bluuebunny/crossref_metadata_2025 huggingface dataset:
The safety of sputum induction in adults with acute exacerbation of COPD
Authors: Gao Peng , Gibson Peter G , Zhang Jie , He Xiaoyan , Hao Yuqiu , Li Ping , Liu Huan
Published: March 2012

Introduction:  Induced sputum is a non‐invasive method, and a useful tool to evaluate inflammatory cells and mediators in the airway lumen in the setting of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the inhalation of hypertonic saline solution to induce sputum may cause a bronchoconstrictive response, so it is important to evaluate the success and safety of sputum induction (SI).

Objectives:  The aims of this study were to assess the safety and efficacy of SI in adults with AECOPD.

Methods:  Eighty‐three AECOPD subjects and 26 healthy controls underwent a modified SI. The outcome measures included fall in lung function during induction and success of SI.

Results:  Adults hospitalized with AECOPD had moderate to very severe airflow obstruction. SI was successful in over 80% of subjects. The percentage decrease in forced expiratory volume in 1 s (FEV1) from baseline by the Global initiative for Chronic Obstructive Lung Disease (GOLD) category was median 1.2(interquartile range, 0.5–3.3)(GOLD II), 2.3(1.3–3.2)(GOLD III), 5.2(3.3–8.6)(GOLD IV) and 1.4(0.5–3.2)(control), respectively. A fall in FEV1 of >20% occurred in only one subject with AECOPD who was in GOLD category III. The decrease in percentage of FEV1 from baseline was greatest in the second stage of induction, and correlated with that of the final stage (r = 0.589; P = 0.01). The fall in FEV1 during induction increased with GOLD category (P < 0.05).

Conclusions:  SI can be safely and successfully performed in patients with moderate to very severe chronic obstructive pulmonary disease who experience an exacerbation using this modified induction protocol. The early decrease in FEV1 can be used to predict the maximum fall.

Please cite this paper as: Gao P, Gibson PG, Zhang J, He XY, Hao YQ, Li P and Liu H. The safety of sputum induction in adults with acute exacerbation of COPD. Clin Respir J 2013; 7: 101–109.
Preparedness of the CTSA's Structural and Scientific Assets to Support the Mission of the National Center for Advancing Translational Sciences (NCATS)
Authors:   CTSA Principal Investigators
Published: March 2012

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic science discoveries to clinical practice, ultimately improving the health of the nation. The Clinical and Translational Science Award (CTSA) sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease‐agnostic infrastructure devoted to clinical and translational (C&T) science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support. Clin Trans Sci 2012; Volume #: 1–9
The detection of EGFR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR‐TKI
Authors: Huang Zhen , Wang Zhijie , Bai Hua , Wu Meina , An Tongtong , Zhao Jun , Yang Lu , Duan Jianchun , Zhuo Minglei , Wang Yuyan , Wang Shuhang , Wang Jie
Published: March 2012

Background:  The validity of epidermal growth factor receptor (EGFR) mutation in serum and plasma DNA as a surrogate of tumor tissue has been comprehensively explored. However, the concordance between peripheral blood and tumor tissue samples in EGFR mutation detection remains variable. The question as to whether real‐time samples for EGFR mutation analysis are required before epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) therapy remains unanswered.

Methods:  This study included two cohorts:(i) 822 non‐small cell lung cancer (NSCLC) patients with primary tumor tissue and matched plasma samples at initial diagnosis; and (ii) 207 patients with advanced NSCLC who had plasma samples taken immediately before EGFR‐TKI therapy, in which 157 cases had matched tumor tissues. Denaturing High‐Performance Liquid Chromatography (DHPLC) determined EGFR mutation status.

Results:  Among a total of 822 patients with matched samples, the EGFR mutation rates were 36.3% and 32.1% in tissue and plasma samples, respectively. Concordance of EGFR mutation between two kinds of samples was 77.0% (631/822),with 63.5% (188/296) of accuracy of EGFR mutation in plasma DNA. In 207 advanced NSCLC patients who had plasma samples taken immediately before EGFR‐TKI therapy, the objective response rate (ORR) after EGFR‐TKI therapy was significantly higher in EGFR mutant patients than those in EGFR wild‐type patients (51.4% vs. 22.6%, P < 0.001), regardless of the treatment lines of EGFR‐TKI. In patients with two or more lines of EGFR‐TKI therapy, EGFR mutation status in plasma samples, but not in tissues, was a predictor for progression‐free survival (PFS) after EGFR‐TKI therapy (mutant vs. wild‐type: 10.1 months vs. 3.7 months, P = 0.038).

Conclusions:  An EGFR mutation test using plasma DNA samples was validated and reproducible. Obtaining real‐time samples for EGFR mutation detection is critical in order to predict the outcomes of EGFR‐TKI.
The effect of calcium silicate‐based sealer on the push‐out bond strength of fibre posts
Authors: Özcan E , Çapar İD , Çetin AR , Tunçdemir AR , Aydınbelge HA
Published: March 2012

Background:  The aim of this study was to assess the effect of the iRoot SP root canal sealer on the push‐out bond strength of fibre posts cemented with self‐adhesive resin cement.

Methods:  Forty‐eight extracted maxillary incisors were randomly divided into four groups according to the tested sealer (n = 12): group 1 – control (only gutta‐percha points, no sealer); group 2 – AH Plus Jet (resin‐based sealer); group 3 – Endofill (zinc oxide‐eugenol‐based sealer); and group 4 – iRoot SP (calcium silicate‐based sealer). All root canals were filled with gutta‐percha, and groups 2–4 additionally received one of the sealers. Fibre posts were cemented with the self‐adhesive resin cement Clearfil SA Cement. The specimens were sectioned in the coronal, middle and apical regions, producing three slices of 1 mm thickness. The push‐out test was performed. All data were submitted to ANOVA and Tukey tests (α = 0.05).

Results:  No statistically significant differences were found between the control group, AH Plus Jet and iRoot SP (p > 0.05). The Endofill sealer showed significantly lower bond strength compared to the other sealers and the control group (p < 0.05).

Conclusions:  The calcium silicate‐based sealer did not adversely affect the bond strength of the fibre posts cemented with self‐adhesive resin cement.
Radical surgical treatment of bisphosphonate related osteonecrosis of the jaw
Authors: Hewson I , Syme D , Bruscino‐Raiola F
Published: March 2012

We describe a case of a 64‐year‐old female diagnosed with multiple myeloma in 2001. She was treated with pamidronate and subsequently zolodronic acid before developing spontaneous bisphosphonate related osteonecrosis (BRONJ) of the left maxilla in December 2008. Over the next two years the BRONJ was treated conservatively but gradually became more symptomatic. About three years after her last dose of zolodronic acid with her symptoms increasing, she underwent radical surgical excision of all diseased bone and flap reconstruction. The patient is now six months postoperative and symptom free.
Exendin-4 treatment enhances L-DOPA evoked release of striatal dopamine and decreases dyskinetic movements in the 6-hydoxydopamine lesioned rat
Authors: Abuirmeileh Amjad , Harkavyi Alexander , Rampersaud Nazir , Lever Rebecca , Tadross John A , Bloom Stephen R , Whitton Peter S
Published: March 2012

Objectives

To determine whether the glucagon-like 1 peptide analogue exendin-4 (EX-4) augments the neurochemical effects of a single L-DOPA treatment and whether EX-4 can decrease L-DOPA induced dyskinesias (LIDS).

Methods

Rats were lesioned with 6-hydroxydopamine (6-OHDA) and 7 days later given EX-4 for 7 days. The following day, rats were given L-DOPA and extracellular dopamine was measured. The animals were then killed to determine tissue dopamine. To study LIDS, EX-4 and/or L-DOPA were co-administered daily, 7 days after 6-OHDA. LIDS were determined on Days 2, 4, 8, 12 and 16 prior to neurochemical assessment.

Key findings

EX-4 reduced 6-OHDA induced damage. Acute effects of L-DOPA were potentiated by EX-4 in lesioned rats. Treatments with EX-4 caused a progressive reduction in LIDS.

Conclusions

EX-4 treatment potentiates the effects of a single dose of L-DOPA. This augmentation indicates that lower L-DOPA doses might be used to the same effect in patients. The reduction in LIDS suggests that co-treatment with EX-4 could allow the use of L-DOPA with fewer side-effects and possibly therefore allow earlier introduction of L-DOPA in the clinic.
Antispasmodic effects of a new kaurene diterpene isolated from Croton argyrophylloides on rat airway smooth muscle
Authors: Aguiar Liza Araújo , Porto Romulo Sousa , Lahlou Saad , Ceccatto Vânia Marilande , Barbosa Roseli , Lemos Telma Leda Gomes , dos Santos Hélcio Silva , Coelho-de-Souza Andrelina Noronha , Magalhães Pedro Jorge Caldas , Zin Walter Araújo , Leal-Cardoso José Henrique
Published: March 2012

Objectives

The effects of rel-(1S,4aS,7S,8aS)-7-(1-vinyl)-tetradecahydro-1,4a-dimethylphenanthrene-7,8a-carbolactone-1-carboxylic acid (TCCA), a new ent-kaurene diterpene isolated from Croton argyrophylloides, on rat tracheal preparations were investigated.

Methods

Tracheae were removed and cut into two-cartilage segments that were mounted in organ baths containing Tyrode's solution.

Results

TCCA reduced the contractions induced by electrical field stimulation, relaxed K+-induced contractions, and inhibited both phasic and tonic components of the K+- and ACh-induced contractions. TCCA reduced the serotonin-induced contraction, abolished that evoked by K+ in the presence of epinephrine, and also reduced the ACh-induced contractions under Ca2+-free conditions. TCCA blocked contractions that depend on divalent cation inflow through voltage-operated Ca2+ channels (VOCCs) and receptor-operated Ca2+ channels (ROCCs), but had greater potency to block VOCC- than ROCC-dependent contractions or contractions induced by ACh in Ca2+-free conditions. TCCA relaxed the phorbol 12,13 dibutyrate (1 µm) induced contraction, but with slight potency.

Conclusions

TCCA induces an antispasmodic effect through several mechanisms including blockade of either VOCCs (with greater potency) or ROCCs, blockade of IP3-induced Ca2+ release from sarcoplasmic reticulum (with intermediate potency) and reduction of the sensitivity of contractile proteins to Ca2+.
The role of general cognitive ability in moderating the relation of adverse life events to emotional and behavioural problems
Authors: Flouri Eirini , Mavroveli Stella , Panourgia Constantina
Published: March 2012

Previous studies have established the role of various measures of cognitive functioning in dampening the association between adverse life events (‘life stress’) and adolescents’ emotional and behavioural problems. However, it is not yet clear if general cognitive ability (‘intelligence’) is a protective factor. In this study of 1,175 10‐ to 19‐year‐olds in five secondary schools in England, we explored this issue. We found that even after controlling for sex, age, family poverty, and special educational needs, the association of life stress with emotional, hyperactivity, and conduct problems was significant. General cognitive ability moderated the association between life stress and conduct problems; among adolescents with higher than average general cognitive ability, the association between life stress and conduct problems was non‐significant.
Lactate flux in astrocytes is enhanced by a non‐catalytic action of carbonic anhydrase II
Authors: Stridh Malin H. , Alt Marco D. , Wittmann Sarah , Heidtmann Hella , Aggarwal Mayank , Riederer Brigitte , Seidler Ursula , Wennemuth Gunther , McKenna Robert , Deitmer Joachim W. , Becker Holger M.
Published: March 2012

Key points 

Rapid exchange of metabolites like glucose and lactate between different cell types is crucial for energy supply to the brain.

Carbonic anhydrase 2 (CAII) enhances lactate transport in mouse cerebellar and cerebral astrocytes.

Enhancement of transport activity is independent of the enzyme's catalytic function, but requires binding of CAII to the C‐terminal tail of the monocarboxylate transporter MCT1.

CAII could enhance lactate flux by acting as a ‘proton collecting antenna’ for MCT1.

By this mechanism CAII could enhance transfer of lactate between astrocytes and neurons and thus provide neurons with an increased supply of energy substrate.
Bleaching of mouse rods: microspectrophotometry and suction‐electrode recording
Authors: Nymark S. , Frederiksen R. , Woodruff M. L. , Cornwall M. C. , Fain G. L.
Published: March 2012

Key points 

When photoreceptors in vertebrate retina are exposed to bright light, a significant proportion of the photopigment in the rods can be bleached.

Bleaching produces a desensitization of the visual system that recovers slowly as pigment is slowly regenerated, by a process known as dark adaptation.

Experiments on isolated amphibian rods have revealed some of the features of bleach‐induced desensitization, but such experiments have not so far been possible on mammals.

We now describe an improved method that makes possible the first direct measurements of pigment concentration and rod photoreceptor responses over a wide range of bleaching exposures from isolated cells or pieces of intact mammalian retina.

Our experiments reveal important features of mammalian bleaching adaptation and will now make possible future studies from mouse animal lines containing genetically altered photoreceptor proteins.
Mechanisms of VIP‐induced inhibition of the lymphatic vessel pump
Authors: von der Weid Pierre‐Yves , Rehal Sonia , Dyrda Peter , Lee Stewart , Mathias Ryan , Rahman Mozibur , Roizes Simon , Imtiaz Mohammad S.
Published: March 2012

Key points

Lymphatic pumping is characterized by the ability of collecting lymphatic vessels to contract in a phasic manner to propel lymph. This activity is critical for tissue fluid homeostasis and immune cell transport to lymph nodes.

Vasoactive intestinal peptide (VIP) is a neuro‐immuno‐modulator with anti‐inflammatory properties released by peptidergic nerves and by inflammatory cells patrolling the interstitium and lymph.

Here we report that VIP is present in lymphatic vessels as well as in the lymph and that it potently inhibits lymphatic pumping and hyperpolarizes the lymphatic muscle via stimulation of VPAC2 VIP receptors, activation of protein kinase A and opening of ATP‐sensitive K+ channels.

These results suggest an important role for VIP in inhibiting lymphatic pumping. This process might become critical during inflammation, where it would lead to decreased lymph drainage, oedema formation and compromised immune cell trafficking.
Pressure Transient Flow Forces for Hydraulic Spool Valves
Authors: Manring Noah D. , Zhang Shusen
Published: March 2012

The objective of this paper is to experimentally investigate the significance of the pressure transient flow force acting on hydraulic spool valves. In the past, this flow force effect has been routinely neglected due to its assumed small size. Through analytical and experimental methods, this research shows that flow forces due to pressure transient effects can be comparable in magnitude to the steady flow forces acting on the valve and that the past tradition of neglecting this effect may not always be justified. The paper also shows that the traditional steady flow force model does a fairly good job predicting the steady flow forces on the valve, but more research must be done to develop a good model for pressure transient flow forces.
Robust Control of Formation Dynamics for Autonomous Underwater Vehicles in Horizontal Plane
Authors: Yang Huizhen , Zhang Fumin
Published: March 2012

This paper presents a novel robust controller design for formation control of autonomous underwater vehicles (AUVs). We consider a nonlinear three-degree-of-freedom dynamic model for the horizontal motion of each AUV. By using the Jacobi transform, the horizontal dynamics of AUVs are explicitly expressed as dynamics for formation shape and formation center, and are further decoupled by feedback control. We treat the coupling terms as perturbations to the decoupled system. An H-infinity state feedback controller is designed to achieve robust stability of the closed loop formation and translation dynamics. By incorporating an orientation controller, the formation shape under control converges and the formation center tracks a desired trajectory simultaneously. Simulation results demonstrate the effectiveness of the controllers.
Oxygen Concentration Dynamic Model and Observer-Based Estimation Through a Diesel Engine Aftertreatment System
Authors: Chen Pingen , Wang Junmin
Published: March 2012

Due to the chemical reactions occurring inside the diesel oxidation catalysts (DOCs) and diesel particulate filters (DPFs) that are commonly equipped on diesel engines, the exhaust gas oxygen concentrations considerably vary through the aftertreatment systems. Oxygen concentration in exhaust gas is important for the performance of catalysts such as the NOx conversion efficiencies of the selective catalytic reduction systems and lean NOx traps. Moreover, in the presence of a low-pressure loop exhaust gas recirculation, the exhaust gas oxygen concentration after DPF also influences the in-cylinder combustion. From system control, estimation, and analysis viewpoints, it is thus imperative to have a control-oriented model to describe the oxygen concentration dynamics across the DOC and DPF. In this paper, a physics-based, lumped-parameter, control-oriented DOC–DPF oxygen concentration dynamic model was developed with a multi-objective optimization method and validated with the experimental data obtained on a medium-duty diesel engine equipped with a full suite of aftertreatment systems. Experimental results show that the model can well capture the oxygen dynamics across the diesel engine aftertreatment systems. As an application of the experimentally validated model, an observer was designed to estimate the DOC-out and DPF-out oxygen concentrations in real time. Experimental results show that the estimated states from the proposed observer can converge to the measured signals fastly and accurately.
Precedent-Free Fault Isolation in a Diesel Engine Exhaust Gas Recirculation System
Authors: Cholette Michael E. , Djurdjanovic Dragan
Published: March 2012

In this paper, a recently introduced model-based method for precedent-free fault detection and isolation (FDI) is modified to deal with multiple input, multiple output (MIMO) systems and is applied to an automotive engine with exhaust gas recirculation (EGR) system. Using normal behavior data generated by a high fidelity engine simulation, the growing structure multiple model system (GSMMS) approach is used to construct dynamic models of normal behavior for the EGR system and its constituent subsystems. Using the GSMMS models as a foundation, anomalous behavior is detected whenever statistically significant departures of the most recent modeling residuals away from the modeling residuals displayed during normal behavior are observed. By reconnecting the anomaly detectors (ADs) to the constituent subsystems, EGR valve, cooler, and valve controller faults are isolated without the need for prior training using data corresponding to particular faulty system behaviors.
Computational Fluid Dynamics-Based Design Optimization for an Implantable Miniature Maglev Pediatric Ventricular Assist Device
Authors: Wu Jingchun , Antaki James F. , Verkaik Josiah , Snyder Shaun , Ricci Michael
Published: March 2012

Computational fluid dynamics (CFD)-based design optimization was applied to achieve the finalized design of the PediaFlow® PF4, a magnetically levitated rotodynamic pediatric ventricular assist device. It features a streamlined blood-flow path with a single annular fluid passage between the rotor and the stationary housing. The resulting impeller is composed of a first-stage mixed-flow section having four blades at the conical nose region followed by a second-stage fully axial-flow section with three blades within the annular gap region. A stator with three inwardly-directed vanes is provided at the conical tail region to recover pressure and straighten the flow. CFD predictions of head and efficiency characteristics agreed remarkably well with the validation experimental data: with overprediction of head by <7 mmHg over the entire operational range and a slight overprediction in best efficiency by ∼1%. The new optimized PF4 extended the maximum flow range of the previous PF3 device by more than 100% to over 2.3 liter per minute (LPM) for the same range of operating speeds, and doubled the maximum hydraulic efficiency to ∼27%. Evaluation of hemolysis was performed by a Lagrangian particle-tracking technique with analysis of regional contributions to the overall blood damage. The simulation revealed that hemolysis increases with an increase in both the flow rate and rotor speed but not necessarily with just an increase in flow rate at a constant rotor speed. At the flow rate of 1.0 LPM and a head of 138 mmHg, PF4 has a hemolysis index of 0.0032 compared to 0.0058 produced by PF3 at the same flow rate with a head of 48 mmHg. Numerical simulation of radial fluid forces performed by the CFD model with an eccentric rotor revealed the presence of negative fluid stiffness that was monotonically related to both flow and speed. Finally, conjugate heat transfer analysis predicted temperature rise adjacent to the motor to be inversely proportional to the length, but not exceeding ∼2 °C over the intended range of operation. In conclusion, CFD-based design optimization greatly expedited and facilitated the completion of the PediaFlow® flow path and contributed to the system-wide optimization to produce a miniature maglev pump with exceptional hemocompatibility.
An Experimental Study of Horizontal Self-Excited Pneumatic Conveying
Authors: Yan Fei , Rinoshika Akira
Published: March 2012

A new pneumatic conveying system that applies soft fins mounted vertically on a center plane of pipe in the inlet of the gas-particle mixture is developed to reduce power consumption and conveying velocity. The effect of different fin’s lengths on a horizontal pneumatic conveying is experimentally studied in terms of the pressure drop, conveying velocity, power consumption, particle flow pattern, and additional pressure drop. The test pipeline consisted of a horizontal smooth acrylic tube with an inside diameter of 80 mm and a length of about 5 m. Two kinds of polyethylene particles with diameters of 2.3 mm and 3.3 mm are used as conveying materials. The superficial air velocity is varied from 10 to 17 m/s, and the solid mass flow rate is from 0.20 to 0.45 kg/s. Compared with conventional pneumatic conveying, the pressure drop, minimum and critical velocities, power consumption, and additional pressure drop can be reduced by using soft fins in a lower air velocity range, and the efficiency of fins becomes more evident when increasing the length of the fins or touching particles stream by the long fins. The maximum reduction rates of the minimum velocity and power consumption by using soft fins are about 20% and 31.5%, respectively. The particle concentrations of using fins are lower than those of non-fin near the bottom of the pipe and are higher than those of non-fin in the upper part of the pipe in the acceleration region. Based on analyzing the frequency features of the fin’s oscillation, the Strouhal number of more efficient fins is about St ≈ 0.75 in the air velocity range of lower than 13 m/s.
The Influence of Lattice Misfit on the Atomic Structures and Defect Energetics of Face Centered Cubic–Body Centered Cubic Interfaces
Authors: Liu X.-Y. , Hoagland R. G. , Demkowicz M. J. , Nastasi M. , Misra A.
Published: March 2012

Using “tunable” interatomic potentials, the lattice misfits for a fcc–bcc metal system have been varied in atomistic models, while keeping other properties essentially unchanged. The procedure and the fitting results of such tunable interatomic potentials for fcc–bcc systems are presented. Varying lattice misfits were found to significantly alter the atomic structure of fcc–bcc interfaces in Kurdjumov–Sachs crystallographic orientation. Defect formation energies at the interfaces were calculated. For vacancies, in general, high numbers of low energy sites are associated with high dislocation junction densities. For interstitials, the formation energies are all substantially below the bulk value, regardless of lattice misfits. These results are relevant to understanding the sink strength of interfaces with different atomic structures.
A Microstructure and Microhardness Characterization of a Friction Plug Weld in Friction Stir Welded 2195 Al-Li
Authors: Metz D. F. , Weishaupt E. R. , Barkey M. E. , Fairbee B. S.
Published: March 2012

In this study, extruded 2195-T8 plugs that were friction welded into the friction stir weld of 2195-T8 base metal plates were examined. This study characterizes the resulting microstructure and microhardness of the plug weld interfaces with the friction stir welded material and base metal in an effort to identify the extent of the thermal, thermomechanical, and mechanical effects introduced by the friction plug welding process. A zone of recrystallized material was observed around the plug weld circumference. The thickness of the recrystallized layer was measured to be 30–122 μm. The hardness measured near the plug weld interface was found to be 110–130 HK100g, or approximately 35% less than the base metal hardness. By characterizing the hardness of these zones, insight can be gathered into the transformation of material from the friction plug welding process around the fusion zone, and areas that may control the fatigue behavior of the joint.
New Tensors for Anisotropic Damage in Continuum Damage Mechanics
Authors: Voyiadjis George Z. , Yousef Mohammed A. , Kattan Peter I.
Published: March 2012

In this work, new proposed damage tensors are studied in order to investigate the damage effect variables in the mechanical behavior of materials. All cases studied in this work are defined in terms of the elasticity of the material and based on the hypotheses of both elastic strain equivalence and elastic energy equivalence. Moreover, the new proposed damage tensors are anisotropically expressed in terms of the well-known damage effect tensor M. The principal-valued damage effect tensor is used to obtain the first scalar invariant of that tensor and its inverse, which are employed in expressing and verifying the new proposed damage tensors. The study demonstrates that most of the new proposed damage tensors are verified within the framework of continuum damage mechanics. In addition, new hybrid damage tensors are proposed which are defined in terms of the damage effect tensor and the new proposed damage tensors. The new hybrid damage tensors are eventually expressed in terms of the damage effect tensor.
Temperature Dependent Elastic Constants of Directionally Solidified Superalloys
Authors: Kuo Chen-Ming
Published: March 2012

Directionally solidified superalloys have been extensively used as turbine blade materials to improve creep-rupture and thermal fatigue performances. Turbine blades are subjected to fluctuant temperature changes. Precise knowledge of material behavior at various temperatures is essential in design and service life evaluation of turbine blades. In this study, coaxial model is extended to consider temperature dependent engineering elastic constants. Although no existing theory predicts the temperature dependence engineering elastic constants over large range of temperature, these constants could be estimated based upon very limited experimental data of direction solidification specimens and other temperature dependent materials data. Excellent agreement is observed between estimations and experimental data of 45 deg and 90 deg off directionally solidified direction specimens.
Degradation of dc characteristics of InAlN/GaN high electron mobility transistors by 5 MeV proton irradiation
Authors: Lo Chien-Fong , Liu L. , Kang T. S. , Ren Fan , Schwarz C. , Flitsiyan E. , Chernyak L. , Kim Hong-Yeol , Kim Jihyun , Pil Yun Sang , Laboutin O. , Cao Y. , Johnson J. W. , Pearton S. J.
Published: March 2012

The dc characteristics of InAlN/GaN high electron mobility transistors were measured before and after irradiation with 5 MeV protons at doses up to 2 × 1015 cm−2. The on/off ratio degraded by two orders of magnitude for the highest dose, while the subthreshold slope increased from 77 to 122 mV/decade under these conditions. There was little change in transconductance or gate or drain currents for doses up to 2 × 1013 cm−2, but for the highest dose the drain current and transconductance decreased by ∼40% while the reverse gate current increased by a factor of ∼6. The minority carrier diffusion length was around 1 μm independent of proton dose. The InAlN/GaN heterostructure is at least as radiation hard as its AlGaN/GaN counterpart.
Science Signaling
Podcast: 27 March 2012
Authors: Glass David J. , VanHook Annalisa M.
Published: March 2012

Regulated protein synthesis and degradation mediate skeletal muscle homeostasis.
Phospholipase D and mTORC1: Nutrients Are What Bring Them Together
Authors: Wiczer Brian M. , Thomas George
Published: March 2012

Activation of PLD1 by amino acids enables mTORC1 to respond to nutrient abundance.
Focus Issue: TOR Signaling, a Tale of Two Complexes
Authors: Gough Nancy R.
Published: March 2012

This issue highlights developments in the regulation and physiological importance of the signaling network associated with the kinase TOR.
Remembering Stressful Events
Authors: Stern Peter R.
Published: March 2012

The infusion of a stress hormone produces fear responses to cues that were not associated with the traumatic event itself.
Btk Keeps Neutrophils Under Control
Authors: Foley John F.
Published: March 2012

The Tec kinase Btk holds the production of reactive oxygen species by neutrophils in check.
Class A Carbapenemase FPH-1 from Francisella philomiragia
Authors: Toth Marta , Vakulenko Viktoria , Antunes Nuno T. , Frase Hilary , Vakulenko Sergei B.
Published: March 2012

FPH-1 is a new class A carbapenemase from
Francisella philomiragia
. It produces high-level resistance to penicillins and the narrow-spectrum cephalosporin cephalothin and hydrolyzes these β-lactam antibiotics with catalytic efficiencies of 10
6
to 10
7
M
−1
s
−1
. When expressed in
Escherichia coli
, the enzyme confers resistance to clavulanic acid, tazobactam, and sulbactam and has

K
i

values of 7.5, 4, and 220 μM, respectively, against these inhibitors. FPH-1 increases the MIC of the monobactam aztreonam 256-fold and the MIC of the broad-spectrum cephalosporin ceftazidime 128-fold, while the MIC of cefoxitin remains unchanged. MICs of the carbapenem antibiotics imipenem, meropenem, doripenem, and ertapenem are elevated 8-, 8-, 16-, and 64-fold, respectively, against an
E. coli
JM83 strain producing the FPH-1 carbapenemase. The catalytic efficiencies of the enzyme against carbapenems are in the range of 10
4
to 10
5
M
−1
s
−1
. FPH-1 is 77% identical to the FTU-1 β-lactamase from
Francisella tularensis
and has low amino acid sequence identity with other class A β-lactamases. Together with FTU-1, FPH-1 constitutes a new branch of the prolific and ever-expanding class A β-lactamase tree.
NDM-1-Producing Klebsiella pneumoniae Resistant to Colistin in a French Community Patient without History of Foreign Travel
Authors: Arpin Corinne , Noury Patrick , Boraud Delphine , Coulange Laure , Manetti Alain , André Catherine , M'Zali Fatima , Quentin Claudine
Published: March 2012

A carbapenem-resistant
Klebsiella pneumoniae
strain, Kp5196, was responsible for an uncomplicated cystitis in a patient living at home and without history of foreign travel. This isolate produced the metallocarbapenemase NDM-1 and was resistant to all antibiotics except tetracyclines and colistin. The
K. pneumoniae
strain belonged to sequence type ST15, and
bla
NDM-1
was carried by a nontypeable conjugative plasmid. Two months later, a similar ST15 isolate, Kp5241, was present in the patient but was additionally colistin resistant.
Dissemination of pCT-Like IncK Plasmids Harboring CTX-M-14 Extended-Spectrum β-Lactamase among Clinical Escherichia coli Isolates in the United Kingdom
Authors: Dhanji Hiran , Khan Parmina , Cottell Jennifer L. , Piddock Laura J. V. , Zhang Jiancheng , Livermore David M. , Woodford Neil
Published: March 2012

IncK plasmids encoding CTX-M-14 extended-spectrum β-lactamase (ESBL) and highly related to plasmid pCT were detected in 13 of 67 (19%) human clinical isolates of
Escherichia coli
with a group 9 CTX-M-type ESBL from the United Kingdom and in 2 quality assurance isolates. None of these
E. coli
strains was related to the cattle strain from which pCT was originally characterized.
Scaling Adult Doses of Antifungal and Antibacterial Agents to Children
Authors: Dawson Thomas H.
Published: March 2012

My general pharmacokinetic scaling theory is discussed for the important matter of determining pediatric dosing for existing and new therapeutic drugs when optimal, or near-optimal, dosing for adults is known. The basis for the scaling is the requirement of a time-scaled likeness of the free-drug concentration time histories of children and adults. Broad categories of single and periodic dosing are considered. The former involves the scaling of dosage, and the latter involves both the dosage and schedule. The validity of the scaling relations is demonstrated by using measurements from previously reported clinical trials with adults and children (with ages generally 1 year or older) for the relatively new antifungal agent caspofungin and for the relatively new antibacterial agent linezolid. Standard pharmacodynamic effectiveness criteria are shown to be satisfied for the scaled dosage and schedule for children to the same extent that they are for the referenced adult. Consideration of scaling from adults to children is discussed for the case of new agents where no pediatric data are available and needed parameters are determined fromin vitromeasurements and preclinical animal data. A connection is also made between the allometric representation of clearance data and the dosing formulas. Limitations of the scaling results for infants because of growth and maturational matters are discussed. The general conclusion from this work is that the scaling theory does indeed have application to pediatric dosing for children, for both confirmation and refinement of present practice and guidance in pediatric treatment with new therapeutic agents.
Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method
Authors: Moreira da Silva Rodrigo , Oliveira Líliam Teixeira , Silva Barcellos Neila Márcia , de Souza Jacqueline , de Lana Marta
Published: March 2012

A combination of drugs in experimental chemotherapy of Chagas' disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (
C
max
) and an increase of 2.66-fold in the volume of distribution (
V
) and 7.5-fold in the elimination half-life (
t
1/2β
) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC

0-
t

), area under the curve extrapolated to infinity (AUC
0-∞
), time to maximum concentration of drug in serum (
T
max
), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole against
Trypanosoma cruzi in vivo
.
Safety and Tolerability of Voriconazole in Patients with Baseline Renal Insufficiency and Candidemia
Authors: Oude Lashof A. M. L. , Sobel J. D. , Ruhnke M. , Pappas P. G. , Viscoli C. , Schlamm H. T. , Rex J. H. , Kullberg B. J.
Published: March 2012

Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.
Multidrug-Resistant Proteus mirabilis Bloodstream Infections: Risk Factors and Outcomes
Authors: Tumbarello Mario , Trecarichi Enrico Maria , Fiori Barbara , Losito Angela Raffaella , D'Inzeo Tiziana , Campana Lara , Ruggeri Alberto , Di Meco Eugenia , Liberto Elvira , Fadda Giovanni , Cauda Roberto , Spanu Teresa
Published: March 2012

Our aims were to identify (i) risk factors associated with the acquisition of multidrug-resistant (MDR, to 3 or more classes of antimicrobials)
Proteus mirabilis
isolates responsible for bloodstream infections (BSIs) and (ii) the impact on mortality of such infections. Risk factors for acquiring MDR
P. mirabilis
BSIs were investigated in a case-case-control study; those associated with mortality were assessed by comparing survivors and nonsurvivors in a cohort study. The population consisted of 99 adult inpatients with
P. mirabilis
BSIs identified by our laboratory over an 11-year period (1999 to 2009), 36 (33.3%) of which were caused by MDR strains, and the overall 21-day mortality rate was 30.3%. Acquisition of an MDR strain was independently associated with admission from a long-term care facility (odds ratio [OR], 9.78; 95% confidence interval [CI], 1.94 to 49.16), previous therapy with fluoroquinolones (OR, 5.52; 95% CI, 1.30 to 23.43) or oxyimino-cephalosporins (OR, 4.72; 95% CI, 1.31 to 16.99), urinary catheterization (OR, 3.89; 95% CI, 1.50 to 10.09), and previous hospitalization (OR, 2.68; 95% CI, 10.4 to 6.89). Patients with MDR
P. mirabilis
BSIs received inadequate initial antimicrobial therapy (IIAT, i.e., treatment with drugs to which the isolate displayed
in vitro
resistance) more frequently than those with non-MDR infections; they also had increased mortality and (for survivors) longer post-BSI-onset hospital stays. In multivariate regression analysis, 21-day mortality was associated with septic shock at BSI onset (OR, 12.97; 95% CI, 32.2 to 52.23),
P. mirabilis
isolates that were MDR (OR, 6.62; 95% CI, 16.4 to 26.68), and IIAT (OR, 9.85; 95% CI, 26.7 to 36.25), the only modifiable risk factor of the 3. These findings can potentially improve clinicians' ability to identify
P. mirabilis
BSIs likely to be MDR, thereby reducing the risk of IIAT—a major risk factor for mortality in these cases—and facilitating the prompt implementation of appropriate infection control measures.
Involvement of the Lon Protease in the SOS Response Triggered by Ciprofloxacin in Pseudomonas aeruginosa PAO1
Authors: Breidenstein Elena B. M. , Bains Manjeet , Hancock Robert E. W.
Published: March 2012

Pseudomonas aeruginosa
PAO1
lon
mutants have phenotypes of deficiencies in cell division, swarming, twitching, and biofilm formation as well as a phenotype of ciprofloxacin supersusceptibility. In this study, we demonstrated that a
lon
mutant was also supersensitive to the DNA-damaging agent UV light. To understand the influence of
lon
in causing these phenotypes, global gene expression was characterized by performing microarrays on the
lon
mutant and the PAO1 wild type grown in the presence of subinhibitory concentrations of ciprofloxacin. This revealed major differences in the expression of genes involved in the SOS response and DNA repair. Real-time quantitative PCR confirmed that these genes were highly upregulated upon ciprofloxacin exposure in the wild type but were significantly less induced in the
lon
mutant, indicating that Lon modulates the SOS response and consequentially ciprofloxacin susceptibility. As the known Lon target SulA is a member of the SOS response regulon, the influence of mutating or overexpressing this gene, and the negative regulator of the SOS response, LexA, was examined. Overexpression of
lexA
had no effect on the Lon-related phenotypes, but
sulA
overexpression recapitulated certain
lon
mutant phenotypes, including altered motility and cell division, indicating that Lon regulates these phenotypes through SulA. However,
sulA
overexpression did not affect ciprofloxacin susceptibility or biofilm formation, indicating that these properties were independently determined. Lon protease was also demonstrated to strongly influence RecA protein accumulation in the presence of ciprofloxacin. A model of DNA repair involving the Lon protease is proposed.
Efficacy of Ceftobiprole Medocaril against Enterococcus faecalis in a Murine Urinary Tract Infection Model
Authors: Singh Kavindra V. , Murray Barbara E.
Published: March 2012

We evaluated ceftobiprole against the well-characterized
Enterococcus faecalis
strain OG1RF (with and without the β-lactamase [Bla] plasmid pBEM10) in a murine urinary tract infection (UTI) model. Ceftobiprole was equally effective for Bla
+
and Bla
−
OG1 strains, while ampicillin was moderately to markedly (depending on the inoculum) less effective against Bla
+
than Bla
−
OG1 strains. These data illustrate an
in vivo
effect on ampicillin of Bla production by
E. faecalis
and the stability and efficacy of ceftobiprole in experimental UTI.
Broad Phenotypic Cross-Resistance to Elvitegravir in HIV-Infected Patients Failing on Raltegravir-Containing Regimens
Authors: Garrido Carolina , Villacian Jorge , Zahonero Natalia , Pattery Theresa , Garcia Federico , Gutierrez Felix , Caballero Estrella , Van Houtte Margriet , Soriano Vincent , de Mendoza Carmen
Published: March 2012

The failure of raltegravir (RAL) is generally associated with the selection of mutations at integrase position Y143, Q148, or N155. However, a relatively high proportion of failures occurs in the absence of these changes. Here, we report the phenotypic susceptibilities to RAL and elvitegravir (EVG) for a large group of HIV-infected patients failing on RAL-containing regimens. Plasma from HIV-infected individuals failing on RAL-containing regimens underwent genotypic and phenotypic resistance testing (Antivirogram v2.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2.5 (interquartile range [IQR], 2.1 to 3.1). Fourteen samples from patients with RAL failures showed diminished RAL susceptibility, with a median FC of 38.5 (IQR, 10.8 to 103.2). Primary integrase resistance mutations were found in 11 of these samples, displaying a median FC of 68.5 (IQR, 23.5 to 134.3). The remaining 3 samples showed a median FC of 2.5 (IQR, 2 to 2.7). EVG susceptibility was diminished in 19/40 samples from patients with RAL failures (median FC, 7.71 [IQR, 2.48 to 99.93]). Cross-resistance between RAL and EVG was high (R2= 0.8;P< 0.001), with drug susceptibility being more frequently reduced for EVG than for RAL (44.3% versus 24.6%;P= 0.035). Susceptibility to RAL and EVG is rarely affected in the absence of primary integrase resistance mutations. There is broad cross-resistance between RAL and EVG, which should preclude their sequential use. Resistance to EVG seems to be more frequent and might be more influenced by integrase variability.
The Aminopeptidase Inhibitor CHR-2863 Is an Orally Bioavailable Inhibitor of Murine Malaria
Authors: Skinner-Adams Tina S. , Peatey Christopher L. , Anderson Karen , Trenholme Katharine R. , Krige David , Brown Christopher L. , Stack Colin , Nsangou Desire M. M. , Mathews Rency T. , Thivierge Karine , Dalton John P. , Gardiner Donald L.
Published: March 2012

Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an ever-increasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria.