bluuebunny/crossref_metadata_2025 huggingface dataset:
Removal Mechanism of Tungsten CMP Process: Effect of Slurry Abrasive Concentration and Process Temperature
Authors: Wang Zhefu , Peng Rixin , Xia Sherry , Kitajima Tomohiko , Tsai Stan
Published: May 2012

This work studied the removal mechanism of a tungsten chemical mechanical planarization (CMP) process on a dual head polishing platform. The two key parameters studied were slurry abrasive concentration and process temperature. The removal rate was observed to scale with the cubic root of the abrasive concentration. The polishing temperature showed a linear relation with the removal rate in the temperature controlled experiment. A potential mechanism was explored for the removal of the tungsten film to explain the experimental results.
The Performance and Density Advantages of 3D FPGA
Authors: Nakagawa Yaoko , Osada Kenichi , Matsumura Tadayuki , Koike Hanpei , Miyamoto Naoto , Takeda Kenichi
Published: May 2012

This paper shows performance and power advantages of three-dimensional (3D)-stacked integrated circuit (IC) with through-silicon-via (TSV) interconnections. We estimated Energy Efficiency Rate (EER) of High-end Router systems using 3D-ICs because High-end Router will dominate the Energy consumption of The Internet. We estimated EER improvement using 3D-ICs based on recent commercial 3D memories characteristics and our 3D FPGA research. For 3D FPGAs, we assumed a 3D FPGA architecture, and evaluated path delay of several FPGA benchmark logics with true 3D CAD (computer aided design) prototype tools and power consumption. Finally, EER improvement of High-end Router systems using 3D-ICs is expected about 45% compared ordinary systems using 2D-ICs.
Phosphate-Based Compounds as Additives for 5-Volt Lithium-Ion Electrolytes
Authors: Von Cresce Arthur , Xu Kang
Published: May 2012

We have shown in previous work that fluorinated phosphate esters make effective additives to the standard carbonate-based electrolyte used in commercial and experimental Li-ion batteries. New results indicate that the degree of fluorination seems to have an effect on the performance of these additives in helping the full cell retain capacity during cycling tests. Experimental evidence gathered from half cell and full cell data lead us to hypothesize that fluorinated phosphate esters are participating in the formation of a tougher, more redox-resistant solid electrolyte interphase layer on both anode and cathode. Therefore, we propose a network-forming mechanism in which fluorinated phosphate esters function to protect the electrolytes from the electrodes in our tested Li-ion battery systems.
First Principles Study of Multicomponent Silicate Materials for Rechargeable Li-Ion Batteries
Authors: Longo Roberto C. , Xiong Ka , Cho Kyeongjae
Published: May 2012

A first principles investigation is performed to study the structural and electrochemical properties of new multicomponent silicate materials that can be suitable for the cathode of rechargeable Li-ion batteries. The distribution of different transition metals in the silicate structure alters the structural and electronic properties of the crystal, affecting its kinetics, redox potentials and both ionic and electronic conductivities. The effect of the multiple interactions between Li and the transition metals is explained, and the implications of these multicomponent structures as a useful strategy to control the electrochemical performance of these compounds in order to improve the design of the battery are also addressed.
Thermochemistry of Neutral and Charged Vapor Complexes over NaBr-LnBr3 Systems
Authors: Kudin Lev S. , Ivanov Dmitry A.
Published: May 2012

The Knudsen effusion cell mass spectrometry and the density functional theory were used to study vapor species over the NaBr−LnBr3 (Ln = La, Lu) binary systems. The complex molecules NaLnBr4, Na2LnBr5 and both positive Na2LnBr4+, Na3LnBr5+ and negative NaLnBr5− complex ions have been observed in saturated vapor in the temperature range 870 - 1184 K (La) and 812 - 1065 К (Lu) for the first time along with the molecules and ions inherent to the pure components. Molecular parameters and energy characteristics were obtained by quantum-chemical calculations. The partial vapor pressures of neutral constituents have been obtained. The equilibrium constants of dissociation reactions of molecular and charged complexes were determined and the enthalpies of reactions have been calculated using the second and third laws of thermodynamics. Also the enthalpies of formation of complex molecules and ions have been obtained.
Acid-Base Reaction of Eutectic LiCl-41m/o KCl Melt Equilibrated with Gas Atmospheres Containing HCl, H2O, and O2 at 600°
Authors: Otsuka Nobuo
Published: May 2012

Potentiometric experiments measuring oxide anion activity of the eutectic LiCl-41m/oKCl melt were conducted at 600°C. A working electrode was made of glassy carbon whereas the RE consisted of a one-end closed zirconia tube filled with (Li,K)Cl -10m/o Li2O contacted by a platinum wire. The melt was equilibrated with gas atmospheres containing 0.09-0.26vol.% HCl, 0.8-12% H2O, 20% O2, balanc N2. Response of the electrode potential due to changes in the gas composition was monitored. At 600°C, basicity depended on the p2HCl/pH2O of the gas atmosphere for a certain range of basicity, suggesting an acid-base equilibrium between the melt and the gas atmosphere containing HCl and H2O.
Metal Dusting Corrosion: Mechanisms and Control
Authors: Ramanarayanan Trikur A. , Chun ChangMin
Published: May 2012

The metal dusting corrosion of Fe, Ni and Co and selected Ni-based and Fe-Ni based alloys in CO-H2 environments in the 400-850oC temperature range is discussed. Where possible, a mechanistic interpretation of the results is included. Based on the corrosion mechanism, control strategies are outlined. These include novel alloy development, the use of coatings and the use of additives to the process stream.
Metal Dusting Resistant Copper-Based Materials
Authors: Chun ChangMin , Desai Sanket , Ramanarayanan Trikur A.
Published: May 2012

Copper and Cu-based alloy coatings suppress carbon transfer to the metal surface from carbon-supersaturated gaseous environments. The metal dusting resistance of such coatings has been investigated in CO-H2 gas mixtures at temperatures ranging from 450°C to 700°C. Conventional plating and cladding methods have been employed to deposit Cu-based materials on the surfaces of commercial materials such as 2.25Cr-0.5Mo steel and carbon steel. In addition to the performance of Cu-based materials under laboratory conditions, the effect of alloying elements such as Sn, Zn, Ni and Al in Cu on the corrosion process and the coating/substrate interface stability are discussed with particular attention to commercial scale applications.
Fireside Corrosion in Oxy-Fuel Combustion of Coal
Authors: Holcomb Gordon R. , Tylczak Joesph , Meier Gerald H. , Jung Kee Young , Mu Nan , Yanar Nazik , Pettit Frederick
Published: May 2012

Oxy-fuel combustion is based on burning fossil fuels in a mixture of recirculated flue gas and oxygen, rather than in air. An optimized oxy-combustion power plant will have ultra-low emissions since the flue gas that results from oxy-fuel combustion consists almost entirely of CO2 and water vapor. Once the water vapor is condensed, it is relatively easy to sequester the CO2 so that it does not escape into the atmosphere. A variety of laboratory tests comparing air-firing to oxy-firing conditions, and tests examining specific simpler combinations of oxidants, were conducted at 650-700 °C. Alloys studied included model Fe-Cr and Ni-Cr alloys, commercial ferritic steels, austenitic steels, and nickel base superalloys. The observed corrosion behavior shows accelerated corrosion even with sulfate additions that remain solid at the tested temperatures, encapsulation of ash components in outer iron oxide scales, and a differentiation between oxy-fuel combustion flue gas recirculation choices.
Evaluating Materials and Fuels Using an Atmospheric-Pressure Low-Velocity Burner Rig
Authors: Shifler David A.
Published: May 2012

In order to meet future Naval performance and safety parameters, it is anticipated that synthetic logistics fuels will be required to meet the current Naval petroleum-based physical, combustion, and chemistry specifications. However, before they are used, these fuels must be certified for use by passing through a series of evaluation tests to ascertain whether their chemical, physical, and combustion properties will have an adverse impact on engines, that herebefore have used specified petroleum,-based fuels. It has been established that low-velocity, atmospheric-pressure burner rigs, when operated properly, simulate the corrosion and degradation of materials operating in the shipboard gas turbines. To evaluate whether new fuels will cause accelerated corrosion in a gas turbine, the corrosion of coated superalloy samples representative of materials in the hot section of gas turbines are exposed to the combustion gaseous products of the new fuels or fuel blends in the burner rig and compared to that of a standard petroleum-based fuel. Parameter control in all tests is critical if proper evaluation and interpretation is to be achieved. Failure to control the parameters leads to uncertainities that will require more testing or deliver unsupportable, indeterminate conclusions. The paper will discuss cases where proper test parameters lead to determining supportable, repeatable conclusions and corrective actions and where improper test procedures and parameter control may lead to unintended, unsupportable conclusions.
Development of Refractory Ceramics for the Oxygen Evolution Reaction (OER) Electrocatalyst Support for Water Electrolysis at Elevated Temperatures
Authors: Nikiforov Aleksey V. , Prag Carsten Brorson , Polonský Jakub , Petrushina Irina M. , Christensen Erik , Bjerrum Niels J.
Published: May 2012

Commercial TaC and Si3N4 powders were tested as possible electrocatalyst support materials for the Oxygen Evolution Reaction (OER) for PEM water electrolysers, operating at elevated temperatures. TaC and Si3N4 were characterised by thermogravimmetric and differential thermal analysis for their thermal stability. The Adams fusion method was implemented to deposit IrO2 on the support surfaces. A series of electrocatalysts was prepared with a composition of (IrO2)x(TaC/ Si3N4)1-x,where x represents the mass fraction of IrO2 and was equal to 0.1 (only for TaC), 0.3, 0.5, 0.7, 0.9 and 1. The thin-film method was used for electrochemical analysis of the prepared electrocatalysts. SEM-EDX, BET and powder conductivity measurements were used as complementary techniques to complete characterisation of the electrocatalysts. Additionally, they were compared in their properties with previously reported data for a SiC-Si support. The stability of the electrocatalysts was assessed by estimation of reversibility of the anodic/cathodic processes.
Interactions between Metallic Interconnects and Ceramic Electrodes in SOFC Operating Environments
Authors: Amendola Roberta , Gannon P. E. , Sofie Stephen W. , Weisenstein Adam J.
Published: May 2012

Ferritic stainless steel bipolar plates are widely used to interconnect individual cells in planar Solid Oxide Fuel Cell stacks. In this study, thin films of electrode ceramic materials, LSM for the cathode and Ni/YSZ for the anode, were screen printed on the selected metallic alloys (with and without surface coatings). Samples were then placed in a test rig which allows simultaneous exposures to single (air/air) and dual atmospheres (air/fuel) at 800°C for 100 hours. This research is focused on the investigation of the thermally grown oxide layer and ionic transport phenomena for a better understanding of materials interactions during realistic SOFC exposures. Morphology of the surfaces and cross sections were analyzed by a Field Emission Scanning Electron Microscope (FESEM) and the composition was assessed using Energy Dispersive X-ray Spectroscopy (EDS).
Electrodeposition of SmCo Nanostructures in Deep Eutectic Solvent
Authors: Gomez Elvira , Valles Elisa , Cojocaru Paula , Raygani Anahit , Magagnin Luca
Published: May 2012

Electrodeposition of some metals at room temperatures have been restricted in aqueous solutions to those that present a standard potential less negative than that of water reduction. Some of these metals could be deposited but with economic expense using either organic solvents or using more drastic conditions as molten salts. In this work we select to study the cobalt-samarium electrodeposition process possibilities, due to that upon depending the ratio between the metals this alloy could derive to potentially hard magnetic material. The interest at first is focused into the study of the deposition process of each metal partner and the corresponding joint process using as solvent the eutectic mixture 1 chlorine chloride: 2 urea.
Pulse Electrodeposited ZnSeTe Films
Authors: Murali K. R. , Florence Sasi , John Rita
Published: May 2012

ZnSexTe1-x films were deposited by pulse electrodeposition technique for the first time. The films exhibited cubic structure. With lattice parameter increasing from 0.579 to 0.605 nm as the Te content increased. Band gap values in the range of 2.35 eV - 2.69 eV are observed as the ZnSe concentration increased. Refractive index was found to vary from 2.83 - 2.53 with increase of 'x' value. Raman spectra exhibit the ZnSe like LO phonons. Photoluminescence spectra of ZnSe1-xTex films with different tellurium content confirms that the Te isovalent impurities exactly replace the Se atoms whose electronic configurations are the same.
Photoelectrochemical Properties of Brush Plated CdSTe Films
Authors: Matheline Mary , John Rita , Murali K. R.
Published: May 2012

CdSxTe1-x films were deposited for the first time by the brush plating technique. The films were pol;ycrystalline with peaks corresponding to the hexagonal phase. The variation of lattice parameters 'a' and 'c' with composition is linear and obeys Vegard's law. The band gap was found to vary from 1.44 eV to 2.41 eV as the percentage of CdTe decreased. The power output characteristics after 80 s photoetching indicates a Voc of 0.62 V, Jsc of 16.00 mA cm-2, ff of 0.76, | of 9.55% for 80 mWcm-2 illumination. The photovoltaic parameters are higher than earlier reports.
Molecular Dynamics Simulation of Grain Growth of Cu Film
Authors: Sasajima Yasushi , Onuki Jin
Published: May 2012

We investigated the growth process of Cu polycrystalline films on three substrates Si, Ti and Ru during isothermal annealing by the molecular dynamics method. We focused on the influence of the adhesion strength and size mismatch between substrate and Cu on crystallinity and orientational order of the film. The present simulation clarified that Ru is excellent material as substare/barrier metal for Cu wire. Based on the findings, a search plot for replacement material of Ru was proposed.
Reducing endoplasmic reticulum stress does not improve steatohepatitis in mice fed a methionine- and choline-deficient diet
Authors: Henkel Anne S. , Dewey Amanda M. , Anderson Kristy A. , Olivares Shantel , Green Richard M.
Published: May 2012

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of nonalcoholic steatohepatitis. The ER stress response is activated in the livers of mice fed a methionine- and choline-deficient (MCD) diet, yet the role of ER stress in the pathogenesis of MCD diet-induced steatohepatitis is unknown. Using chemical chaperones on hepatic steatosis and markers of inflammation and fibrosis in mice fed a MCD diet, we aim to determine the effects of reducing ER stress. C57BL/6J mice were fed a MCD diet with or without the ER chemical chaperones 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) for 2 wk. TUDCA and PBA effectively attenuated the ER stress response in MCD diet-fed mice, as evidenced by reduced protein levels of phosphorylated eukaryotic initiation factor 2α and phosphorylated JNK and suppression of mRNA levels of CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78 kDa, and X-box binding protein 1. However, PBA and TUDCA did not decrease MCD diet-induced hepatic steatosis. MCD diet-induced hepatic inflammation, as evidenced by increased plasma alanine aminotransferase and induction of hepatic TNFα expression, was also not reduced by PBA or TUDCA. PBA and TUDCA did not attenuate MCD diet-induced upregulation of the fibrosis-associated genes tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9. ER chemical chaperones reduce MCD diet-induced ER stress, yet they do not improve MCD diet-induced hepatic steatosis, inflammation, or activation of genes associated with fibrosis. These data suggest that although the ER stress response is activated by the MCD diet, it does not have a primary role in the pathogenesis of MCD diet-induced steatohepatitis.
Neurogenic and myogenic motor patterns of rabbit proximal, mid, and distal colon
Authors: Dinning P. G. , Costa M. , Brookes S. J. , Spencer N. J.
Published: May 2012

The rabbit colon consists of four distinct regions. The motility of each region is controlled by myogenic and neurogenic mechanisms. Associating these mechanisms with specific motor patterns throughout all regions of the colon has not previously been achieved. Three sections of the colon (the proximal, mid, and distal colon) were removed from euthanized rabbits. The proximal colon consists of a triply teniated region and a single tenia region. Spatio-temporal maps were constructed from video recordings of colonic wall diameter, with associated intraluminal pressure recorded from the aboral end. Hexamethonium (100 μM) and tetrodotoxin (TTX; 0.6 μM) were used to inhibit neural activity. Four distinct patterns of motility were detected: 1 myogenic and 3 neurogenic. The myogenic activity consisted of circular muscle (CM) contractions (ripples) that occurred throughout the colon and propagated in both antegrade (anal) and retrograde (oral) directions. The neural activity of the proximal colon consisted of slowly (0.1 mm/s) propagating colonic migrating motor complexes, which were abolished by hexamethonium. These complexes were observed in the region of the proximal colon with a single band of tenia. In the distal colon, tetrodotoxin-sensitive, thus neurally mediated, but hexamethonium-resistant, peristaltic (anal) and antiperistaltic (oral) contractions were identified. The distinct patterns of neurogenic and myogenic motor activity recorded from isolated rabbit colon are specific to each anatomically distinct region. The regional specificity motor pattern is likely to facilitate orderly transit of colonic content from semi-liquid to solid composition of feces.
Effects of fat, protein, and carbohydrate and protein load on appetite, plasma cholecystokinin, peptide YY, and ghrelin, and energy intake in lean and obese men
Authors: Brennan Ixchel M. , Luscombe-Marsh Natalie D. , Seimon Radhika V. , Otto Bärbel , Horowitz Michael , Wishart Judith M. , Feinle-Bisset Christine
Published: May 2012

While protein is regarded as the most satiating macronutrient, many studies have employed test meals that had very high and unsustainable protein contents. Furthermore, the comparative responses between lean and obese subjects and the relationships between energy intake suppression and gut hormone release remain unclear. We evaluated the acute effects of meals with modest variations in 1) fat, protein, and carbohydrate content and 2) protein load on gastrointestinal hormones, appetite, and subsequent energy intake in lean and obese subjects. Sixteen lean and sixteen obese men were studied on four occasions. Following a standardized breakfast, they received for lunch: 1) high-fat (HF), 2) high-protein (HP), 3) high-carbohydrate/low-protein (HC/LP), or 4) adequate-protein (AP) isocaloric test meals. Hunger, fullness, and gut hormones were measured throughout, and at t = 180 min energy intake at a buffet meal was quantified. In lean subjects, hunger was less and fullness greater following HF, HP, and AP compared with HC/LP meals, and energy intake was less following HF and HP compared with HC meals ( P < 0.05). In the obese subjects, hunger was less following HP compared with HF, HC/LP, and AP meals, and energy intake was less following HP and AP compared with HF and HC meals ( P < 0.05). There were no major differences in hormone responses to the meals among subject groups, but the CCK and ghrelin responses to HP and AP were sustained in both groups. In conclusion, HP meals suppress energy intake in lean and obese subjects, an effect potentially mediated by CCK and ghrelin, while obese individuals appear to be less sensitive to the satiating effects of fat.
Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice
Authors: Benight Nancy M. , Stoll Barbara , Marini Juan C. , Burrin Douglas G.
Published: May 2012

Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesized that orally administered MTA would be bioavailable and reduce morbidity associated with experimental colitis. We examined clinical, histological, and molecular markers of disease in mice provided oral MTA before (preventative) or after (therapy) the induction of colitis with 3% dextran sulfate sodium (DSS). We found a reduction in disease activity, weight loss, myeloperoxidase activity, and histological damage in mice given preventative MTA compared with DSS alone. We also found that equivalent supplementation with methionine could not reproduce the anti-inflammatory effects of MTA, and that MTA had no detectable adverse effects in control or DSS mice. Expression microarray analysis of colonic tissue showed several dominant pathways related to inflammatory cytokines/chemokines and extracellular matrix remodeling were upregulation by DSS and suppressed in MTA-supplemented mice. MTA is rapidly absorbed in the gastrointestinal tract and disseminated throughout the body, based on a time course analysis of an oral bolus of MTA. This effect is transient, with MTA levels falling to near baseline within 90 min in most organs. Moreover, MTA did not lead to increased blood or tissue methionine levels, suggesting that its effects are specific. However, MTA provided limited therapeutic benefit when administered after the onset of colitis. Our results show that oral MTA supplementation is a safe and effective strategy to prevent inflammation and tissue injury associated with DSS colitis in mice. Additional studies in chronic inflammatory models are necessary to determine if MTA is a safe and beneficial option for the maintenance of remission in human inflammatory bowel disease.
Motor unit recruitment when neuromuscular electrical stimulation is applied over a nerve trunk compared with a muscle belly: quadriceps femoris
Authors: Bergquist A. J. , Wiest M. J. , Collins D. F.
Published: May 2012

Neuromuscular electrical stimulation (NMES) can be delivered over a nerve trunk or muscle belly and both can generate contractions through peripheral and central pathways. Generating contractions through peripheral pathways is associated with a nonphysiological motor unit recruitment order, which may limit the efficacy of NMES rehabilitation. Presently, we compared recruitment through peripheral and central pathways for contractions of the knee extensors evoked by NMES applied over the femoral nerve vs. the quadriceps muscle. NMES was delivered to evoke 10 and 20% of maximum voluntary isometric contraction torque 2–3 s into the NMES (time1) in two patterns: 1) constant frequency (15 Hz for 8 s); and 2) step frequency (15–100-15 Hz and 25–100-25 Hz for 3–2-3 s, respectively). Torque and electromyographic activity recorded from vastus lateralis and medialis were quantified at the beginning (time1) and end (time2; 6–7 s into the NMES) of each pattern. M-waves (peripheral pathway), H-reflexes, and asynchronous activity (central pathways) during NMES were quantified. Torque did not differ regardless of NMES location, pattern, or time. For both muscles, M-waves were ∼7–10 times smaller and H-reflexes ∼8–9 times larger during NMES over the nerve compared with over the muscle. However, unlike muscles studied previously, neither torque nor activity through central pathways were augmented following 100 Hz NMES, nor was any asynchronous activity evoked during NMES at either location. The coefficient of variation was also quantified at time2to determine the consistency of each dependent measure between three consecutive contractions. Torque, M-waves, and H-reflexes were most variable during NMES over the nerve. In summary, NMES over the nerve produced contractions with the greatest recruitment through central pathways; however, considering some of the limitations of NMES over the femoral nerve, it may be considered a good complement to, as opposed to a replacement for, NMES over the quadriceps muscle for maintaining muscle quality and reducing contraction fatigue during NMES rehabilitation.
Effects of phenylephrine on cardiac output and venous return depend on the position of the heart on the Frank-Starling relationship
Authors: Cannesson Maxime , Jian Zhongping , Chen Guo , Vu Trung Q. , Hatib Feras
Published: May 2012

Introduction: phenylephrine is used daily during anesthesia for treating hypotension. However, the effects of phenylephrine on cardiac output (CO) are not clear. We hypothesized that the impact of phenylephrine on cardiac output is related to preload dependency. Methods: eight pigs were studied at a preload independent stage (after CO augmentation) and at a preload dependent stage (after a 21 ml/kg hemorrhage). At each stage, phenylephrine boluses (0.5, 1.0, 2.0, and 4.0 μg/kg) were given randomly while mean arterial pressure (MAP), CO, inferior vena cava flow (IVCf) (both measured using ultrasonic flow probes), and pulse pressure variation were measured. Results: at the preload independent stage, phenylephrine boluses induced significant increases in MAP (from 72 ± 6 to 100 ± 6 mmHg; P < 0.05) and decreases in CO and IVCf (from 7.0 ± 0.8 to 6.0 ± 1.1 l/min and from 4.6 ± 0.5 to 3.8 ± 0.6 l/min, respectively). At the preload-dependent stage, phenylephrine boluses induced significant increases in MAP (from 40 ± 7 to 65 ± 9 mmHg), CO (from 4.1 ± 0.6 to 4.9 ± 0.7 l/min), and IVCf (from 3.0 ± 0.4 to 3.5 ± 0.6 l/min; all data presented are for 4 μg/kg). Incremental doses of phenylephrine induced incremental changes in cardiac output. A pulse pressure variation >16.4% before phenylephrine predicted an increase in stroke volume with a 93% sensitivity and a 100% specificity. Conclusion: impact of phenylephrine on cardiac output is related to preload dependency. When the heart is preload independent, phenylephrine boluses induce on average a decrease in cardiac output. When the heart is preload dependent, phenylephrine boluses induce on average an increase in cardiac output.
Brain oxygenation and CNS oxygen toxicity after infusion of perfluorocarbon emulsion
Authors: Demchenko Ivan T. , Mahon Richard T. , Allen Barry W. , Piantadosi Claude A.
Published: May 2012

Intravenous perfluorocarbon (PFC) emulsions, administered with supplemental inspired O2, are being evaluated for their ability to eliminate N2from blood and tissue prior to submarine escape, but these agents can increase the incidence of central nervous system (CNS) O2toxicity, perhaps by enhancing O2delivery to the brain. To assess this, we infused a PFC emulsion (Oxycyte, 6 ml/kg iv) into anesthetized rats and measured cerebral Po2and regional cerebral blood flow (rCBF) in cortex, hippocampus, hypothalamus, and striatum with 100% O2at 1, 3, or 5 atmospheres absolute (ATA). At 1 ATA, brain Po2stabilized at >20 mmHg higher in animals infused with PFC emulsion than in control animals infused with saline, and rCBF fell by ∼10%. At 3 ATA, PFC emulsion raised brain Po2>70 mmHg above control levels, and rCBF decreased by as much as 25%. At 5 ATA, brain Po2was ≥159 mmHg above levels in control animals for the first 40 min but then rose sharply; rCBF showed a similar profile, reflecting vasoconstriction followed by hyperemia. Conscious rats were also pretreated with PFC emulsion at 3 or 6 ml/kg iv and exposed to 100% O2at 5 ATA. At the lower dose, 80% of the animals experienced seizures by 33 min compared with 50% of the control animals. At the higher dose, seizures occurred in all rats within 25 min. At these doses, administration of PFC emulsion poses a clear risk of CNS O2toxicity in conscious rats exposed to hyperbaric O2at 5 ATA.
A method for analyzing temporal patterns of variability of a time series from Poincaré plots
Authors: Fishman Mikkel , Jacono Frank J. , Park Soojin , Jamasebi Reza , Thungtong Anurak , Loparo Kenneth A. , Dick Thomas E.
Published: May 2012

The Poincaré plot is a popular two-dimensional, time series analysis tool because of its intuitive display of dynamic system behavior. Poincaré plots have been used to visualize heart rate and respiratory pattern variabilities. However, conventional quantitative analysis relies primarily on statistical measurements of the cumulative distribution of points, making it difficult to interpret irregular or complex plots. Moreover, the plots are constructed to reflect highly correlated regions of the time series, reducing the amount of nonlinear information that is presented and thereby hiding potentially relevant features. We propose temporal Poincaré variability (TPV), a novel analysis methodology that uses standard techniques to quantify the temporal distribution of points and to detect nonlinear sources responsible for physiological variability. In addition, the analysis is applied across multiple time delays, yielding a richer insight into system dynamics than the traditional circle return plot. The method is applied to data sets of R-R intervals and to synthetic point process data extracted from the Lorenz time series. The results demonstrate that TPV complements the traditional analysis and can be applied more generally, including Poincaré plots with multiple clusters, and more consistently than the conventional measures and can address questions regarding potential structure underlying the variability of a data set.
Loss of Fibroblast HIF-1α Accelerates Tumorigenesis
Authors: Kim Jung-whan , Evans Colin , Weidemann Alexander , Takeda Norihiko , Lee Yun Sok , Stockmann Christian , Branco-Price Cristina , Brandberg Filip , Leone Gustavo , Ostrowski Michael C. , Johnson Randall S.
Published: May 2012

Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization. Cancer Res; 72(13); 3187–95. ©2012 AACR.
Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent
Authors: Andraos Rita , Qian Zhiyan , Bonenfant Débora , Rubert Joëlle , Vangrevelinghe Eric , Scheufler Clemens , Marque Fanny , Régnier Catherine H. , De Pover Alain , Ryckelynck Hugues , Bhagwat Neha , Koppikar Priya , Goel Aviva , Wyder Lorenza , Tavares Gisele , Baffert Fabienne , Pissot-Soldermann Carole , Manley Paul W. , Gaul Christoph , Voshol Hans , Levine Ross L. , Sellers William R. , Hofmann Francesco , Radimerski Thomas
Published: May 2012

Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor–induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.

Significance: This study shows that JAK inhibitors can lead to an increase of activation loop phosphorylation in a manner that is binding mode dependent. Our results highlight the need for detailed understanding of inhibitor mechanism of action, and that it may be possible to devise strategies that avoid target priming using alternative modes of inhibiting JAK kinase activity for the treatment of JAK-dependent diseases. Cancer Discov; 2(6); 512–23. © 2012 AACR.

This article is highlighted in the In This Issue feature, p. 473
Changing Epidemiology: Does It Increase Our Understanding?
Authors: Humes David J.
Published: May 2012

During the last decade there have been a number of reports using routinely collected health care administration data and from large cohort studies that have attempted to describe changes in the occurrence and identify risk factors for the development of the condition along with reporting its associated mortality. This article identified all studies reporting the occurrence and mortality associated with diverticulosis, diverticular disease and the complications of diverticular disease, notably, bleeding, perforation, fistula, stricture and abscess formation which show that there is strong evidence of an increasing health care burden associated with diverticular disease in terms of hospitalization. There is evidence of an increase in the incidence of some of the associated complications of diverticular disease, notably perforation. A number of risk factors such as body mass index, comorbidity, smoking and concurrent medications such as opiate analgesics and steroids may predispose to the development of complications. The mortality associated with hospital admission for diverticular disease is significant as is the excess mortality associated with a diagnosis of one of the complications of diverticular disease.
Is It Diverticular Disease or Is It Irritable Bowel Syndrome?
Authors: Spiller Robin
Published: May 2012

Symptomatic diverticular disease (SYMP-DD) and irritable bowel syndrome (IBS) share many features. Both are characterised by recurrent episodes of abdominal pain which may be slightly more frequent in IBS than SYMP-DD. They may also both exhibit an erratic bowel habit with diarrhoea, constipation and alternating types. It is important to assess anxiety, depression and somatisation since this can be increased in both types of patients and may be associated with visceral hypersensitivity. There are also significant differences between IBS and SYMP-DD. In particular, SYMP-DD patients are older, lack the female predominance seen in IBS and may often have fever with prolonged episodes of pain. For them, abnormalities of the gut are probably more important than cerebral factors, while for IBS the reverse is true. Treatments should be directed at the predominant abnormality which will vary in every patient.
The Role of Visceral Fat
Authors: Batra Arvind , Siegmund Britta
Published: May 2012

Until a decade ago, fat tissue had been exclusively considered as an endocrine organ. The emerging functional characterization of adipokines as well as adipocytes and preadipocytes suggested for the first time a close link between the endocrine and the immune system. This is emphasized by the changes of the expression pattern of adipokines when the fat tissue is adjacent to inflamed sites. In addition, adipokines are capable of regulating adaptive and acquired immune responses. Remarkably, adipocytes express functional pattern recognition receptors and can consequently respond to bacterial and viral antigens. This seems to be highly relevant for intestinal inflammation and here in particular transmural inflammation where bacteria or bacterial antigens translocalize into the mesenteric fat tissue. Besides phagocytosis of these antigens, adipocytes as well as preadipocytes can be activated resulting in a release of adipokines and chemokines mediating the infiltration of immune cells thus allowing for an immune response. Recent data suggest that the adipokine milieu of the fat tissue closely regulates the polarization of infiltrating immune cells. This is of increasing interest since the pattern of infiltrating cells allows for a characterization of the underlying disease. Thus, in obesity pro-inflammatory M1 macrophages dominate this site. Remarkably, in colorectal carcinoma the presence of M1 and M2 macrophages represents a prognostic marker for the disease course. In conclusion, the visceral fat tissue represents a complex organ with multifaceted function linking the endocrine and the immune system.
Perception and the Origin of Symptoms in Diverticular Disease
Authors: Simpson John
Published: May 2012

Colonic diverticulosis is a common condition and although the majority of patients are asymptomatic up to 20% experience altered bowel habit and abdominal pain. The mechanisms underlying these symptoms are unclear but several theories now exist. This article briefly outlines a model of GI perception and then highlights past and current theories that may explain the development of symptoms in patients with diverticulosis.
Conservative Management
Authors: Kruis W. , Leifeld L. , Pfützer R.
Published: May 2012

Treatment of diverticulitis comprises at least two options: conservative or surgical management. There is a recent trend to limit surgical treatment of acute diverticulitis and to favor conservative management. This review addresses general aspects of conservative patient care with special focus on the treatment of patients with a first attack of diverticulitis. The presentation does not include a discussion of specific drugs which is given in other sections of this issue.
Aminosalicylates
Authors: Gross Volker
Published: May 2012

Symptomatic diverticular disease has a high prevalence in countries with a western lifestyle. Besides antibiotics for acute diverticulitis there are no established medical interventions to prevent or to treat symptomatic diverticular disease. Due to its broad spectrum of anti-inflammatory activities, mesalazine is a candidate for the treatment of symptomatic diverticular disease. A review of the literature shows that randomized open studies using various treatment designs suggest a protective role of mesalazine in preventing recurrences of diverticulitis. Currently, 5 randomized placebo-controlled trials are active which will clarify the role of mesalazine to prevent recurrence of diverticulitis in the near future. Several randomized uncontrolled studies suggest that mesalazine improves symptoms in patients with symptomatic uncomplicated diverticular disease. The analysis of secondary end points from two randomized placebo-controlled trials suggests that mesalazine improves symptoms in diverticular disease although both studies failed to show a statistically significant advantage for mesalazine for the primary study end point. In segmental colitis associated with diverticulosis no prospective systematic studies are available. However, several case reports show a high efficacy of mesalazine in segmental colitis associated with diverticulosis.
Prophylactic Resection, Uncomplicated Diverticulitis, and Recurrent Diverticulitis
Authors: Wolff Bruce G. , Boostrom Sarah Y.
Published: May 2012

The classifications of acute uncomplicated diverticulitis and complicated diverticulitis have served us well for many years. However, in recent years, we have noted the prevalence of variations of uncomplicated diverticulitis, which have not precisely fit under the classification of ‘acute resolving uncomplicated diverticulitis’, which manifests itself with the typical left lower quadrant pain, fever, diarrhea, elevated white blood count, and CT findings, such as stranding, and which resolves fairly promptly and completely on oral antibiotic therapy. For these other variations, we would suggest we use the term chronic diverticulitis, as a subset of uncomplicated diverticulitis, meaning there is no abscess, stricture, or fistula, but the episode does not respond to the usual antibiotic treatment, and there is a rebound symptomatology once the treatment has stopped, or there is continuing subliminal inflammation that continues, typically, for several weeks after the initial episode without complete resolution. This variation could also be termed ‘smoldering’ diverticulitis. A second variation of uncomplicated diverticulitis should be termed atypical diverticulitis, since this variant does not manifest all of the usual components of acute diverticulitis, particularly an absence of fever, and even white blood count elevation, and there may be a lack of diagnostic evidence of acute diverticulitis. This diagnosis must be compared with diarrhea-predominant irritable bowel syndrome, and it is sometimes very difficult to distinguish between these two entities. The character of the pain in irritable bowel syndrome is typically cramping intermittently, compared with the more constant pain in smoldering diverticulitis. In our study by Horgan, McConnell, Wolff and coworkers, 5% of 930 patients who underwent sigmoid resection fit into this category of atypical uncomplicated diverticulitis. These 47 patients all had diverticulosis, and 76% that had surgery had evidence of acute and chronic inflammation, and 15% had an unsuspected pericolonic abscess. There was no mortality and a low complication mortality rate (4.2%). Complete resolution of symptoms was achieved in 76.5 with 80% being pain free. Therefore, this is mostly a diagnosis of exclusion, and clinicians must be careful to perform a thorough workup and evaluation before proceeding to surgery with this as a diagnosis. Ischemic colitis is also in the differential diagnosis, and many patients who have diverticulitis, have irritable bowel syndrome as well, so caution must be used in predicting positive outcomes after surgery in these patients.
The Gastroenterologist’s View
Authors: Lembcke Bernhard
Published: May 2012

The traditional view that recurrent episodes of diverticulitis lead to progressively complicated disease resulting in a disadvantageous course, more difficult, complicated operations and lethal outcomes did not stand the test of evidence. Only a minority of patients with acute diverticulitis will ever require surgery, and if so, this occurs during or early after the first episode. Complications and recurrence of disease after surgery are enumerable. Strong indicators favoring sigmoid colectomy are major abscess, free air, and fistula, i.e. perforating disease. This occurs predominantly at the initial presentation, frequently in younger or immunosuppressed patients. Important differential diagnoses must be considered both for initial diagnosis of diverticulitis and for recurrent episodes. Conservative management of recurrent diverticulitis is safe and best guided by gastroenterological expertise. Sophisticated ultrasound experience as a part of this competence allows detailed evaluation of the local status and the best evidence in the literature for diagnosing diverticulitis is on US. In practice, however, the question of perforating diverticulitis is adequately answered by subtle CT scan. Medical therapy is usually the treatment of choice for recurrent diverticulitis. Avoidance of drugs bearing the hazard of perforation (e.g. NSAIDs) is emphasized, and smoking is strongly discouraged. A mathematical model based on published data shows that patients with recurrent diverticulitis overall (only) profit from surgery if they are hit by four episodes during the course of disease. This is where theory and reality (should) meet.
Radionuclide Therapy via SSTR: Future Aspects from Experimental Animal Studies
Authors: Forssell-Aronsson Eva , Spetz Johan , Ahlman Håkan
Published: May 2012

There is need for better therapeutic options for neuroendocrine tumours. The aim of this review was to summarize results of experimental animal studies and raise ideas for future radionuclide therapy based on high expression of somatostatin (SS) receptors by many neuroendocrine tumours. In summary, one of the major options is individualized treatment for each patient, including choice of SS analogues, radionuclides and treatment schedules. Other options are methods to increase the treatment effect on tumour tissue (increasing tumour uptake and retention by upregulation of receptor expression and avoiding saturation of receptor binding), methods to increase the tumour tissue response (by choice of radionuclides, SS analogues or combined therapies), and methods to reduce side effects (diminished uptake and retention in critical organs and reduced normal tissue response). Furthermore, combination therapy with other radiopharmaceuticals, cytotoxic drugs or radiosensitizers can be considered to enhance the effects of radiolabelled SS analogues.
Misuse of Medicines in the European Union: A Systematic Review of the Literature
Authors: Casati Alicia , Sedefov Roumen , Pfeiffer-Gerschel Tim
Published: May 2012

Background: Although awareness of the misuse of medicines is increasing, data on the extent of the problem in the European Union (EU) are lacking. Methods: In order to assess the magnitude and severity of the problem, a systematic review of the literature on the misuse of analgesics, opioid substitution medicines and sedatives/hypnotics (with the exception of benzodiazepines) was conducted using the PubMed and Web of Science databases. Relevant literature was identified between 2001 and 2011. Results: The main groups of misused medicines include opioid analgesics, methadone, buprenorphine and Z-drugs. Regional trends in medicine misuse indicate heterogeneity across the EU with respect to misused medicine types and research activities. Prevalence, high-risk populations and factors contributing to medicine misuse are discussed. Conclusion: The implications of these findings for prevention, treatment, and policy in the EU are considered.