive cases. The three criteria that best predicted a mutation in SCN1A included exacerbation with hyperthermia, normal development before seizure onset, and the appearance of ataxia, pyramidal signs, or interictal myoclonus. We have demonstrated a high-sensitivity testing strategy for detecting mutations of SCN1A in children with suspected Dravet syndrome.
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Low molecular weight heparin downregulates tissue factor expression and activity by modulating growth factor receptor-mediated induction of nuclear factor-?B.
Biochim. Biophys. Acta
PUBLISHED: 05-06-2011
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Treatment of cancer patients with low molecular weight heparin (LMWH) appears to have beneficial effects. In this study, the influence of low molecular weight heparin (LMWH) on tissue factor (TF) expression and activity in five cell lines from various tissues was analysed and explored. Incubation of cells with LMWH (0-2000?g/ml) resulted in the downregulation of TF mRNA expression which was both LMWH concentration-dependent and time-dependent. Downregulation of TF was also measured as decreased cellular TF antigen and activity. Consistently, incubation of cells with LMWH suppressed the nuclear localisation and the transcriptional activity of NF?B. Decreased TF mRNA was largely achievable by incubating the cells with an NF?B inhibitor alone whilst incubation with betulinic acid to activate NF?B reversed the inhibitory influence of LMWH. Cells were also incubated with a range of concentrations of EGF (0-10ng/ml), bFGF (0-20ng/ml) or VEGF (0-4ng/ml) in the presence or absence of LMWH (200?g/ml) for 24h and TF antigen measured. Inclusion of LMWH reduced TF expression in response to EGF, bFGF or VEGF but TF expression was partially restored by increasing concentrations of the growth factors. We conclude that LMWH downregulates TF expression in vitro through a mechanism that involves interference with the function of growth factors which in turn is mediated through the downregulation of the transcriptional activity of NF?B. This mechanism may also explain some of the beneficial influences attributed to LMWH therapy in the treatment of cancer patients.
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An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial.
J Drugs Dermatol
PUBLISHED: 05-03-2011
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Atopic dermatitis (AD) is a prevalent skin disorder with significant cost of treatment. Several prescription device moisturizers have been approved by the FDA to treat AD but are significantly more expensive than well-crafted over-the-counter (OTC) moisturizers. No studies have been performed to compare both the clinical efficacy and cost-efficacy of these prescription devices to OTC moisturizers.
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Think globally, learn locally: Multimedia conferencing between two schools of nursing.
Nurs Educ Perspect
PUBLISHED: 04-09-2011
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Three nurse educators, who met at the American Nurses Association Nursing Care in Life, Death and Disaster Conference (Atlanta, June 2007), collaborated on a multimedia conferencing project to teach nursing students about disaster response. This case study examines two outcomes of this project. The project provided students in a disaster nursing course in Indiana an opportunity to meet faculty who helped establish and maintain a special needs shelter in Texas following Hurricanes Katrina and Rita. It also demonstrated, through the use of technology, the ability of nurse faculty to share their expertise with colleagues and students residing in different geographical locations.
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Coronary artery dilation in sickle cell disease.
J. Pediatr.
PUBLISHED: 03-24-2011
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To evaluate the prevalence of coronary artery dilation in children with sickle cell disease (SCD).
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Simultaneous typical and extraordinary imaging findings of AIDS-associated cytomegalovirus encephalitis.
J. Neurol. Sci.
PUBLISHED: 02-21-2011
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Encephalitis caused by cytomegalovirus (CMV) is a devastating disease that occurs mostly in profoundly immunocompromised individuals, particularly in the setting of advanced HIV infection or organ transplantation. Imaging findings in AIDS-associated cytomegalovirus encephalitis that have been described range from ventriculitis (more common) to solitary mass lesions (less common). We describe a fatal case of AIDS-associated cytomegalovirus encephalitis that included typical imaging findings but also atypical features with widespread, multifocal lesions demonstrating restricted diffusion on magnetic resonance imaging (MRI). It is likely that these diffusion abnormalities are appreciated due to changes in imaging technology from the pre-highly active antiretroviral therapy era in which the typical imaging findings of CMV encephalitis were first described. The differential diagnosis of widespread, multifocal lesions with restricted diffusion in the setting of AIDS should now include CMV encephalitis.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

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.