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Find video protocols related to scientific articles indexed in Pubmed.
Evaluation of the association of maternal pertussis vaccination with obstetric events and birth outcomes.
JAMA
PUBLISHED: 11-12-2014
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In 2010, due to a pertussis outbreak and neonatal deaths, the California Department of Health recommended that the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) be administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks' gestation. Limited data exist on Tdap safety during pregnancy.
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Evaluating Washington State's immunization information system as a research tool.
Acad Pediatr
PUBLISHED: 09-18-2014
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Immunization information systems (IISs) are powerful public health tools for vaccination activities. To date, however, their use for public health research has been limited, in part as a result of insufficient understanding on accuracy and quality of IIS data. We evaluated the completeness and accuracy of Washington State IIS (WAIIS) data, with particular attention to data elements of research interest.
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The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats.
Eur. J. Pharmacol.
PUBLISHED: 08-23-2014
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The treatment of dyskinesia in Parkinson?s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets. Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia. H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.
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Differential regulation of NMDAR and NMDAR-mediated metaplasticity by anandamide and 2-AG in the hippocampus.
Hippocampus
PUBLISHED: 07-28-2014
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Endocannabinoids (eCBs), including AEA and 2-AG, are endogenous signaling mediators involved in many physiological and pathological events. The G protein-coupled cannabinoid receptor 1 (CB1 R) is an important target for eCBs, however, additional non-CB1 receptor targets have also been identified. Although recent evidence suggests that NMDA receptor function may be regulated by eCBs, the underlying mechanisms remain poorly characterized. Using acutely isolated CA1 neurons and slices from the hippocampus, we found that both AEA and 2-AG potentiate NMDAR-mediated currents independently of CB1 receptors (CB1 Rs) and via distinct signaling pathways. Potentiation by AEA requires the activation of TRPV1 channels. In contrast, potentiation by 2-AG requires the sequential activation of PKC and Src. Additionally, in hippocampal slices, we found that both AEA and 2-AG induce NMDAR-mediated metaplasticity and facilitate the induction of subsequent LTD independently of CB1 Rs. Enhanced LTD by AEA, but not 2-AG, was dependent on TRPV1 channels. Our findings reveal previously unrecognized non-CB1 R-dependent signaling cascades through which the two major eCBs regulate NMDA receptor function and consequently synaptic plasticity. © 2014 Wiley Periodicals, Inc.
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Use of Screws and Cement in Revision TKA With Primary or Revision Specific Prosthesis With Up to 17Years Followup.
J Arthroplasty
PUBLISHED: 07-25-2014
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The purpose of this study was to investigate the use for screws and cement, and primary and revision specific prosthesis for revision TKA. Between July 1989 and February 2010, 839 consecutive revision TKAs were performed, with 609 knees meeting inclusion criteria. At 17years followup, Kaplan-Meier survivorship was 0.9859 for revision specific prosthesis with screws and cement, 0.9848 for revision prosthesis with no screws, 0.9118 for primary prosthesis with screws, and 0.9424 for primary prosthesis with no screws. Revision TKAs using screws had greater defects (P<.0001). Use of revision prosthesis along with screws and cement to correct largely defective revision TKAs is highly recommended.
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Use of influenza antiviral agents by ambulatory care clinicians during the 2012-2013 influenza season.
Clin. Infect. Dis.
PUBLISHED: 07-16-2014
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Early antiviral treatment (?2 days since illness onset) of influenza reduces the probability of influenza-associated complications. Early empiric antiviral treatment is recommended for those with suspected influenza at higher risk for influenza complications regardless of their illness severity. We describe antiviral receipt among outpatients with acute respiratory illness (ARI) and antibiotic receipt among patients with influenza.
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Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog.
Biochemistry
PUBLISHED: 07-10-2014
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Human sulfide:quinone oxidoreductase (SQOR) catalyzes the conversion of H2S to thiosulfate, the first step in mammalian H2S metabolism. SQOR's inability to produce the glutathione persulfide (GSS(-)) substrate for sulfur dioxygenase (SDO) suggested that a thiosulfate:glutathione sulfurtransferase (TST) was required to provide the missing link between the SQOR and SDO reactions. Although TST could be purified from yeast, attempts to isolate the mammalian enzyme were not successful. We used bioinformatic approaches to identify genes likely to encode human TST (TSTD1) and its yeast ortholog (RDL1). Recombinant TSTD1 and RDL1 catalyze a predicted thiosulfate-dependent conversion of glutathione to GSS(-). Both enzymes contain a rhodanese homology domain and a single catalytically essential cysteine, which is converted to cysteine persulfide upon reaction with thiosulfate. GSS(-) is a potent inhibitor of TSTD1 and RDL1, as judged by initial rate accelerations and ?25-fold lower Km values for glutathione observed in the presence of SDO. The combined action of GSS(-) and SDO is likely to regulate the biosynthesis of the reactive metabolite. SDO drives to completion p-toluenethiosulfonate:glutathione sulfurtransferase reactions catalyzed by TSTD1 and RDL1. The thermodynamic coupling of the irreversible SDO and reversible TST reactions provides a model for the physiologically relevant reaction with thiosulfate as the sulfane donor. The discovery of bacterial Rosetta Stone proteins that comprise fusions of SDO and TSTD1 provides phylogenetic evidence of the association of these enzymes. The presence of adjacent bacterial genes encoding SDO-TSTD1 fusion proteins and human-like SQORs suggests these prokaryotes and mammals exhibit strikingly similar pathways for H2S metabolism.
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Trans Tasman Radiation Oncology Group: Development of the Assessment of New Radiation Oncology Technology and Treatments (ANROTAT) Framework.
J Med Imaging Radiat Oncol
PUBLISHED: 05-01-2014
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The study aim was to develop a generic framework to derive the parameters to populate health-economic models for the rapid evaluation of new techniques and technologies in radiation oncology.
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Interim estimates of 2013-14 seasonal influenza vaccine effectiveness - United States, February 2014.
MMWR Morb. Mortal. Wkly. Rep.
PUBLISHED: 02-21-2014
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In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ?6 months. Each season since 2004-05, CDC has estimated the effectiveness of seasonal influenza vaccine to prevent influenza-associated, medically attended acute respiratory illness (ARI). This report uses data from 2,319 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness (Flu VE) Network during December 2, 2013-January 23, 2014, to estimate an interim adjusted effectiveness of seasonal influenza vaccine for preventing laboratory-confirmed influenza virus infection associated with medically attended ARI. During this period, overall vaccine effectiveness (VE) (adjusted for study site, age, sex, race/ethnicity, self-rated health, and days from illness onset to enrollment) against influenza A and B virus infection associated with medically attended ARI was 61%. The influenza A (H1N1)pdm09 (pH1N1) virus that emerged to cause a pandemic in 2009 accounted for 98% of influenza viruses detected. VE was estimated to be 62% against pH1N1 virus infections and was similar across age groups. As of February 8, 2014, influenza activity remained elevated in the United States, the proportion of persons seeing their health-care provider for influenza-like illness was lower than in early January but remained above the national baseline, and activity still might be increasing in some parts of the country. CDC and the Advisory Committee on Immunization Practices routinely recommend that annual influenza vaccination efforts continue as long as influenza viruses are circulating. Persons aged ?6 months who have not yet been vaccinated this season should be vaccinated. Antiviral medications are an important second line of defense to treat influenza illness and should be used as recommended among suspected or confirmed influenza patients, regardless of patient vaccination status. Early antiviral treatment is recommended for persons with suspected influenza with severe or progressive illness (e.g., hospitalized persons) and those at high risk for complications from influenza, no matter how severe the illness.
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Recent progress in understanding subtype specific regulation of NMDA receptors by G Protein Coupled Receptors (GPCRs).
Int J Mol Sci
PUBLISHED: 02-12-2014
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G Protein Coupled Receptors (GPCRs) are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs), which belong to the ionotropic glutamate receptor family, are likewise ubiquitously expressed in the central nervous system (CNS) and play a pivotal role in learning and memory. Despite its critical contribution to physiological and pathophysiological processes, few pharmacological interventions aimed directly at regulating NMDAR function have been developed to date. However, it is well established that NMDAR function is precisely regulated by cellular signalling cascades recruited downstream of G protein coupled receptor (GPCR) stimulation. Accordingly, the downstream regulation of NMDARs likely represents an important determinant of outcome following treatment with neuropsychiatric agents that target selected GPCRs. Importantly, the functional consequence of such regulation on NMDAR function varies, based not only on the identity of the GPCR, but also on the cell type in which relevant receptors are expressed. Indeed, the mechanisms responsible for regulating NMDARs by GPCRs involve numerous intracellular signalling molecules and regulatory proteins that vary from one cell type to another. In the present article, we highlight recent findings from studies that have uncovered novel mechanisms by which selected GPCRs regulate NMDAR function and consequently NMDAR-dependent plasticity.
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A decision model to estimate the cost-effectiveness of intensity modulated radiation therapy (IMRT) compared to three dimensional conformal radiation therapy (3DCRT) in patients receiving radiotherapy to the prostate bed.
Radiother Oncol
PUBLISHED: 02-11-2014
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Intensity modulated radiation therapy (IMRT) is a radiation therapy technology that facilitates the delivery of an improved dose distribution with less dose to surrounding critical structures. This study estimates the longer term effectiveness and cost-effectiveness of IMRT in patients post radical prostatectomy.
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Use of screws and cement in primary TKA with up to 20 years follow-up.
J Arthroplasty
PUBLISHED: 01-25-2014
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The purpose of this study was to investigate screws and cement for large tibial bone defects during primary TKA. Of 14,686 consecutive primary TKAs performed between December 1988 and February 2010, 256 received screws and cement for tibial defects. Cox regression was used for the analysis. 20-year survival probability was 0.9897 (screws) and 0.9339 (no screws) (P = .4225 log-rank). Tibial bone condition was significantly worse in knees receiving screws (P < .0001) with 73.0% having defects in the screws group and 3.4% (P < .0001) for non-screws. Radiolucency appeared in 13.7% (screws) and 6.4% (no screws) postoperatively. Screws were $137 each, wedges $910 to $2240. Knees with tibial defects and screws performed similarly if not better than knees without defects at substantially lower cost than alternatives.
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Co-pyrolysis of swine manure with agricultural plastic waste: laboratory-scale study.
Waste Manag
PUBLISHED: 01-17-2014
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Manure-derived biochar is the solid product resulting from pyrolysis of animal manures. It has considerable potential both to improve soil quality with high levels of nutrients and to reduce contaminants in water and soil. However, the combustible gas produced from manure pyrolysis generally does not provide enough energy to sustain the pyrolysis process. Supplementing this process may be achieved with spent agricultural plastic films; these feedstocks have large amounts of available energy. Plastic films are often used in soil fumigation. They are usually disposed in landfills, which is wasteful, expensive, and environmentally unsustainable. The objective of this work was to investigate both the energetics of co-pyrolyzing swine solids with spent plastic mulch films (SPM) and the characteristics of its gas, liquid, and solid byproducts. The heating value of the product gas from co-pyrolysis was found to be much higher than that of natural gas; furthermore, the gas had no detectable toxic fumigants. Energetically, sustaining pyrolysis of the swine solids through the energy of the product gas could be achieved by co-pyrolyzing dewatered swine solids (25%m/m) with just 10% SPM. If more than 10% SPM is used, the co-pyrolysis would generate surplus energy which could be used for power generation. Biochars produced from co-pyrolyzing SPM and swine solid were similar to swine solid alone based on the surface area and the (1)H NMR spectra. The results of this study demonstrated the potential of using pyrolysis technology to manage two prominent agricultural waste streams (SPM and swine solids) while producing value-added biochar and a power source that could be used for local farm operations.
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Influenza Vaccine Effectiveness in the 2011-2012 Season: Protection Against Each Circulating Virus and the Effect of Prior Vaccination on Estimates.
Clin. Infect. Dis.
PUBLISHED: 11-13-2013
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Background.?Each year, the US Influenza Vaccine Effectiveness Network examines the effectiveness of influenza vaccines in preventing medically attended acute respiratory illnesses caused by influenza. Methods.?Patients with acute respiratory illnesses of ?7 days duration were enrolled at ambulatory care facilities in 5 communities. Specimens were collected and tested for influenza by real-time reverse-transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or immunization registries. Vaccine effectiveness was estimated in adjusted logistic regression models by comparing the vaccination coverage in those who tested positive for influenza with those who tested negative. Results.?The 2011-2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval [CI], 36-56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44-79) against type A (H1N1) pdm09 but only 39% (95% CI, 23-52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35-73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes. Conclusions.?Vaccine effectiveness in the 2011-2012 season was modest overall, with lower effectiveness against the predominant A (H3N2) virus. This may be related to antigenic drift, but past history of vaccination might also play a role.
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The prion protein ligand, stress-inducible phosphoprotein 1, regulates amyloid-? oligomer toxicity.
J. Neurosci.
PUBLISHED: 10-18-2013
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In Alzheimers disease (AD), soluble amyloid-? oligomers (A?Os) trigger neurotoxic signaling, at least partially, via the cellular prion protein (PrP(C)). However, it is unknown whether other ligands of PrP(C) can regulate this potentially toxic interaction. Stress-inducible phosphoprotein 1 (STI1), an Hsp90 cochaperone secreted by astrocytes, binds to PrP(C) in the vicinity of the A?O binding site to protect neurons against toxic stimuli. Here, we investigated a potential role of STI1 in A?O toxicity. We confirmed the specific binding of A?Os and STI1 to the PrP and showed that STI1 efficiently inhibited A?O binding to PrP in vitro (IC50 of ?70 nm) and also decreased A?O binding to cultured mouse primary hippocampal neurons. Treatment with STI1 prevented A?O-induced synaptic loss and neuronal death in mouse cultured neurons and long-term potentiation inhibition in mouse hippocampal slices. Interestingly, STI1-haploinsufficient neurons were more sensitive to A?O-induced cell death and could be rescued by treatment with recombinant STI1. Noteworthy, both A?O binding to PrP(C) and PrP(C)-dependent A?O toxicity were inhibited by TPR2A, the PrP(C)-interacting domain of STI1. Additionally, PrP(C)-STI1 engagement activated ?7 nicotinic acetylcholine receptors, which participated in neuroprotection against A?O-induced toxicity. We found an age-dependent upregulation of cortical STI1 in the APPswe/PS1dE9 mouse model of AD and in the brains of AD-affected individuals, suggesting a compensatory response. Our findings reveal a previously unrecognized role of the PrP(C) ligand STI1 in protecting neurons in AD and suggest a novel pathway that may help to offset A?O-induced toxicity.
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Determination of fusaric acid in maize using molecularly imprinted SPE clean-up.
J Sep Sci
PUBLISHED: 09-30-2013
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A new LC method to detect fusaric acid (FA) in maize is reported based on a molecularly imprinted SPE clean-up using mimic-templated molecularly imprinted polymers. Picolinic acid was used as a toxin analog for imprinting polymers during a thermolytic synthesis. Both acidic and basic functional monomers were predicted to have favorable binding interactions by MP2 ab initio calculations. Imprinted polymers synthesized with methacrylic acid or 2-dimethylaminoethyl methacrylate exhibited imprinting effects in SPE analysis. FA levels were determined using RP ion-pairing chromatography with diode-array UV detection and tetrabutylammonium hydrogen sulfate in the mobile phase. A method was developed to detect FA in maize using molecularly imprinted SPE analysis within the range of 1-100 ?g/g with recoveries between 83.9 and 92.1%.
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Further evidence for bias in observational studies of influenza vaccine effectiveness: the 2009 influenza A(H1N1) pandemic.
Am. J. Epidemiol.
PUBLISHED: 08-26-2013
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Preinfluenza periods have been used to test for uncontrolled confounding in studies of influenza vaccine effectiveness, but some authors have claimed that confounding differs in preinfluenza and influenza periods. We tested this claim by comparing estimates of the vaccine-mortality association during the 2009/2010 influenza year, when there was essentially no circulation of seasonal influenza in the United States, and 2007/2008, a typical influenza year. We pooled data on seniors (adults aged ?65 years) from 7 US managed care organizations that participated in the Vaccine Safety Datalink Project. We defined influenza vaccination, all-cause mortality, and potential confounders from administrative databases. We quantified the vaccine-mortality association using Cox regression. During 2007/2008, the adjusted hazard ratio was 0.44 prior to influenza season, 0.62 during influenza season, and 0.71 after influenza season. A similar pattern was observed during 2009/2010, when any effect of seasonal influenza vaccine observed during all time periods must have resulted from confounding: 0.65 during the autumn, 0.80 during the winter, and 0.84 during the summer. In a year with minimal seasonal influenza, we found no evidence that confounding in autumn preinfluenza periods is qualitatively different from confounding in winter. This supports the use of preinfluenza periods as control time periods in studies of influenza vaccine effectiveness.
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A model based iterative reconstruction algorithm for high angle annular dark field-scanning transmission electron microscope (HAADF-STEM) tomography.
IEEE Trans Image Process
PUBLISHED: 08-08-2013
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High angle annular dark field (HAADF)-scanning transmission electron microscope (STEM) data is increasingly being used in the physical sciences to research materials in 3D because it reduces the effects of Bragg diffraction seen in bright field TEM data. Typically, tomographic reconstructions are performed by directly applying either filtered back projection (FBP) or the simultaneous iterative reconstruction technique (SIRT) to the data. Since HAADF-STEM tomography is a limited angle tomography modality with low signal to noise ratio, these methods can result in significant artifacts in the reconstructed volume. In this paper, we develop a model based iterative reconstruction algorithm for HAADF-STEM tomography. We combine a model for image formation in HAADF-STEM tomography along with a prior model to formulate the tomographic reconstruction as a maximum a posteriori probability (MAP) estimation problem. Our formulation also accounts for certain missing measurements by treating them as nuisance parameters in the MAP estimation framework. We adapt the iterative coordinate descent algorithm to develop an efficient method to minimize the corresponding MAP cost function. Reconstructions of simulated as well as experimental data sets show results that are superior to FBP and SIRT reconstructions, significantly suppressing artifacts and enhancing contrast.
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Insect resistance in traditional and heirloom sweetpotato varieties.
J. Econ. Entomol.
PUBLISHED: 07-20-2013
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Fifty-nine sweetpotato cultivars, including 16 heirlooms, 11 near-heirlooms (developed in the 1960s and 1970s), 19 cultivars from the 1980s, and 13 modern varieties (since 1990), were evaluated for resistance to soil insects in field experiments during 2010-2011 at the U.S. Department of Agriculture-Agriculture Research Service, U.S. Vegetable Laboratory (USDA-ARS, USVL), Charleston, SC. These experiments included two insect-susceptible control cultivars (Beauregard and SC1149-19) and four insect-resistant control cultivars (Charleston Scarlet,Regal, Ruddy, and Sumor) that were developed by the USDA-ARS, USVL sweetpotato breeding program. Sweetpotato genotypes differed significantly in resistance measured by the overall percentage of injured roots, WDS (Wireworm, Diabrotica, and Systena) index, the percentage of roots damaged by the sweetpotato weevil (Cylas formicarius F.), the percentage of roots damaged by the sweetpotato flea beetle (Chaetonema confinis Crotch), and the percentage of roots damaged by white grub larvae (including Plectris aliena Chapin and Phyllophaga spp.). Twenty-three sweetpotato cultivars had a lower percentage of injured roots than the susceptible control genotype, SC1149-19, while 14 varieties had a lower percentage of injured roots than Beauregard, one of the leading commercial orange-fleshed cultivars in the United States. Over the 2-yr period, Ruddy (7.6%) had the lowest percentage of injured roots and Carolina Ruby (84.6%) the highest percentage of injured roots. Carolina Ruby (1.07) also had the highest WDS index, but 15 genotypes had a significantly lower WDS index than either susceptible control, SC1149-19 (1.03) or Beauregard (0.82). Ruddy (0.07) and Murasaki-29 (0.09) had the lowest WDS indices. Forty-five genotypes had a significantly lower percentage infestation by flea beetles than SC1149-19 (12.3%), and the highest level of flea beetle infestation was for Bonita (18.9%). The highest percent white grub infestation was for Caromex (19.6%), however none of the genotypes had significantly less white grubs than the susceptible controls. The highest infestation of sweetpotato weevils was observed for SC1149-19 (17.9%), while 29 genotypes had significantly lower percentage of sweetpotato weevil infestation than SC1149-19. The moderate to high levels of resistance to soil insect pests exhibited by many of these traditional and heirloom cultivars may provide useful sources of germplasm for sweetpotato breeding programs.
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Chemical probe development versus drug development.
Methods Mol. Biol.
PUBLISHED: 07-18-2013
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Phosphatases as a class of proteins have recently attracted significant attention from the pharmaceutical industry. As our knowledge of this diverse family of proteins has grown, the relationship between phosphatases and human disease has clearly been established, with model systems proving much validation for the potential of some members of this family to be candidate drug targets. This, coupled with the fact that there have been a flood of successful drug development efforts over the past 10 years targeting protein kinases, has led some to propose that phosphatases as a class of enzymes might be equally as rich a source of drug targets as kinases. However to date there remain relatively few molecules targeting protein phosphatases in clinical development. This is less a reflection of their importance in key processes associated with disease, but rather seems to reflect inherent issues with developing drugs for many members of this family. This seems especially so for intracellular phosphatases where the development of selective, potent cell penetrant molecules with good drug-like properties has proven a formidable challenge. This chapter provides a brief outline of the two major processes that have resulted in the existing armament of chemical modulators of protein phosphatases, namely, chemical probe development and drug development. These two processes initially seem to be rather similar and while they do overlap, the stated goals of the two approaches at project initiation are distinct.
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Proteomic Analysis of Striatum from MPTP-Treated Marmosets (Callithrix jacchus) with L-DOPA-Induced Dyskinesia of Differing Severity.
J. Mol. Neurosci.
PUBLISHED: 07-16-2013
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Marmosets rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with L-3,4-dihydroxyphenylalanine (L-DOPA) develop dyskinesia, but with differing degrees of severity. To provide insight into the molecular mechanisms responsible for the different level of dyskinesia to manifest in individual animals, proteins in striatum from MPTP-treated marmosets with different levels of L-DOPA-induced dyskinesia were separated by 2-dimensional (2-D) protein electrophoresis. Thirty-five differentially expressed proteins were identified by mass spectrometry and peptide mass fingerprinting, and comparative analysis found 10 were significantly increased and 3 had significantly reduced expression in animals with a high level of dyskinesia when compared to animals with a low incidence of dyskinesia. These proteins belonged to a range of functional classes, for example, molecular chaperones, metabolic enzymes and synaptic structural proteins. The findings of this study provide clues about the molecular mechanisms that cause dyskinesia to manifest and point towards potential novel targets for the development of therapeutic agents to prevent or treat established dyskinesia.
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Optogenetics and synaptic plasticity.
Acta Pharmacol. Sin.
PUBLISHED: 07-10-2013
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The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity.
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Identification of a neuronal transcription factor network involved in medulloblastoma development.
Acta Neuropathol Commun
PUBLISHED: 06-18-2013
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Medulloblastomas, the most frequent malignant brain tumours affecting children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1, SUFU) are observed in many of these tumours, high throughput genomic analyses have identified few other recurring mutations. Here, we have mutagenised the Ptch+/- murine tumour model using the Sleeping Beauty transposon system to identify additional genes and pathways involved in SHH subgroup medulloblastoma development.
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Primary surgical management with tailored adjuvant radiation for stage IB2 cervical cancer.
Obstet Gynecol
PUBLISHED: 05-03-2013
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To examine the outcome for patients with stage IB2 cervical cancer treated primarily with radical hysterectomy, and to determine the need for adjuvant therapy, the sites of recurrence, and the morbidity of the treatment.
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The inhibitory effects of antimuscarinic autoantibodies in the sera of primary Sjogren syndrome patients on the gastrointestinal motility.
Mol. Immunol.
PUBLISHED: 04-23-2013
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Impairment of gastrointestinal tract (GI) function, including delayed gastric emptying and colonic dysmotility, are common features of primary Sjögrens syndrome (SS). However, the pathogenesis remains largely unknown. The aim of the current study was to investigate the role of functional autoantibodies to the muscarinic receptor in mediating GI dysfunction associated with primary SS. The effect of SS or normal immunoglobulin G (IgG) on smooth muscle (SM) motility was assessed by comparing the amplitude of carbachol (CCh) or electrical field stimulation (EFS) - induced muscle contraction before and after IgG application. Muscarinic receptor type 3 (M3R) played a dominant role in both colon and gastric SM contraction, while M2R was partly involved in gastric smooth muscle contraction. Preincubation for 1h of the colon and gastric SM strips with 1mg/ml purified IgG from the sera of four primary SS patients (SS IgG) significantly inhibited carbachol-induced smooth muscle contraction (CISC) over a range of CCh concentrations, whereas IgG from healthy controls had little effect. Incubation of the colon SM strips with SS IgG also inhibited EFS-induced colon muscle contraction, which was mimicked by the M3R-selective blocker, 4-DAMP. SR1403330, an NK1 antagonist, had little effect on EFS-mediated colonic SM contraction. The results suggest that autoantibodies isolated from primary SS patients sera inhibit muscarinic receptor-mediated cholinergic neurotransmission in mouse colon and stomach, which may provide clues for explaining the GI dysfunction seen in patients with primary SS.
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Long-term Ro60 humoral autoimmunity in primary Sjögrens syndrome is maintained by rapid clonal turnover.
Clin. Immunol.
PUBLISHED: 03-24-2013
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Long-term humoral autoimmunity to RNA-protein autoantigens is considered a hallmark of systemic autoimmune diseases. We use high resolution Orbitrap mass spectrometric autoantibody sequencing to track the evolution of a Ro60-specific public clonotypic autoantibody in 4 patients with primary Sjögrens syndrome. This clonotype is specified by a VH3-23/VK3-20 heavy and light chain pairing. Despite apparent stability by conventional immunoassay, analysis of V-region molecular signatures of clonotypes purified from serum samples collected retrospectively over 7years revealed sequential clonal replacement. Prospective longitudinal studies confirmed clonotype loss and replacement at approximately three-monthly intervals. Levels of secreted anti-Ro60 clonotypes fluctuated markedly over time, despite minimal changes in clonal affinity. Our novel findings indicate a relentless turnover of short-lived clonotypic variants, masquerading as long-lived Ro60 humoral autoimmunity.
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Nonselective cation channels and links to hippocampal ischemia, aging, and dementia.
Adv. Exp. Med. Biol.
PUBLISHED: 03-15-2013
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Stroke is a very strong risk factor for dementia. Furthermore, ischemic stroke and Alzheimers disease (AD) share a number of overlapping mechanisms of neuron loss and dysfunction, including those induced by the inappropriate activation of N-methyl-D-aspartate receptors (NMDARs). These receptors form a major subtype of excitatory glutamate receptor. They are nonselective cation channels with appreciable Ca(2+) permeability, and their overactivation leads to neurotoxicity in the cortex and hippocampus. NMDARs have therefore been therapeutic targets in both conditions, but they have failed in the treatment of stroke, and there is limited rationale for using them in treating AD. In this chapter, we discuss current understanding of subtypes of NMDARs and their potential roles in -ischemic stroke and AD. We also discuss the properties of several other nonselective cation channels, transient receptor potential melastatin 2 and 7 channels, and their implications in linking these conditions.
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Mortality rates and cause-of-death patterns in a vaccinated population.
Am J Prev Med
PUBLISHED: 02-25-2013
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Determining the baseline mortality rate in a vaccinated population is necessary to be able to identify any unusual increases in deaths following vaccine administration. Background rates are particularly useful during mass immunization campaigns and in the evaluation of new vaccines.
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The test-negative design for estimating influenza vaccine effectiveness.
Vaccine
PUBLISHED: 02-13-2013
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The test-negative design has emerged in recent years as the preferred method for estimating influenza vaccine effectiveness (VE) in observational studies. However, the methodologic basis of this design has not been formally developed.
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Challenges in comparing the safety of different vaccination schedules.
Vaccine
PUBLISHED: 01-28-2013
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As vaccine hesitancy has increased in the United States, various authors have begun proposing alternatives to the Advisory Committee on Immunization Practices recommended childhood immunization schedule. Because parents may believe the safety claims made by such authors, evaluations of the safety of alternative vaccination schedules are needed. However, comparing the safety of different vaccination schedules has numerous methodologic challenges. These challenges include defining vaccination history, defining safety, appropriately modeling interactions between vaccines, and appropriately handling age effects. Failure to properly address these challenges can result in biased results.
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Acute 5-HT7 receptor activation increases NMDA-evoked currents and differentially alters NMDA receptor subunit phosphorylation and trafficking in hippocampal neurons.
Mol Brain
PUBLISHED: 01-17-2013
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BACKGROUND: N-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases. Serotonin (5-HT) type 7 receptors are expressed throughout the brain including the thalamus and hippocampus. Long-term (2--24 h) activation of 5-HT7 receptors promotes the expression of neuroprotective growth factor receptors, including the platelet-derived growth factor (PDGF) beta receptors which can protect neurons against NMDA-induced neurotoxicity. RESULTS: In contrast to long-term activation of 5-HT7 receptors, acute (5 min) treatment of isolated hippocampal neurons with the 5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT) enhances NMDA-evoked peak currents and this increase in peak currents is blocked by the 5-HT7 receptor antagonist, SB 269970. In hippocampal slices, acute 5-HT7 receptor activation increases NR1 NMDA receptor subunit phosphorylation and differentially alters the phosphorylation state of the NR2B and NR2A subunits. NMDA receptor subunit cell surface expression is also differentially altered by 5-HT7 receptor agonists: NR2B cell surface expression is decreased whereas NR1 and NR2A surface expression are not significantly altered. CONCLUSIONS: In contrast to the negative regulatory effects of long-term activation of 5-HT7 receptors on NMDA receptor signaling, acute activation of 5-HT7 receptors promotes NMDA receptor activity. These findings highlight the potential for temporally differential regulation of NMDA receptors by the 5-HT7 receptor.
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Natural Language Processing to identify pneumonia from radiology reports.
Pharmacoepidemiol Drug Saf
PUBLISHED: 01-11-2013
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This study aimed to develop Natural Language Processing (NLP) approaches to supplement manual outcome validation, specifically to validate pneumonia cases from chest radiograph reports.
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Validation sampling can reduce bias in health care database studies: an illustration using influenza vaccination effectiveness.
J Clin Epidemiol
PUBLISHED: 01-07-2013
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Estimates of treatment effectiveness in epidemiologic studies using large observational health care databases may be biased owing to inaccurate or incomplete information on important confounders. Study methods that collect and incorporate more comprehensive confounder data on a validation cohort may reduce confounding bias.
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Preterm birth among American Indian/Alaskan natives in Washington and Montana: comparison with non-Hispanic Whites.
Matern Child Health J
PUBLISHED: 01-05-2013
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Preterm birth is the single most important cause of perinatal mortality in North America. Given that American Indians/Alaskan Natives (AI/ANs) in the United States continue to have adverse birth outcomes, the purpose of this study is to compare the risk of preterm birth among AI/AN mothers to Non-Hispanic White mothers living in Washington and Montana from 2003 to 2009. A population-based retrospective cohort study was conducted examining the association between AI/AN mothers (self-reported) and the risk of preterm birth (gestational age <37 weeks) using birth certificate data from Washington and Montana. All AI/AN singleton lives births (n = 26,648) from residents of Washington and Montana from 2003 to 2009 were identified and included in our study. An identical number of Non-Hispanic White singleton infants (n = 26,648) born to residents of Washington and Montana were randomly selected as a comparison group and logistic regression was used to analyze the data. AI/AN mothers living in Washington and Montana between 2003 and 2009 were 1.34 times (95 % CI 1.25-1.44) as likely to have a preterm birth compared to Non-Hispanic Whites after adjusting for maternal and paternal characteristics as well as pregnancy risk factors. AI/AN mothers residing in Washington and Montana from 2003 to 2009 were at a significantly increased risk of having a preterm birth compared to Non-Hispanic Whites. Identifying etiologic differences in preterm birth experienced by AI/ANs is essential in targeting future interventions.
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Guillain-Barré Syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009-2011.
PLoS ONE
PUBLISHED: 01-01-2013
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Guillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited.
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Identifying optimal vaccination strategies for serogroup A Neisseria meningitidis conjugate vaccine in the African meningitis belt.
PLoS ONE
PUBLISHED: 01-01-2013
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The optimal long-term vaccination strategies to provide population-level protection against serogroup A Neisseria meningitidis (MenA) are unknown. We developed an age-structured mathematical model of MenA transmission, colonization, and disease in the African meningitis belt, and used this model to explore the impact of various vaccination strategies.
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Regulation of NMDA receptors by the tyrosine kinase Fyn.
FEBS J.
PUBLISHED: 12-05-2011
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The phosphorylation and trafficking of N-methyl-d-aspartate (NMDA) receptors are tightly regulated by the Src family tyrosine kinase Fyn, through dynamic interactions with various scaffolding proteins in the NMDA receptor complex. Fyn acts as a point of convergence for many signaling pathways that upregulate GluN2B-containing NMDA receptors. In the following review, we focus on Fyn signaling downstream of different G-protein-coupled receptors: the dopamine D1 receptor, and receptors cognate to the pituitary adenylate cyclase-activating polypeptide. The net result of activation of each of these signaling pathways is upregulation of GluN2B-containing NMDA receptors. The NMDA receptor is a major target of ethanol in the brain, and accumulating evidence suggests that Fyn mediates the effects of ethanol by regulating the phosphorylation of GluN2B NMDA receptor subunits. Furthermore, Fyn has been shown to regulate alcohol withdrawal and acute tolerance to ethanol through a GluN2B-dependent mechanism. In addition to its effects on NMDA receptor function, Fyn also modifies the threshold for synaptic plasticity at CA1 synapses, an effect that probably contributes to the effects of Fyn on spatial and contextual fear learning.
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Dependence of NMDA/GSK-3? mediated metaplasticity on TRPM2 channels at hippocampal CA3-CA1 synapses.
Mol Brain
PUBLISHED: 11-08-2011
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Transient receptor potential melastatin 2 (TRPM2) is a calcium permeable non-selective cation channel that functions as a sensor of cellular redox status. Highly expressed within the CNS, we have previously demonstrated the functional expression of these channels in CA1 pyramidal neurons of the hippocampus. Although implicated in oxidative stress-induced neuronal cell death, and potentially in neurodegenerative disease, the physiological role of TRPM2 in the central nervous system is unknown. Interestingly, we have shown that the activation of these channels may be sensitized by co-incident NMDA receptor activation, suggesting a potential contribution of TRPM2 to synaptic transmission. Using hippocampal cultures and slices from TRPM2 null mice we demonstrate that the loss of these channels selectively impairs NMDAR-dependent long-term depression (LTD) while sparing long-term potentiation. Impaired LTD resulted from an inhibition of GSK-3?, through increased phosphorylation, and a reduction in the expression of PSD95 and AMPARs. Notably, LTD could be rescued in TRPM2 null mice by recruitment of GSK-3? signaling following dopamine D2 receptor stimulation. We propose that TRPM2 channels play a key role in hippocampal synaptic plasticity.
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Molecular signature of a public clonotypic autoantibody in primary Sjögrens syndrome: a "forbidden" clone in systemic autoimmunity.
Arthritis Rheum.
PUBLISHED: 11-01-2011
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This study was undertaken to determine the molecular characteristics of clonotypic autoantibodies in the sera of patients with primary Sjögrens syndrome (SS). This characterization is hampered by the presence of mixed anti-Ro/La specificities that may conceal clonotypic species. In order to narrow clonotypic diversity, a positive selection step was performed on a peg-like determinant of Ro 60 (termed Ro 60-peg) prior to analysis of the autoantibody proteome.
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Haemophilus influenzae type b carriage among young children in metropolitan Atlanta in the context of vaccine shortage and booster dose deferral.
Clin. Vaccine Immunol.
PUBLISHED: 10-19-2011
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Short-term deferral of the Haemophilus influenzae type b (Hib) vaccine booster dose during a recent U.S. Hib vaccine shortage did not result in widespread Hib carriage in Atlanta, as the Hib carriage rate was found to be 0.3% (1/342). Hib colonization was significantly more common among males and day care attendees.
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Post-transcriptional exon shuffling events in humans can be evolutionarily conserved and abundant.
Genome Res.
PUBLISHED: 09-23-2011
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In silico analyses have established that transcripts from some genes can be processed into RNAs with rearranged exon order relative to genomic structure (post-transcriptional exon shuffling, or PTES). Although known to contribute to transcriptome diversity in some species, to date the structure, distribution, abundance, and functional significance of human PTES transcripts remains largely unknown. Here, using high-throughput transcriptome sequencing, we identify 205 putative human PTES products from 176 genes. We validate 72 out of 112 products analyzed using RT-PCR, and identify additional PTES products structurally related to 61% of validated targets. Sequencing of these additional products reveals GT-AG dinucleotides at >95% of the splice junctions, confirming that they are processed by the spliceosome. We show that most PTES transcripts are expressed in a wide variety of human tissues, that they can be polyadenylated, and that some are conserved in mouse. We also show that they can extend into 5 and 3 UTRs, consistent with formation via trans-splicing of independent pre-mRNA molecules. Finally, we use real-time PCR to compare the abundance of PTES exon junctions relative to canonical exon junctions within the transcripts from seven genes. PTES exon junctions are present at <0.01% to >90% of the levels of canonical junctions, with transcripts from MAN1A2, PHC3, TLE4, and CDK13 exhibiting the highest levels. This is the first systematic experimental analysis of PTES in human, and it suggests both that the phenomenon is much more widespread than previously thought and that some PTES transcripts could be functional.
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Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study.
J Am Geriatr Soc
PUBLISHED: 09-13-2011
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To examine whether use of opioids or benzodiazepines is associated with risk of community-acquired pneumonia in older adults.
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Serologically confirmed household transmission of 2009 pandemic influenza A (H1N1) virus during the first pandemic wave--New York City, April-May 2009.
Clin. Infect. Dis.
PUBLISHED: 08-17-2011
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Understanding transmissibility of influenza viruses within households is critical for guiding public health response to pandemics. We studied serologically confirmed infection and disease among household contacts of index case patients with 2009 pandemic influenza A (H1N1) virus (pH1N1) infection in a setting of minimal community pH1N1 transmission.
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Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2? in development.
PLoS Genet.
PUBLISHED: 05-11-2011
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Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2? (Sfrs10) is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2? is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2? binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl); Nestin-Cre(tg/+)). This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2? regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2? binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2? protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2?. Versions of Tra2? lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2? protein.
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A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets.
Behav Pharmacol
PUBLISHED: 04-28-2011
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The atypical antidepressant, bupropion, causes a partial reversal of motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. However, its monoamine uptake blocking actions are believed to be mediated by the major metabolites, racemic (-)-(2R,3R)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) (R,R-hydroxybupropion) and (+)-(2S,3S)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) (S,S-hydroxybupropion). Therefore, we have evaluated the ability of enantiomers to improve locomotor activity and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Bupropion produced a little increase in locomotor activity and a more pronounced improvement in motor disability. The S,S-hydroxybupropion, but not the R,R-hydroxybupropion, enantiomer dose-dependently increased both locomotor activity and reversed motor disability. Combined administration of S,S-hydroxybupropion and R,R-hydroxybupropion at the same dose (analogous to the racemate) again improved motor function and to the same extent as produced by S,S-hydroxybupropion alone. The data suggest that the S,S-enantiomer of hydroxybupropion may possess potential antiparkinsonian activity.
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Thermodynamics and solvent effects on substrate and cofactor binding in Escherichia coli chromosomal dihydrofolate reductase.
Biochemistry
PUBLISHED: 04-15-2011
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Chromosomal dihydrofolate reductase from Escherichia coli catalyzes the reduction of dihydrofolate to tetrahydrofolate using NADPH as a cofactor. The thermodynamics of ligand binding were examined using an isothermal titration calorimetry approach. Using buffers with different heats of ionization, zero to a small, fractional proton release was observed for dihydrofolate binding, while a proton was released upon NADP(+) binding. The role of water in binding was additionally monitored using a number of different osmolytes. Binding of NADP(+) is accompanied by the net release of ?5-24 water molecules, with a dependence on the identity of the osmolyte. In contrast, binding of dihydrofolate is weakened in the presence of osmolytes, consistent with "water uptake". Different effects are observed depending on the identity of the osmolyte. The net uptake of water upon dihydrofolate binding was previously observed in the nonhomologous R67-encoded dihydrofolate reductase (dfrB or type II enzyme) [Chopra, S., et al. (2008) J. Biol. Chem. 283, 4690-4698]. As R67 dihydrofolate reductase possesses a nonhomologous sequence and forms a tetrameric structure with a single active site pore, the observation of weaker DHF binding in the presence of osmolytes in both enzymes implicates cosolvent effects on free dihydrofolate. Consistent with this analysis, stopped flow experiments find betaine mostly affects DHF binding via changes in k(on), while betaine mostly affects NADPH binding via changes in k(off). Finally, nonadditive enthalpy terms when binary and ternary cofactor binding events are compared suggest the presence of long-lived conformational transitions that are not included in a simple thermodynamic cycle.
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Why do covariates defined by International Classification of Diseases codes fail to remove confounding in pharmacoepidemiologic studies among seniors?
Pharmacoepidemiol Drug Saf
PUBLISHED: 03-11-2011
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The common practice of using administrative diagnosis codes as the sole source of data on potential confounders in pharmacoepidemiologic studies has been shown to leave substantial residual confounding. We explored reasons why adjustment for comorbid illness defined from International Classification of Diseases (ICD) codes fails to remove confounding.
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Serial intervals and the temporal distribution of secondary infections within households of 2009 pandemic influenza A (H1N1): implications for influenza control recommendations.
Clin. Infect. Dis.
PUBLISHED: 02-24-2011
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A critical issue during the 2009 influenza A (H1N1) pandemic was determining the appropriate duration of time individuals with influenza-like illness (ILI) should remain isolated to reduce onward transmission while limiting societal disruption. Ideally this is based on knowledge of the relative infectiousness of ill individuals at each point during the course of the infection. Data on 261 clinically apparent pH1N1 infector-infectee pairs in households, from 7 epidemiological studies conducted in the United States early in 2009, were analyzed to estimate the distribution of times from symptom onset in an infector to symptom onset in the household contacts they infect (mean, 2.9 days, not correcting for tertiary transmission). Only 5% of transmission events were estimated to take place >3 days after the onset of clinical symptoms among those ill with pH1N1 virus. These results will inform future recommendations on duration of isolation of individuals with ILI.
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Investigating 2009 pandemic influenza A (H1N1) in US schools: what have we learned?
Clin. Infect. Dis.
PUBLISHED: 02-24-2011
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US investigations of school-based outbreaks of 2009 pandemic influenza A (H1N1) virus infection characterized influenza-like illness (ILI) attack rates, transmission risk factors, and adherence to nonpharmaceutical interventions. We summarize seven school-based investigations conducted during April-June 2009 to determine what questions might be answered by future investigations. Surveys were administered 5-28 days after identification of the outbreaks, and participation rates varied among households (39-86%) and individuals (24-49%). Compared with adults (4%-10%) and children aged <4 years (2%-7%), elementary through university students had higher ILI attack rates (4%-32%). Large gatherings or close contact with sick persons were identified as transmission risk factors. More participants reported adherence to hygiene measures, but fewer reported adherence to isolation measures. Challenges included low participation and delays in survey initiation that potentially introduced bias. Although school-based investigations can increase our understanding of epidemiology and prevention strategy effectiveness, investigators should decide which objectives are most feasible, given timing and design constraints.
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Metaplasticity gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases.
EMBO J.
PUBLISHED: 02-16-2011
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Metaplasticity is a higher form of synaptic plasticity that is essential for learning and memory, but its molecular mechanisms remain poorly understood. Here, we report that metaplasticity of transmission at CA1 synapses in the hippocampus is mediated by Src family kinase regulation of NMDA receptors (NMDARs). We found that stimulation of G-protein-coupled receptors (GPCRs) regulated the absolute contribution of GluN2A-versus GluN2B-containing NMDARs in CA1 neurons: pituitary adenylate cyclase activating peptide 1 receptors (PAC1Rs) selectively recruited Src kinase, phosphorylated GluN2ARs, and enhanced their functional contribution; dopamine 1 receptors (D1Rs) selectively stimulated Fyn kinase, phosphorylated GluN2BRs, and enhanced these currents. Surprisingly, PAC1R lowered the threshold for long-term potentiation while long-term depression was enhanced by D1R. We conclude that metaplasticity is gated by the activity of GPCRs, which selectively target subtypes of NMDARs via Src kinases.
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Antibodies interfering with the type 3 muscarinic receptor pathway inhibit gastrointestinal motility and cholinergic neurotransmission in Sjögrens syndrome.
Arthritis Rheum.
PUBLISHED: 02-12-2011
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In primary Sjögrens syndrome (SS), impairment of the gastrointestinal (GI) tract is common, and includes reduced esophageal motor function, delayed gastric emptying, and abnormalities in colonic motility; the pathogenesis is as yet unknown. We undertook this study to investigate the role of functional antibodies to the type 3 muscarinic receptor (M3R) in GI dysfunction associated with primary SS.
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Removal of patulin from aqueous solutions by propylthiol functionalized SBA-15.
J. Hazard. Mater.
PUBLISHED: 01-02-2011
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Propylthiol functionalized SBA-15 silica was investigated to detoxify aqueous solutions contaminated with the regulated mycotoxin patulin. Micelle templated silicas with a specific pore size were synthetically modified to possess propylthiol groups, a functional group known to form Michael reaction products with the conjugated double bond system of patulin. BET surface area analysis indicated the propylthiol functionalized SBA-15 possesses channels with the pore size of 5.4 nm and a surface area of 345 m(2)g(-1). Elemental analysis indicates the silicon/sulfur ratio to be 10:1, inferring one propylthiol substituent for every ten silica residues. The propylthiol modified SBA-15 was effective at significantly reducing high levels of patulin from aqueous solutions (pH 7.0) in batch sorption assays at room temperature. The material was less effective at lower pH; however heating low pH solutions and apple juice to 60 °C in the presence of propylthiol functionalized SBA-15 significantly reduced the levels of patulin in contaminated samples. Composite molecular models developed by semi-empirical PM3 and empirical force field methods support patulin permeation through the mesoporous channels of propylthiol functionalized SBA-15. Density functional study at the B3LYP/6-31G(d,p) level predicts the proposed patulin adducts formed by reaction with the thiol residues exhibit less electrophilic properties than patulin. It is demonstrated the use of propylthiol functionalized SBA-15 is a viable approach to reduce patulin levels in aqueous solutions, including contaminated apple juice.
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The modulation of TRPM7 currents by nafamostat mesilate depends directly upon extracellular concentrations of divalent cations.
Mol Brain
PUBLISHED: 11-27-2010
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Concentrations of extracellular divalent cations (Ca2+ and Mg2+) fall substantially during intensive synaptic transmission as well as during some pathophysiological conditions such as epilepsy and brain ischemia. Here we report that a synthetic serine protease inhibitor, nafamostat mesylate (NM), and several of its analogues, block recombinant TRPM7 currents expressed in HEK293T cells in inverse relationship to the concentration of extracellular divalent cations. Lowering extracellular Ca2+ and Mg2+ also evokes a divalent-sensitive non-selective cation current that is mediated by TRPM7 expression in hippocampal neurons. In cultured hippocampal neurons, NM blocked these TRPM7-mediated currents with an apparent affinity of 27 ?M, as well as the paradoxical Ca2+ influx associated with lowering extracellular Ca2+. Unexpectedly, pre-exposure to NM strongly potentiated TRPM7 currents. In the presence of physiological concentrations of extracellular divalent cations, NM activates TRPM7. The stimulating effects of NM on TRPM7 currents are also inversely related to extracellular Ca2+ and Mg2+. DAPI and HSB but not netropsin, blocked and stimulated TRPM7. In contrast, mono-cationic, the metabolites of NM, p-GBA and AN, as well as protease inhibitor leupeptin and gabexate failed to substantially modulate TRPM7. NM thus provides a molecular template for the design of putative modulators of TRPM7.
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Pardoprunox reverses motor deficits but induces only mild dyskinesia in MPTP-treated common marmosets.
Mov. Disord.
PUBLISHED: 08-20-2010
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Long-acting full dopamine D(2) agonists produce less dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and in Parkinsons disease than effective antiparkinsonian doses of levodopa. They do not however, prevent priming for dyskinesia expression on subsequent levodopa exposure. In contrast, the effects of partial D(2) receptor agonists on dyskinesia are unclear. We now examine the ability of the partial D(2) agonist pardoprunox (SLV308) to improve motor function and its propensity to prime for dyskinesia in drug naïve, MPTP-treated common marmosets. Previously, drug naïve, MPTP-treated common marmosets were treated with equivalent doses of either pardoprunox (SLV308) (0.1 mg/kg po), ropinirole (0.18 mg/kg po), or levodopa (10 mg/kg po BID) for 28 days. All treatments induced a similar reduction of motor disability. Dyskinesia induced by levodopa was of greater intensity than that following administration of either pardoprunox (SLV308) or ropinirole. Administration of pardoprunox (SLV308) resulted in dyskinesia that was less intense and of shorter duration than either ropinirole or levodopa. At the end of drug treatment, acute challenge with levodopa resulted in the expression of marked dyskinesia in animals that had previously received chronic levodopa or ropinirole treatment. However, animals previously treated with pardoprunox (SLV308) showed only mild dyskinesia in response to the levodopa challenge. These results suggest that the partial D(2) agonist pardoprunox (SLV308) is less likely to prime for dyskinesia or to lead to the expression of dyskinesia than either levodopa or full dopamine agonists.
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Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study.
Pharmacoepidemiol Drug Saf
PUBLISHED: 07-13-2010
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To examine whether use of proton pump inhibitors (PPIs) and H2 blockers is associated with increased pneumonia risk.
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A review of in vitro experimental evidence for the effect of spatial and temporal modulation of radiation dose on response.
Acta Oncol
PUBLISHED: 06-16-2010
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Intensity modulated radiation therapy introduces strong spatial and temporal modulation of the dose delivery that may have therapeutic benefits, as yet unrealized.
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Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia.
Neurobiol. Dis.
PUBLISHED: 06-11-2010
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Hyperinnervation of the striatum by serotoninergic (5-HT) terminals occurs after destruction of the dopaminergic nigro-striatal pathway. Recent studies have suggested that non-physiological release of dopamine (DA) formed from levodopa in these serotoninergic terminals underlies abnormal involuntary movement (AIMs) induction in 6-OHDA lesioned rats. In the present study, we used tryptophan hydroxylase (TPH) immunohistochemistry to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and the induction of dyskinesia by levodopa alter the morphology of 5-HT fibres in the striatum of common marmosets. The caudate-putamen of normal monkeys contained numerous fine and smooth TPH positive fibres and numerous varicose fibres, but a marked hyperinnervation of TPH positive fibres characterised by a significant increase in the number and diameter of TPH positive axon varicosities was noted in the dorsal caudate and putamen of MPTP-intoxicated monkeys but not the globus pallidus. In MPTP-intoxicated marmosets that had received chronic levodopa treatment to induce dyskinesia, a further increase in the number and enlargement of TPH positive axonal varicosities in both caudate nucleus and putamen was evident. Following LID induction, a similar pattern of increase was also observed in the external segment of the globus pallidus, but only a significant varicosity enlargement was seen in the internal pallidal segment. These results confirm that striatal 5-HT hyperinnervation follows nigro-striatal pathway loss and provide the first evidence in primates that chronic levodopa treatment and the onset of dyskinesia are associated with a marked hypertrophy of striatal 5-HT axonal varicosities. These findings support the concept that altered 5-HT function may contribute to the genesis or expression of LID.
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The brains voices: comparing nonclinical auditory hallucinations and imagery.
Cereb. Cortex
PUBLISHED: 06-07-2010
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Although auditory verbal hallucinations are often thought to denote mental illness, the majority of voice hearers do not satisfy the criteria for a psychiatric disorder. Here, we report the first functional imaging study of such nonclinical hallucinations in 7 healthy voice hearers comparing them with auditory imagery. The human voice area in the superior temporal sulcus was activated during both hallucinations and imagery. Other brain areas supporting both hallucinations and imagery included fronto temporal language areas in the left hemisphere and their contralateral homologues and the supplementary motor area (SMA). Hallucinations are critically distinguished from imagery by lack of voluntary control. We expected this difference to be reflected in the relative timing of prefrontal and sensory areas. Activity of the SMA indeed preceded that of auditory areas during imagery, whereas during hallucinations, the 2 processes occurred instantaneously. Voluntary control was thus represented in the relative timing of prefrontal and sensory activation, whereas the sense of reality of the sensory experience may be a product of the voice area activation. Our results reveal mechanisms of the generation of sensory experience in the absence of external stimulation and suggest new approaches to the investigation of the neurobiology of psychopathology.
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A mathematical framework for separating the direct and bystander components of cellular radiation response.
Acta Oncol
PUBLISHED: 05-28-2010
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A mathematical model for fractional tumor cell survival was developed incorporating components of cell killing due to direct radiation interactions and bystander signals resulting from non-local dose deposition.
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A novel impedance-based cellular assay for the detection of anti-calcium channel autoantibodies in type 1 diabetes.
J. Immunol. Methods
PUBLISHED: 04-22-2010
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We have recently postulated that functional autoantibodies (Abs) against L-type voltage-gated calcium channels (VGCCs) contribute to autonomic dysfunction in type 1 diabetes (T1D). Previous studies based on whole-organ assays have proven valuable in establishing the mechanism of anti-VGCC Ab activity, but are complex and unsuitable for screening large patient cohorts. In the current study, we used real-time dynamic monitoring of cell impedance to demonstrate that anti-VGCC Abs from patients with T1D inhibit the adherence of Rin A12 cells. The functional effect of the anti-VGCC Abs was mimicked by the dihydropyridine agonist, Bay K8644, and reversed by the antagonist, nicardipine, providing a pharmacological link to the whole-organ studies. IVIg neutralized the effect on cell adhesion of the anti-VGCC Abs, consistent with the presence of anti-idiotypic Abs in IVIg that may prevent the emergence of pathogenic Abs in healthy individuals. The cell impedance assay can be performed in a 96 well plate format, and represents a simple method for detecting the presence of anti-VGCC activity in patient immunoglobulin (IgG). The new cell assay should prove useful for further studies to determine the prevalence of the Ab and its association with symptoms of autonomic dysfunction in patients with T1D.
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Alpha5GABAA receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory.
J. Neurosci.
PUBLISHED: 04-16-2010
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Synaptic plasticity, which is the neuronal substrate for many forms of hippocampus-dependent learning, is attenuated by GABA type A receptor (GABA(A)R)-mediated inhibition. The prevailing notion is that a synaptic or phasic form of GABAergic inhibition regulates synaptic plasticity; however, little is known about the role of GABA(A)R subtypes that generate a tonic or persistent inhibitory conductance. We studied the regulation of synaptic plasticity by alpha5 subunit-containing GABA(A)Rs (alpha5GABA(A)Rs), which generate a tonic inhibitory conductance in CA1 pyramidal neurons using electrophysiological recordings of field and whole-cell potentials in hippocampal slices from both wild-type and null mutant mice for the alpha5 subunit of the GABA(A)R (Gabra5(-/-) mice). In addition, the strength of fear-associated memory was studied. The results showed that alpha5GABA(A)R activity raises the threshold for induction of long-term potentiation in a highly specific band of stimulation frequencies (10-20 Hz) through mechanisms that are predominantly independent of inhibitory synaptic transmission. The deletion or pharmacological inhibition of alpha5GABA(A)Rs caused no change in baseline membrane potential or input resistance but increased depolarization during 10 Hz stimulation. The encoding of hippocampus-dependent memory was regulated by alpha5GABA(A)Rs but only under specific conditions that generate moderate but not robust forms of fear-associated learning. Thus, under specific conditions, alpha5GABA(A)R activity predominates over synaptic inhibition in modifying the strength of both synaptic plasticity in vitro and certain forms of memory in vivo.
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Plasticity of synaptic GluN receptors is required for the Src-dependent induction of long-term potentiation at CA3-CA1 synapses.
Hippocampus
PUBLISHED: 03-29-2010
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The induction of long-term potentiation (LTP) of CA3-CA1 synapses requires activation of postsynaptic N-methyl-D-aspartate receptors (GluNRs). At resting potential, the contribution of GluNRs is limited by their voltage-dependent block by extracellular Mg(2+). High-frequency afferent stimulation is required to cause sufficient summation of excitatory synaptic potentials (EPSPs) to relieve this block and to permit an influx of Ca(2+). It has been assumed that this relief of Mg(2+) block is sufficient for induction. We postulated that the induction of LTP also requires a Src-dependent plasticity of GluNRs. Using whole-cell recordings, LTP (GluARs) of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors-EPSCS was induced by pairing postsynaptic depolarization with presynaptic stimulation. This LTP was both GluNR and Src-dependent, being sensitive to AP-5, a GluNR selective antagonist, or to SU6656, a Src-selective inhibitor. When CNQX was used to block all GluARs, we observed a long-lasting potentiation of GluNR-mediated EPSCs. This plasticity was prevented by transiently blocking GluNRs during the induction protocol or by chelating intracellular Ca(2+). GluNRs plasticity was also prevented by bath applications of SU6656 or intracellular applications of the Src-selective inhibitory peptide, Src(40-58). It was also blocked by preventing activation of protein kinase C, a kinase that is upstream of Src-kinase-dependent regulation of GluNRs. Both GluN2A and GluN2B receptors were found to contribute to the plasticity of GluNRs. The contribution of GluNRs and, in particular, their plasticity to the maintenance of LTP was explored using AP5 and SU6656, respectively. When applied >20 min after induction neither drug influenced the magnitude of LTP. However, when applied immediately after induction, treatment with either drug caused the initial magnitude of LTP to progressively decrease to a sustained phase of reduced amplitude. Collectively, our findings suggest that GluNR plasticity, although not strictly required for induction, is necessary for the maintenance of a nondecrementing component of LTP.
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Clinical trials of a urethral dose measurement system in brachytherapy using scintillation detectors.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 03-12-2010
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To report on the clinical feasibility of a novel scintillation detector system with fiberoptic readout that measures the urethral dose during high-dose-rate brachytherapy treatment of the prostate.
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Household transmission of 2009 influenza A (H1N1) virus after a school-based outbreak in New York City, April-May 2009.
J. Infect. Dis.
PUBLISHED: 03-02-2010
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In April 2009, an outbreak due to infection with the 2009 pandemic influenza A (H1N1) virus (pH1N1) was investigated in a New York City high school. We surveyed household contacts of ill students to characterize the extent of transmission within households, identify contact groups at highest risk for illness, and assess the potential for preventing household transmission. Influenza-like illness (ILI) was reported by 79 of 702 household contacts (11.3% attack rate). Multivariate analysis showed that older age was protective: for each increasing year of age, the risk of ILI was reduced 5%. Additional protective factors included antiviral prophylaxis and having had a household discussion about influenza. Providing care for the index case patient and watching television with the index case patient were risk factors among parents and siblings, respectively. Fifty percent of cases occurred within 3 days of onset of illness in the student. These factors have implications for mitigating the impact of pH1N1 transmission.
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The timing of administration, dose dependence and efficacy of dopa decarboxylase inhibitors on the reversal of motor disability produced by L-DOPA in the MPTP-treated common marmoset.
Eur. J. Pharmacol.
PUBLISHED: 02-15-2010
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Dopa decarboxylase inhibitors are routinely used to potentiate the effects of L-DOPA in the treatment of Parkinsons disease. However, neither in clinical use nor in experimental models of Parkinsons disease have the timing and dose of dopa decarboxylase inhibitors been thoroughly explored. We now report on the choice of dopa decarboxylase inhibitors, dose and the time of dosing relationships of carbidopa, benserazide and L-alpha-methyl dopa (L-AMD) in potentiating the effects of L-DOPA in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated common marmoset. Pre-treatment with benserazide for up to 3h did not alter the motor response to L-DOPA compared to simultaneous administration with L-DOPA. There was some evidence of a relationship between carbidopa and benserazide dose and increased locomotor activity and the reversal of motor disability. But in general, commonly used dose levels of dopa decarboxylase inhibitors appeared to produce a maximal motor response to L-DOPA. In contrast, dyskinesia intensity and duration continued to increase with both carbidopa and benserazide dose. The novel dopa decarboxylase inhibitor, L-AMD, increased locomotor activity and improved motor disability to the same extent as carbidopa or benserazide but importantly this was accompanied by significantly less dyskinesia. This study shows that currently, dopa decarboxylase inhibitors may be routinely employed in the MPTP-treated primate at doses which are higher than those necessary to produce a maximal potentiation of the anti-parkinsonian effect of L-DOPA. This may lead to excessive expression of dyskinesia in this model of Parkinsons disease and attention should be given to the dose regimens currently employed.
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Reactivity with dichotomous determinants of Ro 60 stratifies autoantibody responses in lupus and primary Sjögrens syndrome.
Arthritis Rheum.
PUBLISHED: 02-05-2010
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Analysis of B cell determinants of Ro 60 exposed on the surface of apoptotic cells (apotopes) or intracellular epitopes provides insight into the structural forms of the autoantigen that break immune tolerance. This study was initiated to compare anti-Ro 60 responses in systemic lupus erythematosus (SLE) and primary Sjögrens syndrome (SS) against membrane-bound and intracellular forms of Ro 60.
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The involvement of PACAP/VIP system in the synaptic transmission in the hippocampus.
J. Mol. Neurosci.
PUBLISHED: 01-29-2010
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Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two closely related peptides, which can activate protein kinase A (PKA). At least three receptors for PACAP and VIP have been identified. The PACAP-specific receptor, PAC1 receptor, exhibits a higher affinity for PACAP than VIP, whereas VIP receptors, VPAC1-R and VPAC2-R, have similar affinities for PACAP and VIP. Both PACAP/VIP and their cognate receptors are highly expressed in the brain, including the hippocampus. Recently, their roles in the regulation of synaptic transmission have begun to emerge. PACAP/VIP can signal through different pathways to regulate N-methyl-D: -aspartate (NMDA) receptors in CA1 pyramidal cells. The activation of VPAC1/2-Rs increases evoked NMDA currents via the cyclic AMP/PKA pathway. However, the activation of PAC1-R stimulates a PLC/PKC/Pyk2/Src signaling pathway to enhance NMDA receptor function in hippocampal neurons. Furthermore, different concentrations of PACAP induce different effects on the both ?-amino-3-hydroxy-5-isoxazole-propionic acid-evoked current and basal synaptic transmission by activating different receptors. Their roles in learning and memory are also demonstrated using transgenic mice and pharmacological methods.
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Pramipexole combined with levodopa improves motor function but reduces dyskinesia in MPTP-treated common marmosets.
Mov. Disord.
PUBLISHED: 01-29-2010
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Reduced expression of dyskinesia is observed in levodopa-primed MPTP-treated common marmosets when dopamine agonists are used to replace levodopa. We now investigate whether a combination of the D-2/D-3 agonist pramipexole and levodopa also reduces dyskinesia intensity while maintaining the reversal of motor disability. Drug naïve, non-dyskinetic MPTP-treated common marmosets were treated daily for up to 62 days with levodopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) or pramipexole (0.04-0.3 mg/kg BID) producing equivalent reversal of motor disability and increases in locomotor activity. Levodopa alone resulted in marked dyskinesia induction but little or no dyskinesia resulted from the administration of pramipexole. From day 36, some animals were treated with a combination of levodopa (3.125-6.25 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) and pramipexole (0.1-0.2 mg/kg p.o. SID). This improved motor disability to a greater extent than occurred with levodopa alone. Importantly, while dyskinesia was greater than that produced by pramipexole alone, the combination resulted in less intense dyskinesia than produced by levodopa alone. These results suggest that pramipexole could be administered with a reduced dose of levodopa to minimize dyskinesia in Parkinsons disease while maintaining therapeutic efficacy.
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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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