bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross-sectional study to compare two blood collection methods: direct venous puncture and peripheral venous catheter
Authors: Ortells-Abuye Nativitat , Busquets-Puigdevall Teresa , Díaz-Bergara Maribel , Paguina-Marcos Marta , Sánchez-Pérez Inma
Published: February 2014

Objectives

To demonstrate the equivalence between blood collection methods using direct venous puncture (DVP) and a peripheral venous catheter or cannula (PVC).

Design and setting

A cross-sectional study of simple crossover design with within-subject measures carried out between October 2011 and May 2012 at a regional hospital in Spain.

Participants

272 patients aged 18 or older hospitalised or admitted to the short-stay unit (SSU) who required laboratory testing and PVC to administer saline solution, intravenous fluid therapy and/or intravenous medication. Excluded were those with PVC collection time exceeding 20 s, difficulty of venoclysis, or who presented with arteriovenous fistula, language difficulties, in critical condition or altered consciousness with no family to consent.

Primary and secondary outcome measures

18 variables were recorded for DVP and PVC, along with age, sex, diagnosis, vein location for DVP, location of the PVC, PVC calibre, saline syringe, intravenous fluid therapy, medication, haemolysis and clotted blood during DVP or PVC collection. Univariate analysis, Pearson's product-moment correlation coefficient (r), Lin's concordance correlation coefficient (rc) and Bland-Altman's 95% agreement interval were provided.

Results

Included in the study were 272 patients, primarily aged 65 or older (80.9%), males (52.6%) and receiving intermittent medication (43.4%). Values obtained with both methods showed a positive linear association, being moderate for pO2(r=0.405) and very high for all others (r>0.86). Levels were concordant (rc≥0.9), except for calcium (rc=0.860), pH (rc=0.853), pCO2(rc=0.843) and pO2(rc=0.336) and equivalent for all determinations except pCO2and pO2, where clinically significant differences were found in more than 9% of cases (21.2%, 95% CI 16.6% to 26.5% and 73.1%, 95% CI 67.4% to 78.1%).

Conclusions

Blood collection methods using DVP and PVC can be used interchangeably for most routine laboratory tests.
Predicting parent vessel patency and treatment durability: a proposed grading scheme for the immediate angiographic results following Onyx HD-500 embolization of intracranial aneurysms
Authors: Rahme Ralph , Grande Andrew , Jimenez Lincoln , Abruzzo Todd A , Ringer Andrew J
Published: February 2014

Introduction

Onyx HD-500 embolization of intracranial aneurysms leads to high rates of complete and durable occlusion. However, little information exists as to what constitutes an optimal immediate angiographic result. We devised a simple grading scheme based on the pattern of parent artery and aneurysm neck reconstruction, and correlated it with long term outcome.

Methods

All cases of Onyx embolization for unruptured aneurysms performed between September 2008 and April 2010 were retrospectively reviewed. Immediate angiographic results were categorized according to the pattern of extra-aneurysmal Onyx leakage: grade A, none; grade B, ‘hat brim’ lamination; and grade C, ‘ectopic’ Onyx (C1, non-flow limiting; C2, flow limiting). Results of follow-up vascular imaging were reviewed and correlated with the angiographic grade.

Results

24 embolization procedures were performed in 21 patients with 23 aneurysms. Aneurysm size ranged from 2.5 to 24 mm and neck width from 2 to 8 mm. Complete occlusion was achieved in 20 cases (83.3%) and subtotal occlusion in three (12.5%). Immediate angiographic results were: grade A in ten (41.7%), grade B in eight (33.3%), and grade C in six (25%). Stable angiographic results were seen in 85%, 94%, 94%, and 100% at 6, 12, 24, and 36 months, respectively. Angiographic recurrence was observed in four cases (16.7%), all grade A (p=0.006). Delayed parent vessel occlusion occurred in two cases (8.3%), both grade C2 (p=0.014).

Conclusions

This simple grading system may help predict long term angiographic results. Hat brim Onyx lamination seems to provide an optimal balance between treatment durability and parent vessel patency. Prospective validation is warranted.
Pipeline Embolization Device as primary treatment for blister aneurysms and iatrogenic pseudoaneurysms of the internal carotid artery
Authors: Nerva John D , Morton Ryan P , Levitt Michael R , Osbun Joshua W , Ferreira Manuel J , Ghodke Basavaraj V , Kim Louis J
Published: February 2014

Background

Blood blister type aneurysms (BBAs) and pseudoaneurysms create a unique treatment challenge. Despite many advances in open surgical and endovascular techniques, this subset of patients retains relatively high rates of morbidity and mortality. Recently, BBAs have been treated with flow-diverting stents such as the Pipeline Embolization Device (PED) with overall positive results.

Methods

Four patients presented with dissecting internal carotid artery (ICA) aneurysms treated with the PED (two BBAs presenting with subarachnoid hemorrhage (SAH), two pseudoaneurysms after injury during endoscopic trans-sphenoidal tumor surgery).

Results

Three patients had a successful angiographic and neurological outcome. One patient with a BBA re-ruptured during initial PED placement, again in the postoperative period, and later died. Primary PED treatment involved telescoping stents in two patients and coil embolization supplementation in one patient.

Conclusions

The PED should be used selectively in the setting of acute SAH. Dual antiplatelet therapy can complicate hydrocephalus management, and the lack of immediate aneurysm occlusion creates the risk of short-term re-rupture. PED treatment for iatrogenic ICA pseudoaneurysms can provide a good angiographic and neurological outcome.
Endovascular treatment for M2 occlusions in the era of stentrievers: a descriptive multicenter experience
Authors: Flores Alan , Tomasello Alejandro , Cardona Pere , de Miquel M Angeles , Gomis Meritxell , Garcia Bermejo Pablo , Obach Victor , Urra Xabi , Martí-Fàbregas Joan , Cánovas David , Roquer Jaume , Abilleira Sònia , Ribó Marc
Published: February 2014

Background

Patients with M2 middle cerebral artery (MCA) occlusions are not always considered for endovascular treatment.

Objective

To study outcomes in patients with M2 occlusion treated with endovascular procedures in the era of stentrievers.

Methods

We studied patients prospectively included in the SONIIA registry (years 2011–2012)—a mandatory, externally audited registry that monitors the quality of reperfusion therapies in Catalonia in routine practice. Good recanalization was defined as postprocedure Thrombolysis in Cerebral Infarction (TICI) score 2b–3; dramatic recovery as drop in National Institutes of Health Stroke Scale (NIHSS) score >10 points or NIHSS score <2 at 24–36 h; and good outcome as modified Rankin score (mRS) 0–2 at 3 months. A 24 h CT scan determined symptomatic intracranial hemorrhage (SICH) and infarct volume.

Results

Of 571 patients who received endovascular treatment, 65 (11.4%) presented an M2 occlusion on initial angiogram, preprocedure NIHSS 16 (IQR 6). Mean time from symptom onset to groin puncture was 289±195 min. According to interventionalist preferences 86.2% (n=56) were treated with stentrievers (n=7 in combination with intra-arterial tissue plasminogen activator (tPA), 4.6% (n=3) received intra-arterial tPA only, and 9.2% (n=6) diagnostic angiography only. Good recanalization (78.5%) was associated with dramatic improvement (48% vs 14.8%; p=0.02), smaller infarct volumes (8 vs 82 cc; p=0.01) and better outcome (mRS 0–2: 66.3% vs 30%; p=0.03). SICH (9%) was not associated with treatment modality or device used. After adjusting for age and preprocedure NIHSS, good recanalization emerged as an independent predictor of dramatic improvement (OR=5.9 (95% CI 1.2 to 29.2), p=0.03). Independent predictors of good outcome at 3 months were age ( OR=1.067 (95% CI 1.005 to 1132), p=0.03) and baseline NIHSS ( OR=1.162 (95% CI 1.041 to 1.297), p<0.01).

Conclusions

Endovascular treatment of M2 MCA occlusion with stentrievers seems safe. Induced recanalization may double the chances of achieving a favorable outcome, especially for patients with moderate or severe deficit.
Quantitative evaluation of bone scintigraphy of the spinous processes of the equine thoracic spine at different times after administering 99m Tc‐hydroxymethylene‐diphosphonate
Authors: Sporn A. , Berner D. , Winter K. , Mageed M. , Brehm W. , Gerlach K.
Published: February 2014

Scintigraphic examination of the thoracic spine is well documented. However, there is limited information about the effects of time on image quality in the period following injection of radionuclide. This study aimed to determine the optimal time point after injection of 99m Tc‐HDP (hydroxymethylene‐diphosphonate) to achieve scintigraphic images with the best possible contrast and adequate count rates. Scintigraphic images of the thoracic spine of 21 horses were acquired two, four and six hours after administering 99m Tc‐HDP. Eight regions of interest were drawn in the images, four in the spinous processes and four in the adjacent soft tissue. The bone uptake, soft tissue uptake and the bone‐to‐soft tissue ratio were determined and compared between the different time points. Total count rates decreased with time after injection, but were at least as high as 150,000 counts per image at every time point after injection. The bone‐to‐soft tissue ratio was significantly higher for the images acquired after six hours compared to those acquired after two and four hours (P<0.01). Delayed scintigraphic examinations of the spinous processes of the equine thoracic spine achieved images with high contrast and sufficient count rates. Therefore, the scintigraphic examination of the equine thoracic spine is recommended to be done four to six hours after injecting 99m Tc‐HDP. However, additional studies should be performed to determine the effect of delayed image acquisition compared to images taken after three hours on the detectability of lesions in other parts of the thoracic spine and the soft tissue.
Efficiency of electrofishing in turbid lowland rivers: implications for measuring temporal change in fish populations
Authors: Lyon Jarod P. , Bird Tomas , Nicol Simon , Kearns Joanne , O’Mahony Justin , Todd Charles R. , Cowx Ian G. , Bradshaw Corey J.A.
Published: February 2014

To quantify how electrofishing capture probability varies over time and across physiochemical and disturbance gradients in a turbid lowland river, we tagged between 68 and 95 fish·year−1 with radio transmitters and up to 424 fish·year−1 with external and passive integrated transponder (PIT) tags. We surveyed the site noninvasively using radiotelemetry to determine which of the radio-tagged fish were present (effectively closing the radio-tagged population to emigration) and then electrofished to estimate the proportion of available fish that were captured based on both this and standard mark–recapture methods. We replicated the electrofishing surveys three times over a minimum of 12 days each year, for 7 years. Electrofishing capture probability varied between 0.020 and 0.310 over the 7 years and between four different large-bodied species (Murray cod (Maccullochella peelii), trout cod (Maccullochella macquariensis), golden perch (Macquaria ambigua ambigua), and silver perch (Bidyanus bidyanus)). River turbidity associated with increased river discharge negatively influenced capture probability. Increasing fish length increased detection of fish up to 500 mm for Murray cod, after which capture probability decreased. Variation in capture probability in large lowland rivers results in additional uncertainty when estimating population size or relative abundance. Research and monitoring programs using fish as an indicator should incorporate strategies to lessen potential error that might result from changes in capture probabilities.
Using model simulations to compare performance of two commercial salmon management strategies in Bristol Bay, Alaska
Authors: Carney Justin M. , Adkison Milo D.
Published: February 2014

In this paper, we discuss the costs and benefits, in relation to economics and Alaska’s salmon management policies, associated with two management strategies on the Egegik and Togiak sockeye salmon (Oncorhynchus nerka) fisheries in Bristol Bay, Alaska. “Daily management” allows managers to open or close the fishery on a daily basis, whereas a fixed fishing schedule allows fishing, to the extent practical, on fixed days of the week. To compare the strategies, we simulated the effects of daily management and a fixed fishing schedule on the two fisheries. Our simulations show that a daily management strategy results in higher yearly catches, less yearly variation in escapement, and fewer years of escapement below the goal range. A fixed fishing schedule results in less yearly variation in catch and a more stable harvest rate, with the harvest stability more pronounced when effort was held constant. Daily management is a desirable strategy for fisheries that are managed for maximum sustainable yield, have high fishing effort, have a small fishing area, or have a more temporally compressed run. A fixed fishing schedule is a desirable strategy for fisheries with less intense effort, budgetary or efficiency concerns, or stock components that differ in run timing.
Radiation and heat generation effects on viscous Joule heating MHD-conjugate heat transfer for a vertical flat plate
Authors: Ali M.M. , Mamun A.A. , Maleque M.A.
Published: February 2014

Conjugate heat transfer formed by the coupling effect of conduction inside and free convection flow along the flat plate is analyzed. The Joule heating effect because of considered magnetohydrodynamics (MHD) along with viscous dissipation, heat generation, and radiation phenomena are included in the investigation. The converted dimensionless partial differential equations representing the aforementioned flow characteristics are transformed into nonlinear equations with the help of a stream function with similarity variable. Finally, a numerical solution is carried out using the implicit finite difference method to analyze the flow behaviors in terms of velocity, temperature, skin friction coefficient, heat transfer rate, and surface temperature. A complete parametric analysis is done on the numerical results to show the effects of the radiation parameter, magnetic parameter, Eckert number, heat generation parameter, conjugate conduction parameter, and Prandtl number. It is found that thermal radiation, viscous Joule heating, and internal heat generation in the presence of axial conduction effects have a significant effect on MHD natural convection flow and thermal fields.
Tom Kibble and the early universe as the ultimate high energy experiment
Authors: Turok Neil
Published: February 2014

Tom Kibble pioneered the idea that there were one or more symmetry breaking phase transitions in the very early universe, at which defects like monopoles, strings and domain walls would have formed. In the context of grand unified theories, or their extensions, this idea remains compelling: observing these defects would be one of the very few ways of directly confirming the theories. In contrast, inflationary theory invoked a strongly supercooled transition driving a period of exponential expansion which would sweep all such defects away. If inflation terminated slowly, quantum vacuum fluctuations would be amplified and stretched to cosmological scales, forming density variations of just the character required to explain the formation of galaxies. The ensuing paradigm has dominated cosmology for the last three decades. However, basic problems in the scenario remain unresolved. Extreme tuning both of the initial conditions and of the physical laws are required. There are many different versions, each with slightly different predictions. Finally, inflation brought with it the theory of a "multiverse" — a universe containing infinite number of different, infinite, universes — while providing no "measure" or means of calculating the probability of observing any one of them. I will discuss an alternative to inflation, in which the big bang was a bounce from a previous contracting epoch. The discovery of the Higgs boson at the LHC has provided new evidence for such a picture by showing that, within the minimal standard model, our current vacuum is metastable. This opens the door to a cyclic universe scenario in which the electroweak Higgs plays a central role.
YANG–BAXTER EQUATION, MAJORANA FERMIONS AND THREE BODY ENTANGLING STATES
Authors: GE MO-LIN , YU LI-WEI , XUE KANG , ZHAO QING
Published: February 2014

In this paper, we review some results obtained in our works with extension. The new type of braiding matrices called type-II has been extended to the solutions of Yang–Baxter equations (YBE). It is related to quantum entangling states. The four-dimensional realization is connected with Majorana fermions and the two-dimensional realization for the topological basis is the wigner DJ-function with J = 1/2. The YBE leads to the conclusion that the additivity rule of velocities for two anyons obeys Lorentz rather than Galilean. The discussion is extended to three body S-matrix formed by three two-body S-matrices. The three-qubit entanglement based on two-qubit entanglements is discussed.
Fabrication of 3D photocatalytic α-Fe2O3 structure using direct ink writing method
Authors: Li Yayun , Li Bo , Li Longtu
Published: February 2014

Three-dimensional (3D) photocatalytic devices are economical and environmental, since they can be easily recycled and reused. In this paper, a kind of 3D photocatalytic device with a rod diameter of 250 μm was fabricated using the aqueous-based α- Fe 2 O 3 ceramic inks by direct ink writing (DIW) method. The properties of the DIW woodpile samples were investigated by X-ray diffraction (XRD), scanning electron microscope (SEM) and optical microscope. The result shows that the ink with solid content of 71.4 wt.% exhibits a shear thinning behavior and proper viscoelastic properties, which ensure a feasible extrusion in the whole shaping process. The sample sintered at 800°C in air causes photocatalytic degradation of methylene blue (MB) solution under the ultraviolet (UV) light. The photocatalytic properties of the α- Fe 2 O 3 woodpile structure was characterized by the UV-visible light spectrophotometer, and it was found to be better than that of bulk sample with same weight for its higher specific surface. The DIW technique would offer a potential method for the design and fabrication of 3D photocatalytic devices.
Preparation of micro- and crypto-tephras for quantitative microbeam analysis
Authors: Hall Mike , Hayward Chris
Published: February 2014

The smallest tephra grains present special challenges in their preparation for quantitative microbeam chemical analysis by EPMA and LA-ICP-MS. High-quality polished surfaces are an essential pre-requisite for the collection of high quality quantitative chemical data, as these shards also present significant difficulties for analysis. A method for the preparation of tephra grains as small as 10–50 µm is described in detail. This method uses inexpensive, widely available materials and is easily implemented in facilities in which polished geological samples are prepared for microanalysis. Samples prepared in this way reduce or eliminate the difficulties in microbeam analysis associated with small grains, when appropriate analytical protocols are used.
Holocene tephra from Iceland and Alaska in SE Greenland Shelf Sediments
Authors: Jennings Anne , Thordarson Thorvaldur , Zalzal Kate , Stoner Joseph , Hayward Christopher , Geirsdóttir Áslaug , Miller Gifford
Published: February 2014

The record of Icelandic volcanic events in Holocene marine sediments off SE Greenland provides evidence for the frequency and timing of atmospheric tephra plume dispersal from Iceland towards Greenland. Geochemistry of tephra abundance peaks from two SE Greenland shelf cores: MD99-2322 and JM96-1215-2GC are compared with core MD99-2269, north Iceland shelf, to evaluate the dispersal direction of Icelandic eruptions. Glass shard counts (106–1000 µm) in MD99-2322 revealed 16 distinct cryptotephra peaks. Geochemical analyses of eight cryptotephra peaks in MD99-2322 and two in JM96-1215 indicate sources in the volcanic systems of Iceland and Alaska. A tephra layer matching in geochemistry and stratigraphy to the
c.
3600 BP eruption of the Aniakchak Volcano in the Aleutian Islands was identified in JM96-1215/2GC. The Settlement Tephra (AD 871±2) and Hekla B (H-B) were identified in MD99-2322. A new marker horizon, Katla EG-6.73, was found in both SE Greenland cores. Three basaltic peaks between 9.9 and 10.4 cal kyr BP, exhibit major-element geochemistry indistinguishable from the
c.
10.2 kyr Saksunarvatn tephra. These layers represent 3 out of≥seven westward and northward-dispersed Grímsvötn layers found on the SE Greenland shelf and the north Iceland shelf between 9.9 and 10.4 cal kyr BP.

supplementary material:

a list of all analyses performed for this study is available at
http://www.geolsoc.org.uk/SUP18715
Quaternary tectonics and seismic potential of the Andean retrowedge at 33–34°S
Authors: García Víctor H. , Casa Analía L.
Published: February 2014

The Andean retrowedge, located between 33°S and 34°S, lies in the transition region of the Pampean flat-slab subduction zone to the north and a normal subduction zone to the south. Neotectonic structures and shallow seismicity are very common north of this segment and become progressively less frequent southwards. The Frontal Cordillera and the Cerrilladas Pedemontanas are the main morphostructures involved in the Quaternary deformation of this region. The Frontal Cordillera is a thick-skinned fold-and-thrust belt uplifted since Late Miocene time. The Cerrilladas Pedemontanas are low-relief hills that represent the mild inversion of the Cuyo Triassic rift depocentre since Pliocene time. Middle Miocene–Holocene synorogenic strata cover the Cuyo basin and surrounding foreland areas. The Quaternary tectonic evolution of this area has been established through integration of new data from fieldwork in the Frontal Cordillera piedmont with subsurface information and previously published data. Mean Late Pleistocene uplift rates ranging between 0.21 and 0.92 mm a
−1
and earthquake minimum moment magnitudes (
M
w
) of
c.
6.4–6.7 have been estimated for the morphostructural units analysed in this manuscript.
The north-western margin of the Neuquén Basin in the headwater region of the Maipo drainage, Chile
Authors: Godoy Estanislao
Published: February 2014

Volcanic and pyroclastic rocks of intermediate composition, dating from Kimmeridgian time with peak ages during both the early–middle Tithonian and the late Hauterivian, characterize several localities of the north-western margin of the Neuquén basin along the main Andean Range at 33–34°S. The latter is thought responsible for the desiccation of the basin during Aptian–Albian time. The thick Tithonian submarine lavas at the Volcán valley (33°30′S), on the other hand, coincide spatially with the only pass-way recognized at that time in the Chilean Coast Range. This coincidence may be related to an isolated relic rift-like structure that coexisted with the regional intra-arc extensional setting during Tithonian time. Continental-scale rifting in the southern Andes has been recognized only for the Late Triassic–Early Jurassic period.
Role of basin width variation in tectonic inversion: insight from analogue modelling and implications for the tectonic inversion of the Abanico Basin, 32°–34°S, Central Andes
Authors: Jara P. , Likerman J. , Winocur D. , Ghiglione M. C. , Cristallini E. O. , Pinto L. , Charrier R.
Published: February 2014

We use analogue modelling to investigate the response of compressional deformation superimposed on an extensional basin with along-strike changes in width. Parameters described include extension and shortening distribution and directions, orientation of structures and degree of basin inversion. Two types of model are presented: in the first (Type I), an extensional basin is constructed with variable width (applying differential extension) and subsequently inverted by homogeneous shortening; in the second (Type II), an extensional basin with constant width is subsequently inverted by inhomogeneous shortening (differential compression). From our observations, we compare both types of model to structural patterns observed in some natural cases from the Central Andes. Both models generate oblique structures, but in the Type II model a significant rotation is characteristic. Our results suggest that in the Central Andes region between 32° and 33°S, the Abanico Basin may correspond to a basin of smaller area compared to the larger basin south of 33°S. Our Type I model further explains some patterns observed there, from which we conclude that the control exercised by the width of a pre-existing basin should be considered when interpreting the geological evolution of that area of the Andes.
Body Weight Regulation and Obesity: Dietary Strategies to Improve the Metabolic Profile
Authors: Munsters M.J.M. , Saris W.H.M.
Published: February 2014

This review discusses dietary strategies that may improve the metabolic profile and body weight regulation in obesity. Recent evidence demonstrated that long-term health effects seem to be more beneficial for low-glycemic index (GI) diets compared to high-protein diets. Still, these results need to be confirmed by other prospective cohort studies and long-term clinical trials, and the discrepancy between these study designs needs to be explored in more detail. Furthermore, the current literature is mixed with regard to the efficacy of increased meal frequency (or snacking) regimens in causing metabolic alterations, particularly in relation to body weight control. In conclusion, a growing body of evidence suggests that dietary strategies with the aim to reduce postprandial insulin response and increase fat oxidation, and that tend to restore metabolic flexibility, have a place in the prevention and treatment of obesity and associated metabolic disorders.
Production of Aroma Compounds in Lactic Fermentations
Authors: Smid E.J. , Kleerebezem M.
Published: February 2014

This review describes recent scientific research on the production of aroma compounds by lactic acid bacteria (LAB) in fermented food products. We discuss the various precursor molecules for the formation of aroma compounds in connection with the metabolic pathways involved. The roles of nonmetabolic properties such as cell lysis are also described in relation to aroma formation. Finally, we provide an overview of the literature on methods to steer and control aroma formation by LAB in mixed culture fermentations. We demonstrate that the technological progress made recently in high-throughput analysis methods has been driving the development of new approaches to understand, control, and steer aroma formation in (dairy) fermentation processes. This currently entails proposing new rules for designing stable, high-performance mixed cultures constituting a selection of strains, which in concert and on the basis of their individual predicted gene contents deliver the required functionalities.
Myosin IIB and F-actin control apical vacuolar morphology and histamine-induced trafficking of H-K-ATPase-containing tubulovesicles in gastric parietal cells
Authors: Natarajan Paramasivam , Crothers James M. , Rosen Jared E. , Nakada Stephanie L. , Rakholia Milap , Okamoto Curtis T. , Forte John G. , Machen Terry E.
Published: February 2014

Selective inhibitors of myosin or actin function and confocal microscopy were used to test the role of an actomyosin complex in controlling morphology, trafficking, and fusion of tubulovesicles (TV) containing H-K-ATPase with the apical secretory canaliculus (ASC) of primary-cultured rabbit gastric parietal cells. In resting cells, myosin IIB and IIC, ezrin, and F-actin were associated with ASC, whereas H-K-ATPase localized to intracellular TV. Histamine caused fusion of TV with ASC and subsequent expansion resulting from HCl and water secretion; F-actin and ezrin remained associated with ASC whereas myosin IIB and IIC appeared to dissociate from ASC and relocalize to the cytoplasm. ML-7 (inhibits myosin light chain kinase) caused ASC of resting cells to collapse and most myosin IIB, F-actin, and ezrin to dissociate from ASC. TV were unaffected by ML-7. Jasplakinolide (stabilizes F-actin) caused ASC to develop large blebs to which actin, myosin II, and ezrin, as well as tubulin, were prominently localized. When added prior to stimulation, ML-7 and jasplakinolide prevented normal histamine-stimulated transformations of ASC/TV and the cytoskeleton, but they did not affect cells that had been previously stimulated with histamine. These results indicate that dynamic pools of actomyosin are required for maintenance of ASC structure in resting cells and for trafficking of TV to ASC during histamine stimulation. However, the dynamic pools of actomyosin are not required once the histamine-stimulated transformation of TV/ASC and cytoskeleton has occurred. These results also show that vesicle trafficking in parietal cells shares mechanisms with similar processes in renal collecting duct cells, neuronal synapses, and skeletal muscle.
IL-4 induces columnar-like differentiation of esophageal squamous epithelium through JAK/PI3K pathway: possible role in pathogenesis of Barrett's esophagus
Authors: Shan Jing , Oshima Tadayuki , Farre Ricard , Fukui Hirokazu , Watari Jiro , Miwa Hiroto
Published: February 2014

Barrett's esophagus is characterized by a distinct Th2-predominant cytokine profile (IL-4) from in vivo or ex vivo evidence. The detailed role of cytokines in Barrett's esophagus, particularly whether Th2 cytokines are causative factors driving metaplastic processes, remains unknown. In this study, air-liquid interface-cultured human esophageal epithelial cells were stimulated by a Th2 cytokine, IL-4, and Th1 cytokines, TNF-α and IL-1β, continuously for 10 days. Barrier function was determined by transepithelial electrical resistance. Morphological changes were investigated by hematoxylin and eosin staining. Keratin profile (keratin 7, 8, 13, and 14) and squamous differentiation markers (involucrin) were investigated by RT-quantitative PCR, Western blotting, and immunohistochemical staining. Pharmacological inhibitors were used to identify the underlying cellular signaling. We report that IL-4, TNF-α, and IL-1β decrease barrier function, but only IL-4 significantly increases cell layers and changes cell morphology. IL-4 time dependently downregulates the expression levels of the squamous cell markers involucrin and keratin 13 and upregulates the expression levels of the columnar cell markers keratin 7 and 8. Neither TNF-α nor IL-1β shows any effect on these indexes. JAK inhibitor I and PI3K inhibitors significantly block the IL-4-induced changes in the levels of keratin 8 and 13. In conclusion, IL-4 inhibits squamous differentiation program of esophageal epithelial cells and induces differentiation toward columnar cells through the JAK/PI3K pathway. Thus IL-4 may be involved in the early stages of Barrett's esophagus development.
Reduced hepatic eNOS phosphorylation is associated with NAFLD and type 2 diabetes progression and is prevented by daily exercise in hyperphagic OLETF rats
Authors: Sheldon Ryan D. , Laughlin M. Harold , Rector R. Scott
Published: February 2014

We tested the hypothesis that nonalcoholic fatty liver disease (NAFLD) is associated with reduced hepatic endothelial nitric oxide synthase (eNOS) activation status via S1177 phosphorylation (p-eNOS) and is prevented by daily voluntary wheel running (VWR). Hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an established model of obesity, type 2 diabetes (T2D) and NAFLD, and normophagic controls [Long-Evans Tokushima Otsuka (LETO)] were studied at 8, 20, and 40 wk of age. Basal hepatic eNOS phosphorylation (p-eNOS/eNOS) was similar between LETO and OLETFs with early hepatic steatosis (8 wk of age) and advanced steatosis, hyperinsulinemia, and hyperglycemia (20 wk of age). In contrast, hepatic p-eNOS/eNOS was significantly lower ( P < 0.05) in OLETF rats with T2D advancement and the transition to more advanced NAFLD with inflammation and fibrosis [increased tumor necrosis factor-α (TNF-α), CD68, and CD163 mRNA expression; 40 wk of age]. Reduced hepatic eNOS activation status in 40-wk OLETF rats was significantly correlated with reduced p-Akt/Akt ( r = 0.73, P < 0.05), reduced serum insulin ( r = 0.59, P < 0.05), and elevated serum glucose ( r = −0.78, P < 0.05), suggesting a link between impaired glycemic control and altered hepatic nitric oxide metabolism. VWR by OLETF rats, in conjunction with NAFLD and T2D prevention, normalized p-eNOS/eNOS and p-Akt/Akt to LETO levels. Basal activation of hepatic eNOS and Akt are maintained until advanced NAFLD and T2D development in obese OLETF rats. The prevention of this reduction by VWR may result from maintained insulin sensitivity and glycemic control.
Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence
Authors: Nissan Moriah H. , Pratilas Christine A. , Jones Alexis M. , Ramirez Ricardo , Won Helen , Liu Cailian , Tiwari Shakuntala , Kong Li , Hanrahan Aphrothiti J. , Yao Zhan , Merghoub Taha , Ribas Antoni , Chapman Paul B. , Yaeger Rona , Taylor Barry S. , Schultz Nikolaus , Berger Michael F. , Rosen Neal , Solit David B.
Published: February 2014

Melanoma is a disease characterized by lesions that activate ERK. Although 70% of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the remaining 30% are largely undefined. Vemurafenib, a selective inhibitor of RAF kinases, has clinical utility restricted to BRAF-mutant tumors. MEK inhibitors, which have shown clinical activity in NRAS-mutant melanoma, may be effective in other ERK pathway-dependent settings. Here, we investigated a panel of melanoma cell lines wild type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment. A cohort of the BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of NF1, a RAS GTPase activating protein. In these cell lines, the MEK inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved feedback inhibition of RAS, resulting in induction of pMEK and a rapid rebound in ERK signaling. In contrast, the MEK inhibitor trametinib impaired the adaptive response of cells to ERK inhibition, leading to sustained suppression of ERK signaling and significant antitumor effects. Notably, alterations in NF1 frequently co-occurred with RAS and BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss abrogated negative feedback on RAS activation, resulting in elevated activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence, and resistance to RAF inhibition. Cancer Res; 74(8); 2340–50. ©2014 AACR.
Pharmacologic Suppression of JAK1/2 by JAK1/2 Inhibitor AZD1480 Potently Inhibits IL-6–Induced Experimental Prostate Cancer Metastases Formation
Authors: Gu Lei , Talati Pooja , Vogiatzi Paraskevi , Romero-Weaver Ana L. , Abdulghani Junaid , Liao Zhiyong , Leiby Benjamin , Hoang David T. , Mirtti Tuomas , Alanen Kalle , Zinda Michael , Huszar Dennis , Nevalainen Marja T.
Published: February 2014

Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6–activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6–driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6–induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak–Stat3 signaling pathway, and that IL-6–driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer. Mol Cancer Ther; 13(5); 1246–58. ©2014 AACR.
The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks
Authors: Tahara Makiko , Inoue Takeshi , Sato Futoshi , Miyakura Yasuyuki , Horie Hisanaga , Yasuda Yoshikazu , Fujii Hirofumi , Kotake Kenjiro , Sugano Kokichi
Published: February 2014

Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)–deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase–specific double-strand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage–reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy. Mol Cancer Ther; 13(5); 1170–80. ©2014 AACR.
Renin-Angiotensin System Inhibitors Reduce Serum Asymmetric Dimethylarginine Levels and Oxidative Stress in Normotensive Patients with Chronic Kidney Disease
Authors: Fujii Hideki , Kono Keiji , Nakai Kentaro , Goto Shunsuke , Kitazawa Riko , Fukagawa Masafumi , Nishi Shinichi
Published: February 2014

Background/Aims: The purpose of our study was to elucidate the relationship between asymmetric dimethylarginine (ADMA) and intrarenal lesions and to determine the effect of renin-angiotensin system inhibitors (RAS-Is) on serum ADMA levels, nitric oxide (NO) synthesis and oxidative stress in normotensive patients with chronic kidney disease (CKD). Methods: This study included 23 normotensive patients with chronic glomerulonephritis and normal or mildly impaired renal function who underwent renal biopsy. We evaluated the relationship between serum ADMA levels and intrarenal lesions, and examined renal function, urinary protein excretion, ADMA levels, NO synthesis, oxidative stress and blood pressure (BP) before and 3 months after starting the treatment with RAS-Is. Results: Serum ADMA levels were correlated only with arterial intimal fibroplastic thickness. Despite comparable renal function and BP, serum ADMA levels and excretion of urinary protein excretion significantly decreased, and urinary NO metabolite excretion significantly increased after starting the treatment with RAS-Is. Oxidative stress markers also tended to be reduced by the treatment. Conclusion: These findings suggest that RAS-Is improve the NO system and decrease oxidative stress in normotensive patients with CKD. In addition, ADMA may be associated with intrarenal lesions and can be a useful marker for the effects of treatment in the early stages of CKD.
Noncalcified Coronary Plaque Volumes in Healthy People With a Family History of Early Onset Coronary Artery Disease
Authors: Kral Brian G. , Becker Lewis C. , Vaidya Dhananjay , Yanek Lisa R. , Qayyum Rehan , Zimmerman Stefan L. , Dey Damini , Berman Daniel S. , Moy Taryn F. , Fishman Elliot K. , Becker Diane M.
Published: February 2014

Background—

Although age and sex distributions of calcified coronary plaque have been well described in the general population, noncalcified plaque (NCP) distributions remain unknown. This is important because NCP is a putative precursor for clinical coronary artery disease and could serve as a sentinel for aggressive primary prevention, especially in high-risk populations. We examined the distributions of NCP and calcified coronary plaque in healthy 30- to 74-year-old individuals from families with early onset coronary artery disease.

Methods and Results—

Participants in the GeneSTAR family study (N=805), mean age 51.1±10.8 years, 56% women, were screened for coronary artery disease risk factors and coronary plaque using dual-source computed tomographic angiography. Plaque volumes (mm
3
) were quantified using a validated automated method. The prevalence of coronary plaque was 57.8% in men and 35.8% in women (
P
<0.0001). NCP volume increased with age (
P
<0.001) and was higher in men than women (
P
<0.001). Although NCP, as a percentage of total plaque, was inversely related to age (
P
<0.01), NCP accounted for most of the total plaque volume at all ages, especially in men and women <55 years (>70% and >80%, respectively). Higher Framingham risk was associated with the number of affected vessels (
P
<0.01), but 44% of men and 20.8% of women considered intermediate risk had left main and 3-vessel disease involvement.

Conclusions—

The majority of coronary plaque was noncalcified, particularly in younger individuals. These findings support the importance of assessing family history and suggest that early primary prevention interventions may be warranted at younger ages in families with early onset coronary artery disease.
Right Ventricular Diastolic Performance in Children With Pulmonary Arterial Hypertension Associated With Congenital Heart Disease
Authors: Okumura Kenichi , Slorach Cameron , Mroczek Dariusz , Dragulescu Andreea , Mertens Luc , Redington Andrew N. , Friedberg Mark K.
Published: February 2014

Background—

Right ventricular diastolic dysfunction influences outcomes in pulmonary arterial hypertension (PAH), but echocardiographic parameters have not been investigated in relation to invasive reference standards in pediatric PAH. We investigated echocardiographic parameters of right ventricular diastolic function in children with PAH in relation to simultaneously measured invasive reference measures.

Methods and Results—

We prospectively recruited children undergoing a clinically indicated cardiac catheterization for evaluation of PAH and pulmonary vasoreactivity testing. Echocardiography was performed simultaneously with invasive reference measurements by high-fidelity micromanometer catheter. For analysis, patients were divided into shunt and nonshunt groups. Sixteen children were studied. In the group as a whole, significant correlations were found among τ and tricuspid deceleration time,
E′
,
E/E′
, Time

E
–
E

′
, A wave velocity, and global early and late diastolic strain rate. d
p
/d
t
minimum correlated significantly with late diastolic tricuspid annular velocity (
A′
), tissue Doppler imaging–derived systolic:diastolic duration ratio, and global late diastolic strain rate. End-diastolic pressure correlated significantly with tissue Doppler imaging–derived systolic:diastolic duration ratio. On multivariate analysis, tricuspid deceleration time, Time

E
–
E

′
, and global early diastolic strain rate were independent predictors of τ, whereas tissue Doppler imaging–derived systolic:diastolic duration ratio was an independent predictor of d
p
/d
t
minimum. In general, correlations between echocardiographic and invasive parameters were better in the shunt group than in the nonshunt group.

Conclusions—

Echocardiography correlates with invasive reference measures of right ventricular diastolic function in children with PAH, although it does not differentiate between early versus late diastolic abnormalities. Newer echocardiographic techniques may have added value to assess right ventricular diastolic dysfunction in this population.
Low Socioeconomic Status Over 12 Years and Subclinical Cardiovascular Disease
Authors: Thurston Rebecca C. , El Khoudary Samar R. , Derby Carol A. , Barinas-Mitchell Emma , Lewis Tené T. , McClure Candace K. , Matthews Karen A.
Published: February 2014

Background and Purpose—

The inverse relation between socioeconomic status and cardiovascular disease is well established. However, few studies have investigated socioeconomic status assessed repeatedly during adulthood in relation to subclinical atherosclerosis. We aimed to test whether consistently low socioeconomic status, as indexed by education, income, and financial strain, for 12 years of midlife was related to later carotid intima-media thickness and plaque among women.

Methods—

The Study of Women’s Health Across the Nation is a multisite longitudinal study of midlife women. Education was assessed at the study baseline, income and financial strain were obtained yearly for 12 years, and a carotid ultrasound was obtained at study year 12 among 1402 women. Associations were tested in linear and multinomial logistic regression models adjusted for demographic, biological, and behavioral risk factors.

Results—

A high school education or less (odds ratio [OR] [95% confidence interval {CI}], 1.72 [1.15–2.59];
P
<0.01), some college education (OR [95% CI], 1.65 [1.17–2.32];
P
<0.01), consistently low income (OR [95% CI], 1.83 [1.15–2.89];
P
<0.05), and consistent financial strain (OR [95% CI], 1.78 [1.21–2.61];
P
<0.01) for 12 years were associated with higher carotid plaque, and consistent financial strain was associated with elevated maximal intima-media thickness (β [SE]=0.02 [0.01];
P
<0.05) controlling for standard cardiovascular disease risk factors. When socioeconomic status indices were considered together, financial strain (β [SE]=0.02 [0.01];
P
<0.05) and low education (high school education or less: OR [95% CI], 1.55 [1.01–2.37];
P
<0.05; some college: OR [95% CI], 1.56 [1.09–2.21];
P
<0.05) were most consistently associated with intima-media thickness and plaque, respectively, controlling for risk factors.

Conclusions—

The findings indicate the importance of targeting economically disadvantaged women in efforts to prevent cardiovascular disease among women.