bluuebunny/crossref_metadata_2025 huggingface dataset:
An acoustic startle alters knee joint stiffness and neuromuscular control
Authors: DeAngelis A. I. , Needle A. R. , Kaminski T. W. , Royer T. R. , Knight C. A. , Swanik C. B.
Published: September 2014

Growing evidence suggests that the nervous system contributes to non‐contact knee ligament injury, but limited evidence has measured the effect of extrinsic events on joint stability. Following unanticipated events, the startle reflex leads to universal stiffening of the limbs, but no studies have investigated how an acoustic startle influences knee stiffness and muscle activation during a dynamic knee perturbation. Thirty‐six individuals were tested for knee stiffness and muscle activation of the quadriceps and hamstrings. Subjects were seated and instructed to resist a 40‐degree knee flexion perturbation from a relaxed state. During some trials, an acoustic startle (50 ms, 1000 Hz, 100 dB) was applied 100 ms prior to the perturbation. Knee stiffness, muscle amplitude, and timing were quantified across time, muscle, and startle conditions. The acoustic startle increased short‐range (no startle: 0.044 ± 0.011 N·m/deg/kg; average startle: 0.047 ± 0.01 N·m/deg/kg) and total knee stiffness (no startle: 0.036 ± 0.01 N·m/deg/kg; first startle 0.027 ± 0.02 N·m/deg/kg). Additionally, the startle contributed to decreased [vastus medialis (VM): 13.76 ± 33.6%; vastus lateralis (VL): 6.72 ± 37.4%] but earlier (VM: 0.133 ± 0.17 s; VL: 0.124 ± 0.17 s) activation of the quadriceps muscles. The results of this study indicate that the startle response can significantly disrupt knee stiffness regulation required to maintain joint stability. Further studies should explore the role of unanticipated events on unintentional injury.
A Hybrid Spatial Index for Massive Point Cloud Data Management and Visualization
Authors: Yang Jiansi , Huang Xianfeng
Published: September 2014

With the wide use of laser scanning technology, point cloud data collected from airborne sensors and terrestrial sensors are often integrated to depict a complete scenario from the top and ground views, even though points from different platforms and sensors have quite different densities. These massive point clouds with various structures create many problems for both data management and visualization. In this article, a hybrid spatial index method is proposed and implemented to manage and visualize integrated point cloud data from airborne and terrestrial scanners. This hybrid spatial index structure combines an extended quad‐tree model at the global level to manage large area airborne sensor data, with a 3‐D R‐tree to organize high density local area terrestrial point clouds. These massive point clouds from different platforms have diverse densities, but this hybrid spatial index system has the capability to organize the data adaptively and query efficiently, satisfying the requirements for fast visualization. Experiments using point cloud data collected from the Dunhuang area were conducted to evaluate the efficiency of our proposed method.
A Review and Evaluation of Uncertainty Classification and the Error‐Band Geometry Model
Authors: Foy Andrew S. , Carstensen Laurence W. , Prisley Stephen P. , Campbell James B. , Dymond Randel L.
Published: September 2014

Advances in computer technologies have improved the quality of maps, making map comparison and analysis easier, but uncertainty and error still exist in GIS when overlaying geographic data with multiple or unknown confidence levels. The goals of this research are to review current geospatial uncertainty literature, present the Error‐Band Geometry Model (EBGM) for classifying the size and shape of spatial confidence intervals for vector GIS data, and to analyze the interpretability of the model by looking at how people use metadata to classify the uncertainty of geographic objects. The results from this research are positive and provide important insight into how people interpret maps and geographic data. They suggest that uncertainty is more easily interpreted for well defined point data and GPS data. When data is poorly defined, people are unable to determine an approach to model uncertainty and generate error‐bands. There is potential for using the EBGM to aid in the development of a GIS tool that can help individuals parameterize and model spatial confidence intervals, but more research is needed to refine the process by which people use the decision tree. A series of guiding questions or an “uncertainty wizard” tool that helps one select an uncertainty modeling approach might improve the way people apply this model to real‐world applications.
Clinical utility of serum biochemical variables for predicting acid–base balance in critically ill horses
Authors: Stämpfli Henry R. , Schoster Angelika , Constable Peter D.
Published: September 2014

Background

Profiles from serum biochemical analyzers include the concentration of strong electrolytes (includingl‐lactate), total carbon dioxide (tCO2), and total protein. These variables are associated with changes in acid–base balance. Application of physicochemical principles may allow predicting acid–base balance from serum biochemistry without measuring whole bloodpHandpCO2.

Objectives

The purpose of the study was to determine if the acid–base status of critically ill horses could be accurately predicted using variables included in standard serum biochemical profiles.

Methods

Two jugular venous blood samples were prospectively obtained from critically ill horses and foals. Samples were analyzed using a whole blood gas andpHanalyzer (BG) and a serum biochemistry multi analyzer system (AMAS). Linear regression, Deming regression, and Bland–Altman plots were used for method comparison andP < .05 was considered significant.

Results

Values from 70 horses and foals for Na, K, Cl, and total protein concentrations, and consequently the calculated variables used for acid base interpretation, were different between the AMAS and BG analyzer. Using physicochemical principles, BG results accurately predictedpH, whereas the AMAS results did not when a fixed value forpCO2was used.

Conclusions

Measurement ofpCO2is required in critically ill horses for accurate prediction of whole bloodpH. Differences in the measured values of Na and Cl concentration exist when measured in serum by the AMAS and in whole blood or plasma by BG, indicating that the accurate prediction of whole bloodpHis analyzer‐dependent. Application of physicochemical principles to plasma or serum provides a practical method to evaluate analyzer accuracy.
NMDA and AMPA receptors contribute similarly to temporal processing in mammalian retinal ganglion cells
Authors: Stafford Benjamin K. , Manookin Michael B. , Singer Joshua H. , Demb Jonathan B.
Published: September 2014

Key points

In most areas of the brain, NMDA‐type glutamate receptors (NMDARs) exhibit slower kinetics than do AMPA‐type receptors (AMPARs).

Most retinal ganglion cells express a combination of AMPARs and NMDARs, but whether NMDAR kinetics limit temporal encoding of light stimulation is not well understood.

In this study, we measured AMPAR‐ and NMDAR‐mediated conductances evoked by visual stimulation in two types of guinea pig retinal ganglion cell.

In both cell types, AMPAR‐ and NMDAR‐mediated responses encoded rapidly varying contrast modulation within the physiological range (up to 18 temporal cycles s–1).

In retinal ganglion cells, NMDARs and AMPARs act together to encode a wide range of temporal frequencies, suggesting that NMDARs in some sensory neurons have relatively fast kinetics.

Postsynaptic AMPA‐ and NMDA‐type glutamate receptors (AMPARs, NMDARs) are commonly expressed at the same synapses. AMPARs are thought to mediate the majority of fast excitatory neurotransmission whereas NMDARs, with their relatively slower kinetics and higher Ca2+ permeability, are thought to mediate synaptic plasticity, especially in neural circuits devoted to learning and memory. In sensory neurons, however, the roles of AMPARs and NMDARs are less well understood. Here, we tested in the in vitro guinea pig retina whether AMPARs and NMDARs differentially support temporal contrast encoding by two ganglion cell types. In both OFF Alpha and Delta ganglion cells, contrast stimulation evoked an NMDAR‐mediated response with a characteristic J‐shaped I–V relationship. In OFF Delta cells, AMPAR‐ and NMDAR‐mediated responses could be modulated at low frequencies but were suppressed during 10 Hz stimulation, when responses were instead shaped by synaptic inhibition. With inhibition blocked, both AMPAR‐ and NMDAR‐mediated responses could be modulated at 10 Hz, indicating that NMDAR kinetics do not limit temporal encoding. In OFF Alpha cells, NMDAR‐mediated responses followed stimuli at frequencies up to ∼18 Hz. In both cell types, NMDAR‐mediated responses to contrast modulation at 9–18 Hz showed delays of <10 ms relative to AMPAR‐mediated responses. Thus, NMDARs combine with AMPARs to encode rapidly modulated glutamate release, and NMDAR kinetics do not limit temporal coding by OFF Alpha and Delta ganglion cells substantially. Furthermore, glutamatergic transmission is differentially regulated across bipolar cell pathways: in some, release is suppressed at high temporal frequencies by presynaptic inhibition.
High Resolution RANS Nonlinear Harmonic Study of Stage 67 Tip Injection Physics
Authors: Grosvenor Allan D. , Rixon Gregory S. , Sailer Logan M. , Matheson Michael A. , Gutzwiller David P. , Demeulenaere Alain , Gontier Mathieu , Strazisar Anthony J.
Published: September 2014

Numerical prediction of the Stage 67 transonic fan stage employing wall jet tip injection flow control and study of the physical mechanisms leading to stall suppression and stability enhancement afforded by endwall recirculation/injection is the focus of this paper. Reynolds averaged Navier–Stokes (RANS) computations were used to perform detailed analysis of the Stage 67 configuration experimentally tested at NASA's Glenn Research Center in 2004. Time varying predictions of the stage plus recirculation and injection flowpath were executed utilizing the nonlinear harmonic (NLH) approach. Significantly higher grid resolution per passage was achieved than what has been generally employed in prior reported numerical studies of spike stall phenomena in transonic compressors. This paper focuses on characterizing the physics of spike stall embryonic stage phenomena and the influence of tip injection, resulting in experimentally and numerically demonstrated stall suppression.
Structural defects responsible for excessive leakage current in Schottky diodes prepared on undoped n-GaN films grown by hydride vapor phase epitaxy
Authors: Polyakov Alexander Y. , Yakimov Eugene B. , Smirnov Nikolai B. , Govorkov Anatoliy V. , Usikov Alexander S. , Helava Heikki , Makarov Yuri N. , Lee In-Hwan
Published: September 2014

Schottky diodes fabricated on undoped n-GaN films grown by hydride vapor phase epitaxy showed more than two orders of magnitude higher reverse current if the films contained open core defects. The open core defects were revealed by scanning electron microscope observation in secondary electrons, microcathodoluminescence (MCL), and electron beam induced current (EBIC) modes. Plan-view EBIC imaging showed that such films contained a relatively high density of large (∼10 μm in diameter) dark defects that were absent in good films with low leakage current. In plan-view scanning electron microscope images, pits with the density similar to the density of dark defects were observed. Cross-sectional MCL observation showed that the pits terminated the vertical micropipes starting near the interface with the substrate. Some of the micropipes closed approximately halfway through the grown thickness. The regions of micropipes, either closed or not, showed a higher intensity of bandedge and defect MCL bands. Possible reasons for the formation of such structures are discussed.
Fractal structure enables temporal prediction in music
Authors: Rankin Summer K. , Fink Philip W. , Large Edward W.
Published: September 2014

1/f serial correlations and statistical self-similarity (fractal structure) have been measured in various dimensions of musical compositions. Musical performances also display 1/f properties in expressive tempo fluctuations, and listeners predict tempo changes when synchronizing. Here the authors show that the 1/f structure is sufficient for listeners to predict the onset times of upcoming musical events. These results reveal what information listeners use to anticipate events in complex, non-isochronous acoustic rhythms, and this will entail innovative models of temporal synchronization. This finding could improve therapies for Parkinson's and related disorders and inform deeper understanding of how endogenous neural rhythms anticipate events in complex, temporally structured communication signals.
The influence of amplitude envelope information on resolving lexically ambiguous spoken words
Authors: Szostak Christine M. , Pitt Mark A.
Published: September 2014

Abstract: Prior studies exploring the contribution of amplitude envelope information to spoken word recognition are mixed with regard to the question of whether amplitude envelope alone, without spectral detail, can aid isolated word recognition. Three experiments show that the amplitude envelope will aid word identification only if two conditions are met: (1) It is not the only information available to the listener and (2) lexical ambiguity is not present. Implications for lexical processing are discussed.
Recognition of time-compressed speech does not predict recognition of natural fast-rate speech by older listeners
Authors: Gordon-Salant Sandra , Zion Danielle J. , Espy-Wilson Carol
Published: September 2014

This study investigated whether recognition of time-compressed speech predicts recognition of natural fast-rate speech, and whether this relationship is influenced by listener age. High and low context sentences were presented to younger and older normal-hearing adults at a normal speech rate, naturally fast speech rate, and fast rate implemented by time compressing the normal-rate sentences. Recognition of time-compressed sentences over-estimated recognition of natural fast sentences for both groups, especially for older listeners. The findings suggest that older listeners are at a much greater disadvantage when listening to natural fast speech than would be predicted by recognition performance for time-compressed speech.
Bubble migration in two-dimensional foam sheared in a wide-gap Couette device: Effects of non-Newtonian rheology
Authors: Mohammadigoushki Hadi , Yue Pengtao , Feng James J.
Published: September 2014

We report experiments on the migration of a large bubble in an otherwise monodisperse two-dimensional (2D) foam sheared in a wide-gap Couette device. The bubble migrates away from the walls toward an equilibrium position between the center of the gap and the inner cylinder. This differs from the situation in a narrow-gap Couette device, where the equilibrium position is at the center of the gap [Mohammadigoushki and Feng, Phys. Rev. Lett. 109, 084502 (2012)]. The shift in equilibrium position is attributed to the non-Newtonian rheology of the foam, which is brought out by the nonhomogeneous shearing in a wide-gap geometry. Two aspects of the rheology, shear-thinning and the first normal stress difference, are examined separately by comparing with bubble migration in a xanthan gum solution and a Boger fluid. Shear-thinning shifts the equilibrium position inward while the normal stress does the opposite. Bubble migration in the 2D foam is the outcome of the competition between the two effects.
Complete Genome Sequence of Polychlorinated Biphenyl Degrader Comamonas testosteroni TK102 (NBRC 109938)
Authors: Fukuda Kohei , Hosoyama Akira , Tsuchikane Keiko , Ohji Shoko , Yamazoe Atsushi , Fujita Nobuyuki , Shintani Masaki , Kimbara Kazuhide
Published: September 2014

Comamonas testosteroni
TK102 (NBRC 109938; JCM 19603) can utilize biphenyl as a sole carbon source and degrade polychlorinated biphenyls (PCBs). The complete nucleotide sequence of the TK102 genome was determined. TK102 possesses several integrative and conjugative element-like regions, and one of them carries biphenyl-degradative genes.
Draft Genome Sequence of a Serratia marcescens Strain Isolated from a Preterm Neonatal Blood Sepsis Patient at the Royal Infirmary, Edinburgh, Scotland, United Kingdom
Authors: Kropp K. A. , Lucid A. , Carroll J. , Belgrudov V. , Walsh P. , Kelly B. , Smith C. , Dickinson P. , O'Driscoll A. , Templeton K. , Ghazal P. , Sleator R. D.
Published: September 2014

Herein, we report the draft genome sequence for isolate ED-NGS-1015 of
Serratia marcescens
, cultivated from a blood sample obtained from a neonatal sepsis patient at the Royal Infirmary in Edinburgh, Scotland, United Kingdom.
Pulmonary embolism with haemorrhagic pericardial effusion and tamponade: a clinical dilemma
Authors: Thomas Charlotte , Lane Katie , Cecconi Maurizio
Published: September 2014

The synchronous presentation of a patient with pulmonary embolism (PE) and haemorrhagic cardiac tamponade is uncommon and presents a therapeutic dilemma. Both conditions can be life-threatening and require opposing management strategies. The authors report a 50-year-old woman who presented with abdominal symptoms and subsequent rapid development of dyspnoea and cardiogenic shock. Investigations demonstrated bilateral segmental PEs and a large pericardial effusion causing cardiac tamponade. This large blood-stained effusion was drained urgently. She developed acute kidney injury and acute hepatic injury with synthetic failure. She was initially deemed unsuitable for anticoagulation so an inferior vena cava filter was placed to minimise risk of further PE. When no early re-accumulation of pericardial fluid occurred, a heparin infusion was started to treat the PEs. Pericardial fluid cytology was suggestive of metastatic carcinoma, with the immunophenotype most consistent with metastatic non-small cell lung cancer. She was subsequently treated with the tyrosine kinase inhibitor, erlotinib.
ASD closure under pressure
Authors: Shebani Suhair Omar , Skinner Gregory James , Duke Christopher
Published: September 2014

Transcatheter atrial septal defect device implantation in elderly patients may cause acute pulmonary oedema when impaired left ventricular diastolic function causes an abrupt increase in left atrial pressure. Though left atrial pressure is often monitored during test occlusion of a defect, it is not clear at what cut-off value device implantation is contraindicated. We report successful closure of an atrial septal defect in a 73-year-old patient, even though the mean left atrial pressure increased from 18 to 25 mm Hg with device implantation. Although a fenestrated device was used, this did not prevent the rise in left atrial pressure. The patient was supported with mechanical ventilation, milrinone and intravenous diuretics following the procedure and did not develop pulmonary oedema. Her dyspnoea improved and her functional status increased from New York Heart Association (NYHA) III to NYHA II. In conclusion, successful device closure can be accomplished even with high left atrial pressure.
The General Practitioner and the military veteran
Authors: Simpson Robin G , Leach J
Published: September 2014

Objectives

To assess the knowledge of members of the Royal College of General Practitioners (RCGP) on veteran's health issues, assess present support, and establish what support is required for GPs when treating veterans.

Methods

An electronic survey of RCGP members across selected faculties.

Results

Forty-seven per cent of respondents were ‘unsure’ or ‘didn't know’ how many veterans they were responsible for. However, many GPs replied that they had seen a veteran in the last month. Only 7.9% of respondents used the unique Read Code for veterans. Disappointingly, 75% of GPs indicated that they had not seen the RCGP leaflet on veterans’ health, and less than 2% had used the RCGP On-Line e-learning resource.

Conclusions

Surveyed GPs had little understanding of how many veterans were registered with their practice, and only a few had accessed learning resources available. GPs requested more information on how to assess veterans and where they could be referred. Further work is required to identify the true size of the problem, while continuing to provide proactive guidance and support to GPs on the health needs of veterans.
Multiseptate gallbladder in an African lioness (Panthera leo)
Authors: Garcia‐Gonzalez Beatriz , Cuesta‐Garcia Nerea
Published: September 2014

A 12‐year‐old African lioness from a safari park presented with abdominal discomfort and severe jaundice. Postmortem examination revealed a tortuous gallbladder, divided internally by thin septa into multiple chambers. Microscopically, multiple sacculations separated by septa of loose fibrovascular tissue were seen. These sacculations had intercommunicating openings and pouch‐like endings. The gallbladder epithelium showed diffuse coagulative necrosis, but numerous cystic formations were visible. Neither thickening of the gallbladder wall nor inflammatory infiltrates were identified. The lesion was diagnosed as multiseptate gallbladder, a rare congenital malformation described in human beings.
Timing of the emergence of the Europe–Sicily bridge (40–17 cal ka BP) and its implications for the spread of modern humans
Authors: Antonioli Fabrizio , Lo Presti Valeria , Morticelli Maurizio Gasparo , Bonfiglio Laura , Mannino Marcello A. , Palombo Maria Rita , Sannino Gianmaria , Ferranti Luigi , Furlani Stefano , Lambeck Kurt , Canese Simonepietro , Catalano Raimondo , Chiocci Francesco Latino , Mangano Gabriella , Scicchitano Giovanni , Tonielli Renato
Published: September 2014

The submerged sill in the Strait of Messina, which is located today at a minimum depth of 81 m below sea level (bsl), represents the only land connection between Sicily and mainland Italy (and thus Europe) during the last lowstand when the sea level locally stood at about 126 m bsl. Today, the sea crossing to Sicily, although it is less than 4 km at the narrowest point, faces hazardous sea conditions, made famous by the myth of Scylla and Charybdis. Through a multidisciplinary research project, we document the timing and mode of emergence of this land connection during the last 40 kyr. The integrated analysis takes into consideration morphobathymetric and lithological data, and relative sea-level change (both isostatic and tectonic), resulting in the hypothesis that a continental land bridge lasted for at least 500 years between 21.5 and 20 cal ka BP. The emergence may have occurred over an even longer time span if one allows for seafloor erosion by marine currents that have lowered the seabed since the Last Glacial Maximum (LGM). Modelling of palaeotidal velocities shows that sea crossings when sea level was lower than present would have faced even stronger and more hazardous sea currents than today, supporting the hypothesis that earliest human entry into Sicily most probably took place on foot during the period when the sill emerged as dry land. This hypothesis is compared with an analysis of Pleistocene vertebrate faunas in Sicily and mainland Italy, including a new radiocarbon date on bone collagen of an
Equus hydruntinus
specimen from Grotta di San Teodoro (23–21 cal ka BP), the dispersal abilities of the various animal species involved, particularly their swimming abilities, and the Palaeolithic archaeological record, all of which support the hypothesis of a relatively late land-based colonization of Sicily by
Homo sapiens
.
In-situ and Ex-situ Characterizations of Electrode Interfaces in Energy Storage Electrolyzers
Authors: Steen Stuart M. , Zhang Feng-Yuan
Published: September 2014

In a PEMWE the oxygen electrode is in a harsh environment during electrolysis. This paper highlights recent efforts to investigate the material corrosion and interfacial effects that occur in the electrode interface between gas diffusion layers (GDLs) and catalyst layers of the PEMWE. The in-situ performance and impedance were studied with different GDLs. Both SEM microscopy and EDX spectroscopy were utilized as ex-situ tools to examine and detail the GDLs used before and after testing. A significant interfacial degradation was discovered due to the electrode corrosion with stainless steel.
Fabrication of a Flexible Lithium-Ion Battery on Stainless Steel by Radio-Frequency Magnetron Sputtering
Authors: Su CHI-Hung , Hsueh Tien-Hsiang , Jheng Yuan-Ruei , Yu Yuh-Jeng , Jan Der-Jun , Wang Min-Chuan
Published: September 2014

Flexible rechargeable all solid-state lithium ion battery was fabricated on 70 μm thick, flexible stainless steel substrates with the cell composition of LiMn2O4 thin films. The cell includes thin film electrode of Lithium metal as an anode, LiMn2O4 as a cathode and LiPON as a solid electrolyte. LiMn2O4 thin films were deposited on the flexible stainless steel substrates (SS304) by radio frequency magnetron sputtering at room temperature. The electrochemical characterization of flexible lithium-ion battery shows discharge capacity of 12.8 μAh between 4.3V and 3V at a current density of 5 μA/cm2 (0.5C). And the flexible lithium-ion battery exhibits the best capacity retention over 85 % after 200 charge-discharge cycles between 4.2V and 3V at a current density of 10 μA/cm2 (1C). The flexible lithium-ion battery also exhibits the high C-rate performances. The capacity retention of 83% at 50 μA/cm2 (5C) and 73% at 200 μA/cm2 (20C).
The Linear Expansion of Mayenite (Ca12Al14O32)O under the Change in Oxygen Activity
Authors: Shkerin Sergey Nikolaevich , Tolkacheva Anna Sergeevna , Khrustov Vladimir Rudolfovich , Kuzmin Anton Valerievich
Published: September 2014

The paper studies the chemical expansion of mayenite induced by variation in oxygen activity. The value of the former is measured by dilatometry. Peculiar structural features of mayenite allow one to predict its high stability under the oxygen activity gradient. The change in the mayenite size is shown to be remarkably smaller compared to that in conventional materials.
Preparing of Carbon-Supported Ir-V Nanoparticles as Anode Catalyst by a Pulse-Microwave Assisted Chemical Reduction Process
Authors: Gao Yuan , Zheng Jun-Sheng , Tian Tian , Ma Jian-Xin
Published: September 2014

The non-Platinum Ir-V/C as the anode catalysts for proton exchange membrane fuel cell(PEMFC) were synthesized by a pulsed microwave-assisted chemical reduction process. The microstructure and morphology of the as-prepared nanoparticles were characterized by high resolution transmission electron microscopy (TEM). The electrochemical catalytic activity was evaluated by cyclic voltammetry techniques (CV). The results show that pH value, water content in precursor solution, and heat-treatment process have significant influence on particle size and distribution of Ir-V/C nanoparticles. CV and HRTEM indicated that the Ir-V/C nanoparticles possessed the smallest mean particle size (2.25nm) and the most uniform distribution among all the synthesized catalysts when the pH value is 12 and with no water containing in the precursor solution. The optimized parameter of microwave reaction was on for 12 s and off for 180 s, and this process was repeated 6 times at a microwave power of 2 kW. Membrane electrode assemblies(MEA) were fabricated, and the maximum power density reached 654 mW/cm2 when the current density was 1200mA/cm2.
Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms
Authors: Srinivasan Padmanabhan , Kapadia Rubina , Biswas Arundhati , Said Hamid M.
Published: September 2014

Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.
Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure
Authors: Isegawa Kengo , Hirooka Yoshitaka , Katsuki Masato , Kishi Takuya , Sunagawa Kenji
Published: September 2014

Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT1R) in the brain stem leads to sympathoexcitation due to neuronal AT1R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT1R are only weakly expressed in astrocytes. We hypothesized that AT1R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT1R, we investigated whether AT1R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT1R knockout (GFAP/AT1RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/AT1RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT1RKO mice than in control mice. Prognosis was significantly improved in GFAP/AT1RKO-MI mice compared with control-MI mice. Our findings indicated that AT1R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT1R, AT1R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.
Mechanical loading increases detection of estrogen receptor-alpha in osteocytes and osteoblasts despite chronic energy restriction
Authors: Swift Sibyl N. , Swift Joshua M. , Bloomfield Susan A.
Published: September 2014

Estrogen receptor-α (ER-α) is an important mediator of the bone response to mechanical loading. We sought to determine whether restricting dietary energy intake by 40% limits the bone formation rate (BFR) response to mechanical loading (LOAD) by downregulating ER-α-expressing osteocytes, or osteoblasts, or both. Female rats ( n = 48, 7 mo old) were randomized to ADLIB-SHAM and ADLIB-LOAD groups fed AIN-93M purified diet ad libitum or to ER40-SHAM and ER40-LOAD groups fed modified AIN-93M with 40% less energy (100% of all other nutrients). After 12 wk, LOAD rats were subjected to a muscle contraction protocol three times every third day. ER40 produced lower proximal tibia bone volume (−22%), trabecular thickness (−14%), and higher trabecular separation (+127%) in SHAM but not LOAD rats. ER40 rats exhibited reductions in mineral apposition rate, but not percent mineralizing surface or BFR. LOAD induced similar relative increases in these kinetic measures of osteoblast activity/recruitment in both diet groups., but absolute values for ER40 LOAD rats were lower vs. ADLIB-LOAD. There were fourfold and eightfold increases in proportion of estrogen receptor-α protein-positive osteoblast and osteocytes, respectively, in LOAD vs. SHAM rats, with no effect of ER40. These data suggest that a brief period of mechanical loading significantly affects estrogen receptor-α in cancellous bone osteoblasts and osteocytes. Chronic energy restriction does result in lower absolute values in indices of osteoblast activity after mechanical loading, but not by a smaller increment relative to unloaded bones; this change is not explained by an associated downregulation of ER-α in osteoblasts or osteocytes.
Effective Cancer Vaccine Platform Based on AttenuatedSalmonellaand a Type III Secretion System
Authors: Xu Xin , Hegazy Wael A.H. , Guo Linjie , Gao Xiuhua , Courtney Amy N. , Kurbanov Suhrab , Liu Daofeng , Tian Gengwen , Manuel Edwin R. , Diamond Don J. , Hensel Michael , Metelitsa Leonid S.
Published: September 2014

Vaccines explored for cancer therapy have been based generally on injectable vector systems used to control foreign infectious pathogens, to which the immune system evolved to respond naturally. However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. Taken together, our results demonstrate how antigen delivery using an oral Salmonella vector can provide an effective platform for the development of cancer vaccines. Cancer Res; 74(21); 6260–70. ©2014 AACR.
Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells
Authors: Wennerberg Erik , Pfefferle Aline , Ekblad Lars , Yoshimoto Yuya , Kremer Veronika , Kaminskyy Vitaliy O , Juhlin C Christofer , Höög Anders , Bodin Inger , Svjatoha Vitalijs , Larsson Catharina , Zedenius Jan , Wennerberg Johan , Lundqvist Andreas
Published: September 2014

Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell–based immunotherapy.

Experimental Design: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.

Results: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell–mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor–derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell–mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.

Conclusions: ATC cell lines are sensitive to NK cell–mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell–based immunotherapy. Clin Cancer Res; 20(22); 5733–44. ©2014 AACR.
A Phase I Study of Continuous Oral Dosing of OSI-906, a Dual Inhibitor of Insulin-Like Growth Factor-1 and Insulin Receptors, in Patients with Advanced Solid Tumors
Authors: Puzanov Igor , Lindsay Colin R. , Goff Laura , Sosman Jeff , Gilbert Jill , Berlin Jordan , Poondru Srinivasu , Simantov Ronit , Gedrich Rich , Stephens Andrew , Chan Emily , Evans T.R. Jeffry
Published: September 2014

Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors.

Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules.

Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified.

Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 701–11. ©2014 AACR.

See related commentary by Yee, p. 667
Initial High-Dose Prednisolone Combination Therapy Using COBRA and COBRA-Light in Early Rheumatoid Arthritis
Authors: Rasch Linda A. , van Tuyl Lilian H.D. , Lems Willem F. , Boers Maarten
Published: September 2014

Treatment with initial high-dose prednisolone and a combination of methotrexate (MTX) and sulfasalazine (SSZ) according to the COBRA regimen (Dutch acronym for combinatietherapie bij reumatoide artritis, ‘combination therapy for rheumatoid arthritis'), has repeatedly been demonstrated to be very effective in early rheumatoid arthritis (RA). COBRA combination therapy is superior to initial monotherapy of SSZ and MTX, is also associated with a good long-term outcome, is as safe as other treatment regimes, and performs as well as the combination of high-dose MTX and the tumor necrosis factor antagonist infliximab. A pilot study with an intensified version of the COBRA combination therapy showed that strict monitoring and aggressive treatment intensification based on the Disease Activity Score can result in a remission rate of 90% in patients with active early RA. Also, the first results indicate that an attenuated variation on COBRA combination therapy, called ‘COBRA-light', is effective in decreasing disease activity and is generally well tolerated. Based on these results, we conclude that initial high-dose prednisolone in combination with MTX and SSZ could or should be the first choice in early active RA since it is effective and safe, and the cost price of the drugs is low.
Glucocorticoids in Juvenile Idiopathic Arthritis
Authors: Schiappapietra Benedetta , Varnier Giulia , Rosina Silvia , Consolaro Alessandro , Martini Alberto , Ravelli Angelo
Published: September 2014

Glucocorticoid (GC) drugs are a potent and rapidly effective therapeutic option for the treatment of juvenile idiopathic arthritis (JIA). These medications are mainly used for the management of the extra-articular features of systemic-onset disease. A course of low-dose prednisone may be considered for achieving a rapid disease control in patients with severe polyarthritis refractory to other therapies or while awaiting the full therapeutic effect of a recently initiated disease-modifying antirheumatic drug or biologic agent. Short-term systemic GC administration may also be indicated for chronic iridocyclitis unresponsive to topical therapy. The general objective of GC therapy is to limit the maximum dose and exposure to the highest doses to what is needed to achieve disease control, and then to gradually taper the dose until the minimum level sufficient to maintain disease quiescence over time is reached. High-dose intravenous ‘pulse' methylprednisolone administration is sometimes chosen to treat the most severe or acute disease manifestations of systemic JIA, particularly macrophage activation syndrome. Intra-articular GC injection is a safe and rapidly effective treatment for synovitis in children with chronic arthritis. Triamcinolone hexacetonide is the optimal GC preparation for pediatric patients. Local injection therapy is used most frequently to treat oligoarthritis, but the strategy of performing multiple injections to induce disease remission, while simultaneously initiating therapy with second-line or biologic agents, has also been proposed for children with polyarticular JIA. Administration of GCs is associated with potentially deleterious adverse effects, some of which can be irreversible. This highlights the need of a judicious use of these medications and careful monitoring of their toxicity. The recently published recommendations for the management of JIA provide useful guidance to the clinicians for the administration of GCs in children with chronic arthritis.
Coexistence of Perineural Invasion and Lymph Node Metastases Is a Poor Prognostic Factor in Patients with Locally Advanced Rectal Cancer after Preoperative Chemoradiotherapy Followed by Radical Resection and Adjuvant Chemotherapy
Authors: Huang Chun-Ming , Huang Ching-Wen , Huang Ming-Yii , Lin Chih-Hung , Chen Chin-Fan , Yeh Yung-Sung , Ma Cheng-Jen , Huang Chih-Jen , Wang Jaw-Yuan
Published: September 2014

Objective: To determine the role of lymph node metastases (ypN) and perineural invasion (PNI) in patients with locally advanced rectal cancer (LARC). Subjects and Methods: Eighty-eight LARC patients receiving preoperative chemoradiotherapy from April 2006 to November 2011 were enrolled in this study. Univariate and multivariate analyses were conducted to determine the association between clinicopathologic features and clinical outcome. Results: The presence of ypN (p = 0.011) and PNI (p = 0.032) was a significant adverse prognostic factor for disease-free survival (DFS). High histologic grade (p = 0.015), PNI+ (p = 0.043) and ypN+ (p = 0.041) were adverse prognostic factors for overall survival (OS). Positive PNI was significantly associated with a higher risk of distant failure (odds ratio = 6.09; 95% CI: 1.57-27.05; p = 0.008). Moreover, patients with a coexistence of ypN+ and PNI+ had the significantly worst DFS (p < 0.001) and OS rates (p < 0.001) compared with other phenotypes. Conclusions: The presence of either PNI or ypN was a significant prognostic factor for predicting poor survival rates in LARC patients, especially those with a coexistence of both factors. Accordingly, we recommend an intensive follow-up and therapeutic programs for LARC patients with simultaneous PNI+ and ypN+.
Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals
Authors: Ho Jennifer E. , Arora Pankaj , Walford Geoffrey A. , Ghorbani Anahita , Guanaga Derek P. , Dhakal Bishnu P. , Nathan Daniel I. , Buys Emmanuel S. , Florez Jose C. , Newton‐Cheh Christopher , Lewis Gregory D. , Wang Thomas J.
Published: September 2014

Background

Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (
cGMP
) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase‐5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals.

Methods and Results

We conducted a randomized, double‐blinded, placebo‐controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/
mL
). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m
2
) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m
2
), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (
P
=0.02, respectively). Furthermore, one measure of β‐cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (
P
=0.009) and in the subgroup with severe obesity (
P
=0.01).

Conclusion

Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β‐cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of
cGMP
modulation in obesity are warranted.

Clinical Trial Registration

URL: ClinicalTrials.gov. Unique Identifier: NCT01444651.