bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of electronic prescription implementation in polymedicated users of Catalonia, Spain: a population-based longitudinal study
Authors: Lizano-Díez Irene , Modamio Pilar , López-Calahorra Pilar , Lastra Cecilia F , Segú Jose L , Gilabert-Perramon Antoni , Mariño Eduardo L
Published: November 2014

Objectives

To assess whether electronic prescribing is a comprehensive health management tool that may contribute to rational drug use, particularly in polymedicated patients receiving 16 or more medications in the public healthcare system in the Barcelona Health Region (BHR).

Design

16 months of retrospective study followed by 12 months of prospective monitoring.

Setting

Primary healthcare in BHR, Catalonia, Spain.

Participants

All insured patients, especially those who are polymedicated in six basic health areas (BHA). Polymedicated patients were those with a consumption of ≥16 drugs/month.

Interventions

Monitoring demographic and consumption variables obtained from the records of prescriptions dispensed in pharmacies and charged to the public health system, as well as the resulting drug use indicators. Territorial variables related to implementation of electronic prescribing were also described and were obtained from the institutional data related to the deployment of the project.

Main outcome measures

Trend in drug use indicators (number of prescriptions per polymedicated user, total cost per polymedicated user and total cost per prescription) according to e-prescription implementation.

Results

There was a significant upward trend in the number of polymedicated users, number of prescriptions and total cost (p<0.05), which seemed independent from the implementation of electronic prescribing when comparing the preimplementation and postimplementation period. Prescriptions per user and cost per user showed a decrease between the preimplementation and postimplementation period, being significant in two BHAs (p<0.05).

Conclusions

Results suggest that after the implementation of electronic prescribing, the rationality of prescribing in polymedicated patients improved. In addition, this study provides a very valuable approach for future impact assessment.
Project JOINTS: What factors affect bundle adoption in a voluntary quality improvement campaign?
Authors: Khodyakov Dmitry , Ridgely M Susan , Huang Christina , DeBartolo Katherine O , Sorbero Melony E , Schneider Eric C
Published: November 2014

Background

Diffusion and adoption of effective evidence-based clinical practices can be slow, especially if complex changes are required to implement new practices.

Objective

To examine how hospital adherence to quality improvement (QI) methods and hospital engagement with a large-scale QI campaign could facilitate the adoption of an enhanced prevention bundle designed to reduce surgical site infection (SSI) rates after orthopaedic surgery (hip and knee arthroplasty).

Methods

We conducted telephone interviews with hospital QI leaders from 73 of the 109 hospitals (67% response rate) in five states that participated in Project JOINTS (JoiningOrganizationsIN TacklingSSIs), a QI campaign run by Institute for Healthcare Improvement (IHI). Using QI methods grounded in the IHI Model for Improvement, this campaign encouraged hospitals to implement an enhanced SSI prevention bundle. Hospital QI leaders reported on their hospital's adherence to the Project JOINTS QI methods; their level of engagement with Project JOINTS activities; and adoption of the SSI prevention bundle components. Interview data were analysed quantitatively and qualitatively.

Results

Both adherence to the QI methods and hospital engagement were positively associated with complete bundle adoption. Hospital engagement, especially the use of project materials and tools, was also positively associated with the initiation of and improved adherence to individual bundle components.

Conclusions

Our findings suggest that greater adherence to the QI methods and active hospital engagement in a QI campaign facilitate adoption of evidence-based patient safety bundles in orthopaedic practice.
Molecular pathology analyses of two fatal human infections of avian influenza A(H7N9) virus
Authors: Feng Yanling , Hu Lvyin , Lu Shuihua , Chen Qingguo , Zheng Ye , Zeng Dong , Zhang Jun , Zhang Anli , Chen Liang , Hu Yunwen , Zhang Zhiyong
Published: November 2014

Aims

To investigate the histopathological manifestations of two fatal cases of H7N9 influenza A virus infection.

Methods

Pulmonary and hepatic specimens from two fatal cases of H7N9 influenza virus infection were examined using H&E staining. Additionally, in situ hybridisation was performed with probes (ViewRNA) targeting H7N9 RNA and IP-10, interleukin (IL)-6 mRNA. The distribution of surfactant protein A (SP-A), surfactant protein B (SP-B), CD3, CD4, CD8, CD68 and C4d were determined with immunohistochemistry.

Results

 Apart from the typical diffuse alveolar damage and hyaline membrane observed in severe influenza infection, we detected H7N9 RNA and massive intrapulmonary production of IP-10 and IL-6 mRNA using in situ hybridisation. Hyperplasia of type II pneumocytes was observed by H&E staining and immunohistochemistry. Proliferating macrophages and clustered neutrophils in the infected lungs were observed, whereas T lymphocytes, especially CD4T helper cells, were markedly depleted. No obvious complement deposition was found in lung tissues.

Conclusions

 Our findings suggest that H7N9 influenza virus induced an immunological response towards overt pulmonary inflammation and systemic lymphopenia which led to intense alveolar damage and respiratory failure.
Collateral flow as causative of good outcomes in endovascular stroke therapy
Authors: Sheth Sunil A , Sanossian Nerses , Hao Qing , Starkman Sidney , Ali Latisha K , Kim Doojin , Gonzalez Nestor R , Tateshima Satoshi , Jahan Reza , Duckwiler Gary R , Saver Jeffrey L , Vinuela Fernando , Liebeskind David S ,   for the UCLA Collateral Investigators
Published: November 2014

Background

Endovascular reperfusion techniques are a promising intervention for acute ischemic stroke (AIS). Prior studies have identified markers of initial injury (arrival NIH stroke scale (NIHSS) or infarct volume) as predictive of outcome after these procedures. We sought to define the role of collateral flow at the time of presentation in determining the extent of initial ischemic injury and its influence on final outcome.

Methods

Demographic, clinical, laboratory, and radiographic data were prospectively collected on a consecutive cohort of patients who received endovascular therapy for acute cerebral ischemia at a single tertiary referral center from September 2004 to August 2010.

Results

Higher collateral grade as assessed by the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading scheme on angiography at the time of presentation was associated with improved reperfusion rates after endovascular intervention, decreased post-procedural hemorrhage, smaller infarcts on presentation and discharge, as well as improved neurological function on arrival to the hospital, discharge, and 90 days later. Patients matched by vessel occlusion, age, and time of onset demonstrated smaller strokes on presentation and better functional and radiographic outcome if found to have superior collateral flow. In multivariate analysis, lower collateral grade independently predicted higher NIHSS on arrival.

Conclusions

Improved collateral flow in patients with AIS undergoing endovascular therapy was associated with improved radiographic and clinical outcomes. Independent of age, vessel occlusion and time, in patients with comparable ischemic burdens, changes in collateral grade alone led to significant differences in initial stroke severity as well as ultimate clinical outcome.
Aceroryctes dulcis, a new palaeoryctid (Mammalia, Eutheria) from the early Eocene of the Wasatch Formation of southwestern Wyoming, USA
Authors: Rankin Brian D. , Holroyd Patricia A.
Published: November 2014

The Palaeoryctidae are a group of small-bodied, likely insectivorous mammals known principally from the Paleocene and early Eocene (from approximately 65 to 53 Ma) of North America. Here we report on a new palaeoryctid from the early Eocene (early Wasatchian (Wa3) North American Land Mammal Age) Main Body of the Wasatch Formation, Washakie Basin, near Bitter Creek station in southwestern Wyoming, USA. Acerorcytes dulcis gen. et sp. nov. is unique among palaeoryctids in having a double-rooted P2 with a small anterior cusp, P3 with pronounced para- and metastylar cusps and a reduced but conspicuous metacone, P4 with a weakly developed metacone and an anteroposteriorly compressed protocone, and M1-2 with deep ectoflexus and a sharp metastylar blade. A phylogenetic analysis based on 32 dental characters of the nine known North American palaeoryctid species, including Aceroryctes dulcis, recovered eight equally parsimonious cladograms. Similar to prior studies, the analysis suggests that the genus Palaeoryctes is non-monophyletic, with Palaeoryctes cruoris and Aaptoryctes ivyi closely related. Aceroryctes dulcis is grouped with Ottoryctes winkleri and positioned in a more inclusive clade with Eoryctes melanus; the remaining palaeoryctid taxa, including Lainoryctes youzwyshyni, are part of an unresolved polytomy. These new findings indicate that early Eocene palaeoryctids were more diverse than previously thought, with genus richness during the early Eocene at least as great as that during the middle Paleocene.
Cellular automaton models for traffic flow considering opposite driving of an emergency vehicle
Authors: Zhao Han-Tao , Li Jing-Ru , Nie Cen
Published: November 2014

Aiming at two-lane road, this paper establishes three models to analyze the opposite-overtaking rules of emergency vehicle based on cellular automaton (CCA) model. Based on the simulation of mixed traffic flow for multi-density conditions, the density-speed diagrams have been obtained consequently. According to the analysis, when the traffic density of the opposite lane is low, the opposite driving behavior of emergency vehicle can improve the average speed effectively. At the same time, if the cocurrent lane is in high-density traffic, the traffic in the opposite lane will be disturbed, but the vehicles in the cocurrent lane will not be affected. The paper has further discussed the influence of different emergency vehicle driving behaviors on traffic. The results reveal that as the traffic of the opposite lane is in a low-density range, if emergency vehicle operates overtaking behavior precisely, the greater the density of the cocurrent lane is, the more obviously the speed improve. Meanwhile large random fluctuation of overtaking times will occur. While the risky lane change behavior displays different traffic characteristics, that is when the same direction lane is in high density, the speed increases slightly and the lane change number is changed regularly.
Robust Pornography Classification Solving the Image Size Variation Problem Based on Multi-Agent Learning
Authors: Zaidan A. A. , Karim H. Abdul , Ahmad N. N. , Zaidan B. B. , Kiah M. L. Mat
Published: November 2014

This study proposed a pornography classifier using multi-agent learning as a combination of the Bayesian method using color features extracted from skin detection based on the YCbCr color space and the back-propagation neural network method using shape features also extracted from skin detection. The classification of pornographic images was made more robust to the variation of images despite size engineering problems. Previous studies failed to achieve such robustness. Findings showed that the proposed multi-agent learning-based pornography classifier has produced significant TP and TN average rates (i.e., 96% and 97.33%, respectively). In addition, the proposed classifier has achieved a significantly low average rate of FN and FP (i.e., only 4% and 2.67%, respectively). The implementation of this algorithm is crucial and significant not only in identifying pornography but also in blocking Web sites that covertly promote pornography.
Lattices of regular closed subsets of closure spaces
Authors: Santocanale Luigi , Wehrung Friedrich
Published: November 2014

For a closure space (P, φ) with φ(ø) = ø, the closures of open subsets of P, called the regular closed subsets, form an ortholattice Reg (P, φ), extending the poset Clop (P, φ) of all clopen subsets. If (P, φ) is a finite convex geometry, then Reg (P, φ) is pseudocomplemented. The Dedekind–MacNeille completion of the poset of regions of any central hyperplane arrangement can be obtained in this way, hence it is pseudocomplemented. The lattice Reg (P, φ) carries a particularly interesting structure for special types of convex geometries, that we call closure spaces of semilattice type. For finite such closure spaces,

• Reg (P, φ) satisfies an infinite collection of stronger and stronger quasi-identities, weaker than both meet- and join-semidistributivity. Nevertheless it may fail semidistributivity.

• If Reg (P, φ) is semidistributive, then it is a bounded homomorphic image of a free lattice.

• Clop (P, φ) is a lattice if and only if every regular closed set is clopen.

The extended permutohedron R (G) on a graph G and the extended permutohedron Reg S on a join-semilattice S, are both defined as lattices of regular closed sets of suitable closure spaces. While the lattice of all regular closed sets is, in the semilattice context, always the Dedekind–MacNeille completion of the poset of clopen sets, this does not always hold in the graph context, although it always does so for finite block graphs and for cycles. Furthermore, both R (G) and Reg S are bounded homomorphic images of free lattices.
Descending entropy in expanding the universe
Authors: Portnov Yuriy A.
Published: November 2014

Inter-relation between 1-form of nonmetricity and change of entropy in the course of time is considered in the study. It is shown that change of entropy in expanding universe will be always negative. The obtained result contravenes the second law of thermodynamics, however it explains available ordered macrostructures in the universe.
Preparation of phthalocyanines fused with four tetrathiafulvalene units via the functional group transformation of tetrakis(o-xylylenedithio)phthalocyanines with toluene/aluminum chloride
Authors: Kimura Takeshi , Chiba Tadafumi , Nakajo Shiduko
Published: November 2014

Tetrakis(o-xylylenedithio)phthalocyanine 5 and its nickel complex 5-Ni were treated with aluminum chloride in toluene to eliminate the peripheral o-xylylene groups. The thiolate anions generated from 5 and 5-Ni were reacted with carbonyldiimidazole to produce phthalocyanines 6 and 6-Ni with four 1,3-dithiole-2-one rings, respectively. Phthalocyanine 7a having four ethylenedithiotetrathiafulvalene units was prepared via the condensation of 6-Ni with ethylenedithio-1,3-dithiole-2-thiones. The reaction of 6-Ni with bis(methylthio)-1,3-dithiole-2-thiones gave phthalocyanine 7b with the corresponding TTF units. The structures of the products were determined by 1 H NMR and MALDI-TOF-MS. Their electrochemical and optical properties were examined by cyclic voltammetry and UV-vis spectroscopy.
Osmotic shrinkage elicits FAK- and Src phosphorylation and Src-dependent NKCC1 activation in NIH3T3 cells
Authors: Rasmussen Line Jee Hartmann , Müller Helene Steenkær Holm , Jørgensen Bente , Pedersen Stine Falsig , Hoffmann Else Kay
Published: November 2014

The mechanisms linking cell volume sensing to volume regulation in mammalian cells remain incompletely understood. Here, we test the hypothesis that activation of nonreceptor tyrosine kinases Src, focal adhesion kinase (FAK), and Janus kinase-2 (Jak2) occurs after osmotic shrinkage of NIH3T3 fibroblasts and contributes to volume regulation by activation of NKCC1. FAK phosphorylation at Tyr397, Tyr576/577, and Tyr861 was increased rapidly after exposure to hypertonic (575 mOsm) saline, peaking after 10 (Tyr397, Tyr576/577) and 10–30 min (Tyr861). Shrinkage-induced Src family kinase autophosphorylation (pTyr416-Src) was induced after 2–10 min, and immunoprecipitation indicated that this reflected phosphorylation of Src itself, rather than Fyn and Yes. Phosphorylated Src and FAK partly colocalized with vinculin, a focal adhesion marker, after hypertonic shrinkage. The Src inhibitor pyrazolopyrimidine-2 (PP2, 10 μM) essentially abolished shrinkage-induced FAK phosphorylation at Tyr576/577 and Tyr861, yet not at Tyr397, and inhibited shrinkage-induced NKCC1 activity by ∼50%. The FAK inhibitor PF-573,228 augmented shrinkage-induced Src phosphorylation, and inhibited shrinkage-induced NKCC1 activity by ∼15%. The apparent role of Src in NKCC1 activation did not reflect phosphorylation of myosin light chain kinase (MLC), which was unaffected by shrinkage and by PP2, but may involve Jak2, a known target of Src, which was rapidly activated by osmotic shrinkage and inhibited by PP2. Collectively, our findings suggest a major role for Src and possibly the Jak2 axis in shrinkage-activation of NKCC1 in NIH3T3 cells, whereas no evidence was found for major roles for FAK and MLC in this process.
CaV3.2 T-type Ca2+ channels in H2S-mediated hypoxic response of the carotid body
Authors: Makarenko Vladislav V. , Peng Ying-Jie , Yuan Guoxiang , Fox Aaron P. , Kumar Ganesh K. , Nanduri Jayasri , Prabhakar Nanduri R.
Published: November 2014

Arterial blood O2 levels are detected by specialized sensory organs called carotid bodies. Voltage-gated Ca2+ channels (VGCCs) are important for carotid body O2 sensing. Given that T-type VGCCs contribute to nociceptive sensation, we hypothesized that they participate in carotid body O2 sensing. The rat carotid body expresses high levels of mRNA encoding the α1H-subunit, and α1H protein is localized to glomus cells, the primary O2-sensing cells in the chemoreceptor tissue, suggesting that CaV3.2 is the major T-type VGCC isoform expressed in the carotid body. Mibefradil and TTA-A2, selective blockers of the T-type VGCC, markedly attenuated elevation of hypoxia-evoked intracellular Ca2+ concentration, secretion of catecholamines from glomus cells, and sensory excitation of the rat carotid body. Similar results were obtained in the carotid body and glomus cells from CaV3.2 knockout ( Cacna1h−/−) mice. Since cystathionine-γ-lyase (CSE)-derived H2S is a critical mediator of the carotid body response to hypoxia, the role of T-type VGCCs in H2S-mediated O2 sensing was examined. Like hypoxia, NaHS, a H2S donor, increased intracellular Ca2+ concentration and augmented carotid body sensory nerve activity in wild-type mice, and these effects were markedly attenuated in Cacna1h−/− mice. In wild-type mice, TTA-A2 markedly attenuated glomus cell and carotid body sensory nerve responses to hypoxia, and these effects were absent in CSE knockout mice. These results demonstrate that CaV3.2 T-type VGCCs contribute to the H2S-mediated carotid body response to hypoxia.
Loss of mitochondrial exo/endonuclease EXOG affects mitochondrial respiration and induces ROS-mediated cardiomyocyte hypertrophy
Authors: Tigchelaar Wardit , Yu Hongjuan , de Jong Anne Margreet , van Gilst Wiek H. , van der Harst Pim , Westenbrink B. Daan , de Boer Rudolf A. , Silljé Herman H. W.
Published: November 2014

Recently, a locus at the mitochondrial exo/endonuclease EXOG gene, which has been implicated in mitochondrial DNA repair, was associated with cardiac function. The function of EXOG in cardiomyocytes is still elusive. Here we investigated the role of EXOG in mitochondrial function and hypertrophy in cardiomyocytes. Depletion of EXOG in primary neonatal rat ventricular cardiomyocytes (NRVCs) induced a marked increase in cardiomyocyte hypertrophy. Depletion of EXOG, however, did not result in loss of mitochondrial DNA integrity. Although EXOG depletion did not induce fetal gene expression and common hypertrophy pathways were not activated, a clear increase in ribosomal S6 phosphorylation was observed, which readily explains increased protein synthesis. With the use of a Seahorse flux analyzer, it was shown that the mitochondrial oxidative consumption rate (OCR) was increased 2.4-fold in EXOG-depleted NRVCs. Moreover, ATP-linked OCR was 5.2-fold higher. This increase was not explained by mitochondrial biogenesis or alterations in mitochondrial membrane potential. Western blotting confirmed normal levels of the oxidative phosphorylation (OXPHOS) complexes. The increased OCR was accompanied by a 5.4-fold increase in mitochondrial ROS levels. These increased ROS levels could be normalized with specific mitochondrial ROS scavengers (MitoTEMPO, mnSOD). Remarkably, scavenging of excess ROS strongly attenuated the hypertrophic response. In conclusion, loss of EXOG affects normal mitochondrial function resulting in increased mitochondrial respiration, excess ROS production, and cardiomyocyte hypertrophy.
Depressed excitability and ion currents linked to slow exocytotic fusion pore in chromaffin cells of the SOD1G93A mouse model of amyotrophic lateral sclerosis
Authors: Calvo-Gallardo Enrique , Pascual Ricardo de , Fernández-Morales José-Carlos , Arranz-Tagarro Juan-Alberto , Maroto Marcos , Nanclares Carmen , Gandía Luis , de Diego Antonio M. G. , Padín Juan-Fernando , García Antonio G.
Published: November 2014

Altered synaptic transmission with excess glutamate release has been implicated in the loss of motoneurons occurring in amyotrophic lateral sclerosis (ALS). Hyperexcitability or hypoexcitability of motoneurons from mice carrying the ALS mutation SOD1G93A (mSOD1) has also been reported. Here we have investigated the excitability, the ion currents, and the kinetics of the exocytotic fusion pore in chromaffin cells from postnatal day 90 to postnatal day 130 mSOD1 mice, when motor deficits are already established. With respect to wild-type (WT), mSOD1 chromaffin cells had a decrease in the following parameters: 95% in spontaneous action potentials, 70% in nicotinic current for acetylcholine (ACh), 35% in Na+ current, 40% in Ca2+-dependent K+ current, and 53% in voltage-dependent K+ current. Ca2+ current was increased by 37%, but the ACh-evoked elevation of cytosolic Ca2+ was unchanged. Single exocytotic spike events triggered by ACh had the following differences (mSOD1 vs. WT): 36% lower rise rate, 60% higher decay time, 51% higher half-width, 13% lower amplitude, and 61% higher quantal size. The expression of the α3-subtype of nicotinic receptors and proteins of the exocytotic machinery was unchanged in the brain and adrenal medulla of mSOD1, with respect to WT mice. A slower fusion pore opening, expansion, and closure are likely linked to the pronounced reduction in cell excitability and in the ion currents driving action potentials in mSOD1, compared with WT chromaffin cells.
Disturbed flow induces systemic changes in metabolites in mouse plasma: a metabolomics study using ApoE−/−mice with partial carotid ligation
Authors: Go Young-Mi , Kim Chan Woo , Walker Douglas I. , Kang Dong Won , Kumar Sandeep , Orr Michael , Uppal Karan , Quyyumi Arshed A. , Jo Hanjoong , Jones Dean P.
Published: November 2014

Disturbed blood flow (d-flow) occurring in branched and curved arteries promotes endothelial dysfunction and atherosclerosis, in part, by altering gene expression and epigenomic profiles in endothelial cells. While a systemic metabolic change is known to play a role in atherosclerosis, it is unclear whether it can be regulated by local d-flow. Here, we tested this hypothesis by carrying out a metabolomics study using blood plasma samples obtained from ApoE−/−mice that underwent a partial carotid ligation surgery to induce d-flow. Mice receiving sham ligation were used as a control. To study early metabolic changes, samples collected from 1 wk after partial ligation when endothelial dysfunction occurs, but before atheroma develops, were analyzed by high-resolution mass spectrometry. A metabolome-wide association study showed that 128 metabolites were significantly altered in the ligated mice compared with the sham group. Of these, sphingomyelin (SM; m/z 703.5747), a common mammalian cell membrane sphingolipid, was most significantly increased in the ligated mice. Of the 128 discriminatory metabolites, 18 and 41 were positively and negatively correlated with SM, respectively. The amino acids methionine and phenylalanine were increased by d-flow, while phosphatidylcholine and phosphatidylethanolamine were decreased by d-flow, and these metabolites were correlated with SM. Other significantly affected metabolites included dietary and environmental agents. Pathway analysis showed that the metabolic changes of d-flow impacted broad functional networks. These results suggest that signaling from d-flow occurring in focal regions induces systemic metabolic changes associated with atherosclerosis.
Vasopressin regulation of multisite phosphorylation of UT-A1 in the inner medullary collecting duct
Authors: Hoban Carol A. , Black Lauren N. , Ordas Ronald J. , Gumina Diane L. , Pulous Fadi E. , Sim Jae H. , Sands Jeff M. , Blount Mitsi A.
Published: November 2014

Vasopressin signaling is critical for the regulation of urea transport in the inner medullary collecting duct (IMCD). Increased urea permeability is driven by a vasopressin-mediated elevation of cAMP that results in the direct phosphorylation of urea transporter (UT)-A1. The identification of cAMP-sensitive phosphorylation sites, Ser486 and Ser499, in the rat UT-A1 sequence was the first step in understanding the mechanism of vasopressin action on the phosphorylation-dependent modulation of urea transport. To investigate the significance of multisite phosphorylation of UT-A1 in response to elevated cAMP, we used highly specific and sensitive phosphosite antibodies to Ser486 and Ser499 to determine cAMP action at each phosphorylation site. We found that phosphorylation at both sites was rapid and sustained. Furthermore, the rate of phosphorylation of the two sites was similar in both mIMCD3 cells and rat inner medullary tissue. UT-A1 localized to the apical membrane in response to vasopressin was phosphorylated at Ser486 and Ser499. We confirmed that elevated cAMP resulted in increased phosphorylation of both sites by PKA but not through the vasopressin-sensitive exchange protein activated by cAMP pathway. These results elucidate the multisite phosphorylation of UT-A1 in response to cAMP, thus providing the beginning of understanding the intracellular factors underlying vasopressin stimulation of urea transport in the IMCD.
Effect of nitric oxide on spinal evoked potentials and survival rate in rats with decompression sickness
Authors: Randsoe T. , Meehan C. F. , Broholm H. , Hyldegaard O.
Published: November 2014

Nitric oxide (NO) releasing agents have, in experimental settings, been shown to decrease intravascular nitrogen bubble formation and to increase the survival rate during decompression sickness (DCS) from diving. The effect has been ascribed to a possible removal of preexisting micronuclei or an increased nitrogen washout on decompression through augmented blood flow rate. The present experiments were conducted to investigate whether a short- or long-acting NO donor [glycerol trinitrate (GTN) or isosorbide-5-mononitrate (ISMN), respectively] would offer the same protection against spinal cord DCS evaluated by means of spinal evoked potentials (SEPs). Anesthetized rats were decompressed from a 1-h hyperbaric air dive at 506.6 kPa (40 m of seawater) for 3 min and 17 s, and spinal cord conduction was studied by measurements of SEPs. Histological samples of the spinal cord were analyzed for lesions of DCS. In total, 58 rats were divided into 6 different treatment groups. The first three received either saline ( group 1), 300 mg/kg iv ISMN ( group 2), or 10 mg/kg ip GTN ( group 3) before compression. The last three received either 300 mg/kg iv ISMN ( group 4), 1 mg/kg iv GTN ( group 5), or 75 μg/kg iv GTN ( group 6) during the dive, before decompression. In all groups, decompression caused considerable intravascular bubble formation. The ISMN groups showed no difference compared with the control group, whereas the GTN groups showed a tendency toward faster SEP disappearance and shorter survival times. In conclusion, neither a short- nor long-acting NO donor had any protective effect against fatal DCS by intravenous bubble formation. This effect is most likely due to a fast ascent rate overriding the protective effects of NO, rather than the total inert tissue gas load.
Sodium nitrite supplementation improves motor function and skeletal muscle inflammatory profile in old male mice
Authors: Justice Jamie N. , Gioscia-Ryan Rachel A. , Johnson Lawrence C. , Battson Micah L. , de Picciotto Natalie E. , Beck Hannah J. , Jiang Hong , Sindler Amy L. , Bryan Nathan S. , Enoka Roger M. , Seals Douglas R.
Published: November 2014

Aging is associated with motor declines that lead to functional limitations and disability, necessitating the development of therapies to slow or reverse these events. We tested the hypothesis that sodium nitrite supplementation attenuates declines in motor function in older C57BL/6 mice. Motor function was assessed using a battery of tests (grip strength, open-field distance, rota-rod endurance) in old animals (age 20–24 mo) at baseline and after 8 wk of sodium nitrite (old nitrite, n = 22, 50 mg/liter) or no treatment (old control, n = 40), and in young reference animals (3 mo, n = 87). Eight weeks of sodium nitrite supplementation improved grip strength (old nitrite, +12.0 ± 14.9% vs. old control, +1.5 ± 15.2%, P < 0.05) and open field distance (old nitrite, +9.5 ± 7.7%, P < 0.01 vs. old control, −28.1 ± 2.0%) and completely restored rota-rod endurance-run time (old nitrite, +3.2 ± 7.1%, P < 0.01 vs. old control, −21.5 ± 7.2%; old nitrite after treatment P > 0.05 vs. young reference). Inflammatory cytokines were markedly increased in quadriceps of old compared with young reference animals (by ELISA, interleukin-1β [IL-1β] 3.86 ± 2.34 vs. 1.11 ± 0.74, P < 0.05; interferon-gamma [INF-γ] 8.31 ± 1.59 vs. 3.99 ± 2.59, P < 0.01; tumor necrosis factor-alpha [TNF-α] 1.69 ± 0.44 vs. 0.76 ± 0.30 pg/ml, P < 0.01), but were reduced to young reference levels after treatment (old nitrite, IL-1β 0.67 ± 0.95; INF-γ 5.22 ± 2.01, TNF-α 1.21 ± 0.39 pg/ml, P < 0.05 vs. old control, P > 0.05 vs. young reference). Cytokine expression and treatment (old nitrite vs. old control) predicted strength ( R2 = 0.822, P < 0.001, IL-1β, INF-γ, group), open field distance ( R2 = 0.574, P < 0.01, IL-1β, group) and endurance run time ( R2 = 0.477, P < 0.05, INF-γ). Our results suggest that sodium nitrite improves motor function in old mice, in part by reducing low-grade inflammation in muscle.
Neurocognitive stages of spatial cognitive mapping measured during free exploration of a large-scale virtual environment
Authors: Plank Markus , Snider Joseph , Kaestner Erik , Halgren Eric , Poizner Howard
Published: November 2014

Using a novel, fully mobile virtual reality paradigm, we investigated the EEG correlates of spatial representations formed during unsupervised exploration. On day 1, subjects implicitly learned the location of 39 objects by exploring a room and popping bubbles that hid the objects. On day 2, they again popped bubbles in the same environment. In most cases, the objects hidden underneath the bubbles were in the same place as on day 1. However, a varying third of them were misplaced in each block. Subjects indicated their certainty that the object was in the same location as the day before. Compared with bubble pops revealing correctly placed objects, bubble pops revealing misplaced objects evoked a decreased negativity starting at 145 ms, with scalp topography consistent with generation in medial parietal cortex. There was also an increased negativity starting at 515 ms to misplaced objects, with scalp topography consistent with generation in inferior temporal cortex. Additionally, misplaced objects elicited an increase in frontal midline theta power. These findings suggest that the successive neurocognitive stages of processing allocentric space may include an initial template matching, integration of the object within its spatial cognitive map, and memory recall, analogous to the processing negativity N400 and theta that support verbal cognitive maps in humans.
The complete frequency spectrum of physiological tremor can be recreated by broadband mechanical or electrical drive
Authors: Vernooij Carlijn Andrea , Lakie Martin , Reynolds Raymond Francis
Published: November 2014

Two frequency peaks of variable preponderance have been reported for human physiological finger tremor. The high-frequency peak (20–25 Hz, seen only in postural tremor) is generally attributed to mechanical resonance, whereas the lower frequency peak (8–12 Hz, seen in both postural and kinetic tremor) is usually attributed to synchronous central or reflexive neural drive. In this study, we determine whether mechanical resonance could generate both peaks. In relaxed subjects, an artificial finger tremor was evoked by random mechanical perturbations of the middle finger or random electrical muscular stimulation of the finger extensor muscle. The high and the low frequencies observed in physiological tremor could both be created by either type of artificial input at appropriate input intensity. Resonance, inferred from cross-spectral gain and phase, occurred at both frequencies. To determine any neural contribution, we compared truly passive subjects with those who exhibited some electromyographic (EMG) activity in the finger extensor; artificially created tremor spectra were almost identical between groups. We also applied electrical stimuli to two clinically deafferented subjects lacking stretch reflexes. They exhibited the same artificial tremor spectrum as control subjects. These results suggest that both typical physiological finger tremor frequencies can be reproduced by random artificial input; neither requires synchronized neural input. We therefore suggest that mechanical resonance could generate both dominant frequency peaks characteristic of physiological finger tremor. The inverse relationship between the input intensity and the resulting tremor frequency can be explained by a movement-dependent reduction in muscle stiffness, a conjecture we support using a simple computational model.
Myeloid Expression of Adenosine A2A Receptor Suppresses T and NK Cell Responses in the Solid Tumor Microenvironment
Authors: Cekic Caglar , Day Yuan-Ji , Sag Duygu , Linden Joel
Published: November 2014

High concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role for myeloid cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study, we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2af/f–LysMCre+/− mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL12 expression in tumor-associated macrophages and with >90% reductions in IL10 expression in tumor-associated macrophages, dendritic cells (DC), and Ly6C+ or Ly6G+ myeloid-derived suppressor cells (MDSC). Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and natural killer (NK) cells. Depletion of CD8+ T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8+ T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen-specific CD8+ T cells in lung infiltrates. Overall, the findings indicate that myeloid cell A2ARs have direct myelosuppressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs, and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors. Cancer Res; 74(24); 7250–9. ©2014 AACR.
Mig-6 Suppresses Endometrial Cancer Associated with Pten Deficiency and ERK Activation
Authors: Kim Tae Hoon , Yoo Jung-Yoon , Kim Hong Im , Gilbert Jenifer , Ku Bon Jeong , Li Jane , Mills Gordon B. , Broaddus Russell R. , Lydon John P. , Lim Jeong Mook , Yoon Ho-Geun , Jeong Jae-Wook
Published: November 2014

PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α–dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice, where Mig-6 was overexpressed in progesterone receptor–expressing cells, exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PRcre/+Ptenf/f mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer. Cancer Res; 74(24); 7371–82. ©2014 AACR.
Mitochondrial MKP1 Is a Target for Therapy-Resistant HER2-Positive Breast Cancer Cells
Authors: Candas Demet , Lu Chung-Ling , Fan Ming , Chuang Frank Y.S. , Sweeney Colleen , Borowsky Alexander D. , Li Jian Jian
Published: November 2014

The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here, we report that after cell irradiation, MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF–MEK–ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was also detected in irradiated HER2-positive breast cancer stem-like cells (HER2+/CD44+/CD24−/low) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization. Cancer Res; 74(24); 7498–509. ©2014 AACR.
Comparison of Uptake of Colorectal Cancer Screening Based on Fecal Immunochemical Testing (FIT) in Males and Females: A Systematic Review and Meta-analysis
Authors: Clarke Nicholas , Sharp Linda , Osborne Aoife , Kearney Patricia M.
Published: November 2014

Background: Colorectal cancer is the third most common cancer in males and the second in females worldwide. Incidence and mortality are higher in men than women. Colorectal cancer screening is effective in reducing mortality. Internationally, fecal immunochemical testing (FIT) is increasingly being recommended as the primary screening test. This systematic review and meta-analysis aimed to determine whether uptake of FIT screening differs between men than women.

Methods: We searched PubMed and Embase for peer-reviewed articles published in English during 2000–2013 for randomized controlled trials (RCT) or observational studies of screening using FIT that quantified numbers invited and participating by gender. Meta-analysis was performed using a random effects model.

Results: Six hundred and eighty-five citations were identified, 19 meeting the inclusion criteria. Random effects meta-analysis found male uptake was significantly lower than female uptake [odds ratio (OR), 0.84; 95% confidence interval (CI), 0.75–0.95; P < 0.01]. This generally persisted throughout subgroup analysis of study design (RCTs vs. observational studies and study quality), screening organization (methods of invitation, number of samples, age range of screening, recommendations, and reminders), and setting.

Conclusions: Meta analysis of FIT screening studies indicates significantly lower uptake among men.

Impact: Further investigation is required into factors influencing acceptability and participation of FIT screening in both sexes. Cancer Epidemiol Biomarkers Prev; 24(1); 39–47. ©2014 AACR.
ΔNP63α Transcriptionally Activates Chemokine Receptor 4 (CXCR4) Expression to Regulate Breast Cancer Stem Cell Activity and Chemotaxis
Authors: DeCastro Andrew J. , Cherukuri Pratima , Balboni Amanda , DiRenzo James
Published: November 2014

ΔNP63α, the predominant TP63 isoform expressed in diverse epithelial tissues, including the mammary gland, is required for the preservation of stem cells and has been implicated in tumorigenesis and metastasis. Despite data characterizing ΔNP63α as a master regulator of stem cell activity, identification of the targets underlying these effects is incompletely understood. Recently, ΔNP63α was identified as a key regulator in the promotion of proinflammatory programs in squamous cell carcinoma of the head and neck. Inflammation has been implicated as a potent driver of cancer stem cell phenotypes and metastasis. In this study, we sought to identify novel targets of ΔNP63α that confer cancer stem cell and prometastatic properties. Data presented here identify the gene encoding the chemokine receptor 4 (CXCR4) as a transcriptional target of ΔNP63α. Our data indicate that ΔNP63α enhances CXCR4 expression in breast cancer cells via its binding at two regions within the CXCR4 promoter. The CXCR4 antagonist AMD3100 was used to demonstrate that the pro–stem cell activity of ΔNP63α is mediated through its regulation of CXCR4. Importantly, we show that ΔNP63α promotes the chemotaxis of breast cancer cells towards the CXCR4 ligand SDF1α, a process implicated in the trafficking of breast cancer cells to sites of metastasis. This study highlights CXCR4 as a previously unidentified target of ΔNP63α, which plays a significant role in mediating ΔNP63α-dependent stem cell activity and chemotaxis toward SDF1α. Our findings suggest that ΔNP63α regulation of CXCR4 may have strong implications in the regulation of cancer stem cells and metastasis. Mol Cancer Ther; 14(1); 225–35. ©2014 AACR.
The Protein Phosphatase 2A Inhibitor LB100 Sensitizes Ovarian Carcinoma Cells to Cisplatin-Mediated Cytotoxicity
Authors: Chang Ki-Eun , Wei Bih-Rong , Madigan James P. , Hall Matthew D. , Simpson R. Mark , Zhuang Zhengping , Gottesman Michael M.
Published: November 2014

Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA-damage response (DDR) and cell-cycle checkpoint pathways. Recent studies have shown that LB100, a small-molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, -4, and -6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell-cycle regulation, and DDR signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization via LB100 was mediated by abrogation of cell-cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and γH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation. Mol Cancer Ther; 14(1); 90–100. ©2014 AACR.
Effectiveness of a Mobile Diabetic Retinopathy Screening Campaign to Encourage Diabetics to Undergo Regular Ophthalmic Follow-Up
Authors: Creuzot-Garcher Catherine , Martin-Phipps Till , Beynat Julien , Astruc Karine , Brassac Karima , Bron Alain M.
Published: November 2014

Aim: To evaluate the effectiveness of a mobile diabetic retinopathy (DR) screening campaign with a non-mydriatic camera to encourage diabetics to undergo a subsequent ophthalmic follow-up. Methods: Diabetic patients who underwent free DR screening with a non-mydriatic fundus camera were given the recommendation to have an ophthalmic visit, in a time frame suited to the DR stage or in case abnormalities in the macula, the optic nerve or intra-ocular pressure were detected. The photographs were performed by a trained orthoptist. The date of the visit to their ophthalmologist and the report of this consultation were recorded. Results: During 5 annual campaigns, 4,699 diabetics were screened. Of the 1,573 ophthalmic examinations recommended at the screening, 1,241 (79%) were actually conducted. A total of 623 new cases of DR were found in the course of this screening campaign, with a fair concordance between the diagnosis suggested at screening and the examination by the ophthalmologist (κ = 0.48). Conclusion: Information and recommendations given during DR screening helped to reintroduce patients to a regular ophthalmic follow-up, at least in the short term.