bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomised controlled crossover trial of the effect on Ptco2of oxygen-driven versus air-driven nebulisers in severe chronic obstructive pulmonary disease
Authors: Edwards Llifon , Perrin Kyle , Williams Mathew , Weatherall Mark , Beasley Richard
Published: December 2011

Background

The comparative safety of oxygen versus air-driven nebulised bronchodilators in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) is uncertain. A randomised controlled trial was performed to assess the effect on the arterial partial pressure of carbon dioxide of nebulised bronchodilator driven with oxygen versus air in stable severe COPD.

Methods

In an open label randomised study, 18 subjects with stable severe COPD attended on 2 days to receive nebulised bronchodilator therapy driven by air or oxygen. Subjects received 5 mg salbutamol and 0.5 mg ipratropium bromide by nebulisation over 15 min, then, after 5 min, 5 mg salbutamol nebulised over 15 min, followed by 15 min of observation. Transcutaneous carbon dioxide tension (Ptco2) and oxygen saturations were recorded at 5 min intervals during the study. The primary outcome was the Ptco2after the completion of the second bronchodilator treatment.

Results

Ptco2was higher with nebulised bronchodilator therapy delivered by oxygen, but decreased back to the level associated with air nebulisation 15 min after completion of the second nebulised dose. One subject experienced an increase in Ptco2of 11 mm Hg after the first bronchodilator nebulisation driven by oxygen. The mean Ptco2difference between the oxygen and air groups after the second nebulisation was 3.1 mm Hg (95% CI 1.6 to 4.5, p<0.001).

Conclusion

Nebulisers driven with oxygen result in significantly higher levels of Ptco2than those driven with air in patients with severe COPD.

Clinical trial registration number

The study was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12610000080022).
Emergency triage, assessment and treatment at a district hospital in Malawi
Authors: Harrison Hooi-Ling , Raghunath Nigel , Twomey Michele
Published: December 2011

Rumphi District Hospital in Northern Malawi had no emergency triage, assessment or treatment system for the over 5 year olds. Eighty healthcare workers were trained on the South African Triage Scale, which was then implemented within a modified outpatient department. Provision of medical equipment and construction of an emergency room took place to allow early life saving treatment.
MULTIFUNCTIONAL CMOS STRUCTURE WITH IMPROVED LINEARITY
Authors: POPA COSMIN
Published: December 2011

An original low-power low-voltage multifunctional structure with improved performances will be further presented, allowing to implement (with minor changes in the design) four important functions: the signal gain with theoretical null distortions, voltage multiplying with very good linearity and simulation of a perfect linear resistor with both positive and negative equivalent resistance. The linearity will be strongly increased by implementing original techniques, while the silicon occupied area per function will be reduced as a result of the circuit multifunctionality. The structure is implemented in 0.35 μm CMOS technology and is supplied at ±3 V. The circuit presents a very good linearity (THD < 0.1% for differential amplifier and active resistors and THD < 0.15% for multiplier), correlated with an extended range of the input voltage (-1.5 V < v1 - v2 < 1.5 V ). The tuning range of the active resistor is about 100kΩ – 1.5MΩ. The second-order effects are also considered, being proposed an original technique based on an anti-parallel connection for compensating the linearity degradation introduced by these effects.
HIGH-SLEW RATE LOW-QUIESCENT CURRENT RAIL-TO-RAIL CMOS BUFFER AMPLIFIER FOR FLAT PANEL DISPLAYS
Authors: YILDIZ MERIH , MINAEI SHAHRAM , ARSLAN EMRE
Published: December 2011

This work presents a high-slew rate rail-to-rail buffer amplifier, which can be used for flat panel displays. The proposed buffer amplifier is composed of two transconductance amplifiers, two current comparators and a push-pull output stage. Phase compensation technique is also used to improve the phase margin value of the proposed buffer amplifier for different load capacitances. Post-layout simulations of the proposed buffer amplifier are performed using 0.35 μm AMS CMOS process parameters and 3.3 V power supply. The circuit is tested under a 600 pF capacitive load. An average settling time of 0.85 μs under a full voltage swing is obtained, while only 3 μA quiescent current is drawn from the power supply. Monte Carlo analysis is also added to show the process variation effects on the circuit.
MODELING OF EDDY CURRENT LOSS AND TEMPERATURE OF THE MAGNETS IN PERMANENT MAGNET MACHINES
Authors: DING XIAOFENG , MI CHRIS
Published: December 2011

The eddy current loss in the magnets of permanent magnet (PM) motors in a hybrid electric vehicle (HEV) and plug-in HEV is usually not taken into consideration in traditional motor design and analysis. However, due to the high conductivity of the rare-earth magnet, neodymium-iron-boron (NdFeB), and slot/tooth harmonics, there is eddy current loss generated inside the magnets. This loss may not attribute very much to the efficiency of the motor, but the temperature-rise inside the magnets caused by this loss can lead to the unpredictable deterioration of the magnets, such as the degradation of performance and potential demagnetization. In addition, the output voltage of pulse-width-modulated (PWM) inverter contains abundant high frequency harmonics, which induce excessive loss in the magnets. The excessive heat in PM motor induced by the eddy current loss combined with other losses can degrade the performance of the machine. This paper presents the modeling and analysis of eddy current loss in surface-mounted-magnets PM synchronous motors (SPMSM) and interior-magnets PM synchronous motors (IPMSM), operated by PWM inverter supply. Analytical methods are implemented, in conjunction with time-stepped finite-element analysis (FEA) for the calculation of eddy current loss in the magnet. Based on the calculated losses in the machines, simplified analytical models are developed as thermal circuits with network of interconnected nodes, thermal resistances and heat sources representing the heat processes within the SPMSM and IPMSM, to predict the temperature of the magnets. The predicted machine temperatures are found to be consistent with the experimental measurement.
AN EFFECTIVE TEST ALGORITHM AND DIAGNOSTIC IMPLEMENTATION FOR EMBEDDED STATIC RANDOM ACCESS MEMORIES
Authors: CHEN ZE-WANG , SU JIAN-HUA , WANG YOU-REN
Published: December 2011

An effective test algorithm and built-in self-test (BIST) with diagnostic support for embedded static random access memories (SRAM) is proposed. This work focuses on implementing the algorithm using the BIST with diagnostic support for a 64 × 8 bit embedded SRAM. The algorithm can locate and identify all the target faults in SRAM. The BIST with diagnostic support is realized by programming using very high speed integrated circuit hardware description language codes and proved very valuable for diagnosing the target faults. When analyzing experimental results, the fault dictionary is constructed from the simulated responses under the given test algorithm and fault models. The fault dictionary shows that the algorithm has a completely diagnostic ratio.
ANALYTICAL MODELING OF OVERSHOOTING EFFECT IN SUB-100 nm CMOS INVERTERS
Authors: BISDOUNIS LABROS
Published: December 2011

Modeling of CMOS inverters and consequently, CMOS gates, is a critical task for improving accuracy and speed of simulation in modern sub-100 nm digital circuits. One of the key factors that determine the operation of a CMOS structure is the influence of the input-to-output coupling capacitance, also called overshooting effect. In this paper, an analytical model for this effect is presented, that computes the time period which is necessary to eliminate the extra output charge transferred through the input-to-output capacitance at the beginning of the switching process in a CMOS inverter. In addition, the maximum or minimum output voltage (depending on the considered edge) is analytically computed. The derived model is based on analytical expressions of the CMOS inverter output voltage waveform, which include the influences of both transistor currents and the input-to-output (gate-to-drain) coupling and load capacitances. An accurate version of the alpha-power law MOSFET model is used to relate the terminal voltages to the drain current in sub-100 nm devices, with an extension for varying transistor widths. The resulting model also accounts for the influences of input voltage transition time, transistors' sizes, as well as device carrier velocity saturation and narrow-width effects. The results produced by the presented model for three sub-100 nm CMOS technologies, several input voltage transition times, capacitive loads and device sizes, show very good agreement with BSIM4 HSPICE simulations.
ROBUSTNESS OF DIFFERENT INDICATORS OF QUANTUMNESS IN THE PRESENCE OF DISSIPATION
Authors: GIORGI GIAN LUCA , GALVE FERNANDO , ZAMBRINI ROBERTA
Published: December 2011

The dynamics of a pair of coupled harmonic oscillators in separate or common thermal environments is studied, focusing on different indicators of quantumness, such as entanglement, twin oscillators correlations, and quantum discord. We compare their decay under the effect of dissipation and show, through a phase diagram, that entanglement is more likely to survive asymptotically than twin oscillators correlations.
QUANTUMNESS OF CORRELATIONS AND ENTANGLEMENT
Authors: USHA DEVI A. R. , RAJAGOPAL A. K. , SUDHA
Published: December 2011

Generalized measurement schemes on one part of bipartite states, which would leave the set of all separable states insensitive are explored here to understand quantumness of correlations in a more general perspective. This is done by employing linear maps associated with generalized projective measurements. A generalized measurement corresponds to a quantum operation mapping a density matrix to another density matrix, preserving its positivity, hermiticity, and trace class. The positive operator valued measure (POVM) — employed earlier in the literature to optimize the measures of classical/quantum correlations — correspond to completely positive (CP) maps. The other class, the not completely positive (NCP) maps, are investigated here, in the context of measurements, for the first time. It is shown that such NCP projective maps provide a new clue to the understanding of quantumness of correlations in a general setting. Especially, the separability–classicality dichotomy gets resolved only when both the classes of projective maps (CP and NCP) are incorporated as optimizing measurements. An explicit example of a separable state — exhibiting nonzero quantum discord, when possible optimizing measurements are restricted to POVMs — is reexamined with this extended scheme incorporating NCP projective maps to elucidate the power of this approach.
ENTANGLED IDENTICAL PARTICLES AND NOISE
Authors: ARGENTIERI G. , BENATTI F. , FLOREANINI R. , MARZOLINO U.
Published: December 2011

For systems of identical Bosons, it is necessary to reformulate the notions of separability and entanglement in algebraic terms shifting the emphasis from the particle aspect of first quantization to the mode description typical of second quantization. Within this new framework, we show that, unlike for systems consisting of distinguishable qubits, negativity is an exhaustive bipartite entanglement witness for systems with fixed number of Bosons; further, we investigate the impact of dephasing noise in relation to the use of such many-body Bosonic systems in metrological applications.
DYNAMICS OF QUANTUM CORRELATIONS OF TWO INTERFERING BIPARTITE GAUSSIAN STATES
Authors: OLIVARES STEFANO
Published: December 2011

We address the interference of a pair of two-mode Gaussian states, interacting pairwise through a beam-splitter Hamiltonian. In the framework of a suitable phase-space analysis, the correlations generated through the interaction are studied by considering a quantity proportional to the variance of difference between the detected photocurrents of all the possible couples of modes. We use this quantity to demonstrate the invariance through the interaction and the correlations swapping also in the presence of nonideal photodetection.
DYNAMICS AND EXTRACTION OF QUANTUM DISCORD IN A MULTIPARTITE OPEN SYSTEM
Authors: BELLOMO B. , COMPAGNO G. , LO FRANCO R. , RIDOLFO A. , SAVASTA S.
Published: December 2011

We consider a multipartite system consisting of two noninteracting qubits each embedded in a single-mode leaky cavity, in turn connected to an external bosonic reservoir. Initially, we take the two qubits in an entangled state while the cavities and the reservoirs have zero photons. We investigate, in this six-partite quantum system, the transfer of quantum discord from the qubits to the cavities and reservoirs. We show that this transfer also occurs when the cavities are not entangled. Moreover, we discuss how quantum discord can be extracted from the cavities and transferred to distant systems by traveling leaking photons, using the input–output theory.
THEORETICAL AND EXPERIMENTAL ASPECTS OF QUANTUM DISCORD AND RELATED MEASURES
Authors: CÉLERI LUCAS C. , MAZIERO JONAS , SERRA ROBERTO M.
Published: December 2011

Correlations are a very important tool in the study of multipartite systems, for both classical and quantum ones. The discussion about the quantum nature of correlations permeates Physics since Einstein, Podolski and Rosen published their famous article criticizing quantum mechanics. Here, we provide a short review about the quantum nature of correlations, discussing both its theoretical and experimental aspects. We focus on quantum discord and related measures. After discussing their fundamental aspects (theoretically and experimentally), we proceed by analysing the dynamical behavior of correlations under decoherence as well as some applications in different scenarios, such as quantum computation and relativity, passing through critical and biological systems.
ON BELL INEQUALITY VIOLATIONS WITH HIGH-DIMENSIONAL SYSTEMS
Authors: DADA ADETUNMISE C. , ANDERSSON ERIKA
Published: December 2011

Quantum correlations resulting in violations of Bell inequalities have generated a lot of interest in quantum information science and fundamental physics. In this paper, we address some questions that become relevant in Bell-type tests involving systems with local dimension greater than 2. For CHSH-Bell tests within 2D subspaces of such high-dimensional systems, it has been suggested that experimental violation of Tsirelson's bound indicates that more than 2D entanglement was present. We explain that the overstepping of Tsirelson's bound is due to violation of fair sampling, and can in general be reproduced by a separable state, if fair sampling is violated. For a class of Bell-type inequalities generalized to d-dimensional systems, we then consider what level of violation is required to guarantee d-dimensional entanglement of the tested state, when fair sampling is satisfied. We find that this can be used as an experimentally feasible test of d-dimensional entanglement for up to quite high values of d.
Multiple photosynthetic reaction centers composed of supramolecular assemblies of a zinc porphyrin dendrimer with pyridylnaphthalenediimide
Authors: Fukuzumi Shunichi , Ohkubo Kei , Saito Kenji , Kashiwagi Yukiyasu , Khoury Tony , Crossley Maxwell J.
Published: December 2011

Multiple photosynthetic reaction centers have successfully been constructed using a supramolecular complex of zinc porphyrin dendrimer [D(ZnP)16] with pyridylnaphthalenediimide (PyNIm) in benzonitrile. The apparent formation constant determined from the fluorescence quenching of the singlet excited state of porphyrin moieties by PyNIm is significantly larger than that determined from the UV-vis spectral change. This indicates that efficient energy migration occurs between the porphyrin units of the dendrimer prior to the electron transfer from the singlet excited state of zinc porphyrin to PyNIm. The charge-separated (CS) state has been successfully detected as the transient absorption spectrum in the laser flash photolysis. The CS lifetime of in the supramolecular complex of D(ZnP)16 with PyNIm was determined to be 0.83 ms at 298 K.
GUIDED NANOSTRUCTURES USING ANODIZED ALUMINUM OXIDE TEMPLATES
Authors: NOH KUNBAE , BRAMMER KARLA S. , SEONG TAE-YEON , JIN SUNGHO
Published: December 2011

In this paper, we review recent advances in nanotemplate fabrication using anodized aluminum oxide (AAO). In addition to self-ordered AAO nanoarrays, guided AAO self-assembly is of great interest since it can offer highly ordered, vertically aligned nanoporous templates which are suitable for various materials synthesis and alignment of nanosized structures. Moreover, structural modification of AAO nanoarrays by controlling fabrication process parameters are reviewed which can be applicable for advanced micro- and nanosystems. In this aspect, potential applications using AAO will be revealed in the aspects of self-ordered AAO, guided self-assembly of AAO, and biomedical and magnetic applications.
LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c-Fos-dependent pathway
Authors: Singla Amika , Kumar Anoop , Priyamvada Shubha , Tahniyath Maliha , Saksena Seema , Gill Ravinder K. , Alrefai Waddah A. , Dudeja Pradeep K.
Published: December 2011

DRA (downregulated in adenoma) or SLC26A3 is the major apical anion exchanger mediating Cl− absorption in intestinal epithelial cells. Disturbances in DRA function and expression have been implicated in diarrheal conditions such as congenital chloride diarrhea and inflammatory bowel diseases. Previous studies have shown that DRA is subject to regulation by short-term and transcriptional mechanisms. In this regard, we have recently shown that short-term treatment by lysophosphatidic acid (LPA), an important bioactive phospholipid, stimulates Cl−/HCO3−(OH−) exchange activity via an increase in DRA surface levels in human intestinal epithelial cells. However, the long-term effects of LPA on DRA at the level of gene transcription have not been examined. The present studies were aimed at investigating the effects of LPA on DRA function and expression as well as elucidating the mechanisms underlying its transcriptional regulation. Long-term LPA treatment increased the Cl−/HCO3− exchange activity in Caco-2 cells. LPA treatment (50–100 μM) of Caco-2 cells significantly stimulated DRA mRNA levels and DRA promoter activity (−1183/+114). This increase in DRA promoter activity involved the LPA2 receptor and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. Progressive deletions from −1183/+114 to −790/+114 abrogated the stimulatory effects of LPA, indicating that the −1183/−790 promoter region harbors LPA response elements. Utilizing EMSA and mutational studies, our results showed that LPA induced the DRA promoter activity in a c-Fos-dependent manner. LPA also increased the protein expression of c-Fos and c-Jun in Caco-2 cells. Furthermore, overexpression of c-Fos but not c-Jun enhanced the DRA promoter activity. This increase in DRA transcription in response to LPA indicates that LPA may act as an antidiarrheal agent and could be exploited for the treatment of diarrhea associated with inflammatory or infectious diseases of the gut.
Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression
Authors: Xu Qing , Nakayama Mizuho , Suzuki Yoshinori , Sakai Katsuya , Nakamura Takahiro , Sakai Yoshiki , Matsumoto Kunio
Published: December 2011

Previous studies have demonstrated that mice disrupted with the cyclooxygenase-2 gene showed much more severe liver damage compared with wild-type mice after liver injury, and prostaglandins (PGs) such as PGE1/2 and PGI2 have decreased hepatic injury, but the mechanisms by which prostaglandins exhibit protective action on the liver have yet to be addressed. In the present study, we investigated the mechanism of the protective action of PGI2 using the synthetic IP receptor agonist ONO-1301. In primary cultures of hepatocytes and nonparenchymal liver cells, ONO-1301 did not show protective action directly on hepatocytes, whereas it stimulated expression of hepatocyte growth factor (HGF) in nonparenchymal liver cells. In mice, peroral administration of ONO-1301 increased hepatic gene expression and protein levels of HGF. Injections of CCl4 induced acute liver injury in mice, but the onset of acute liver injury was strongly suppressed by administration of ONO-1301. The increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by CCl4 were suppressed by 10 mg/kg ONO-1301 to 39.4 and 33.6%, respectively. When neutralizing antibody against HGF was administered with ONO-1301 and CCl4, the decreases by ONO-1301 in serum ALT and AST, apoptotic liver cells, and expansion of necrotic areas in liver tissue were strongly reversed by neutralization of endogenous HGF. These results indicate that ONO-1301 increases expression of HGF and that hepatoprotective action of ONO-1301 in CCl4-induced liver injury may be attributable to its activity to induce expression of HGF, at least in part. The potential for involvement of HGF-Met-mediated signaling in the hepatotrophic action of endogenous prostaglandins generated by injury-dependent cyclooxygenase-2 induction is considerable.
EP2and EP4receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals
Authors: Tajima Tsuyoshi , Murata Takahisa , Aritake Kosuke , Urade Yoshihiro , Michishita Masaki , Matsuoka Toshiyuki , Narumiya Shuh , Ozaki Hiroshi , Hori Masatoshi
Published: December 2011

Intestinal resident macrophages play an important role in gastrointestinal dysmotility by producing prostaglandins (PGs) and nitric oxide (NO) in inflammatory conditions. The causal correlation between PGs and NO in gastrointestinal inflammation has not been elucidated. In this study, we examined the possible role of PGE2in the LPS-inducible inducible NO synthase (iNOS) gene expression in murine distal ileal tissue and macrophages. Treatment of ileal tissue with LPS increased the iNOS and cyclooxygenase (COX)-2 gene expression, which lead to intestinal dysmotility. However, LPS did not induce the expression of iNOS and COX-2 in tissue from macrophage colony-stimulating factor-deficient op/op mice, indicating that these genes are expressed in intestinal resident macrophages. iNOS and COX-2 protein were also expressed in dextran-phagocytized macrophages in the muscle layer. CAY10404, a COX-2 inhibitor, diminished LPS-dependent iNOS gene upregulation in wild-type mouse ileal tissue and also in RAW264.7 macrophages, indicating that PGs upregulate iNOS gene expression. EP2and EP4agonists upregulated iNOS gene expression in ileal tissue and isolated resident macrophages. iNOS mRNA induction mediated by LPS was decreased in the ileum isolated from EP2or EP4knockout mice. In addition, LPS failed to decrease the motility of EP2and EP4knockout mice ileum. EP2- or EP4-mediated iNOS expression was attenuated by KT-5720, a PKA inhibitor and PD-98059, an ERK inhibitor. Forskolin or dibutyryl-cAMP mimics upregulation of iNOS gene expression in macrophages. In conclusion, COX-2-derived PGE2induces iNOS expression through cAMP/ERK pathways by activating EP2and EP4receptors in muscularis macrophages. NO produced in muscularis macrophages induces dysmotility during gastrointestinal inflammation.
Relationships between the extent of apnea-induced bradycardia and the vascular response in the arm and leg during dynamic two-legged knee extension exercise
Authors: Nishiyasu Takeshi , Tsukamoto Rina , Kawai Katsuhito , Hayashi Keiji , Koga Shunsaku , Ichinose Masashi
Published: December 2011

Our aim was to test the hypothesis that apnea-induced hemodynamic responses during dynamic exercise in humans differ between those who show strong bradycardia and those who show only mild bradycardia. After apnea-induced changes in heart rate (HR) were evaluated during dynamic exercise, 23 healthy subjects were selected and divided into a large response group (L group; n = 11) and a small response group (S group; n = 12). While subjects performed a two-legged dynamic knee extension exercise at a work load that increased HR by 30 beats/min, apnea-induced changes in HR, cardiac output (CO), mean arterial pressure (MAP), arterial O2 saturation (SaO2), forearm blood flow (FBF), and leg blood flow (LBF) were measured. During apnea, HR in the L group (54 ± 2 beats/min) was lower than in the S group (92 ± 3 beats/min, P < 0.05). CO, SaO2, FBF, LBF, forearm vascular conductance (FVC), leg vascular conductance (LVC), and total vascular conductance (TVC) were all reduced, and MAP was increased in both groups, although the changes in CO, TVC, LBF, LVC, and MAP were larger in the L group than in the S group ( P < 0.05). Moreover, there were significant positive linear relationships between the reduction in HR and the reductions in TVC, LVC, and FVC. We conclude that individuals who show greater apnea-induced bradycardia during exercise also show greater vasoconstriction in both active and inactive muscle regions.
Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species
Authors: O'Hara Thomas , Rudy Yoram
Published: December 2011

Explanations for arrhythmia mechanisms at the cellular level are usually based on experiments in nonhuman myocytes. However, subtle electrophysiological differences between species may lead to different rhythmic or arrhythmic cellular behaviors and drug response given the nonlinear and highly interactive cellular system. Using detailed and quantitatively accurate mathematical models for human, dog, and guinea pig ventricular action potentials (APs), we simulated and compared cell electrophysiology mechanisms and response to drugs. Under basal conditions (absence of β-adrenergic stimulation), Na+/K+-ATPase changes secondary to Na+ accumulation determined AP rate dependence for human and dog but not for guinea pig where slow delayed rectifier current ( IKs) was the major rate-dependent current. AP prolongation with reduction of rapid delayed rectifier current ( IKr) and IKs (due to mutations or drugs) showed strong species dependence in simulations, as in experiments. For humans, AP prolongation was 80% following IKr block. It was 30% for dog and 20% for guinea pig. Under basal conditions, IKs block was of no consequence for human and dog, but for guinea pig, AP prolongation after IKs block was severe. However, with β-adrenergic stimulation, IKs played an important role in all species, particularly in AP shortening at fast rate. Quantitative comparison of AP repolarization, rate-dependence mechanisms, and drug response in human, dog, and guinea pig revealed major species differences (e.g., susceptibility to arrhythmogenic early afterdepolarizations). Extrapolation from animal to human electrophysiology and drug response requires great caution.
Diameter-dependent axial prestretch of porcine coronary arteries and veins
Authors: Guo Xiaomei , Liu Yi , Kassab Ghassan S.
Published: December 2011

The pressure-diameter relation (PDR) and the wall strain of coronary blood vessels have important implications for coronary blood flow and arthrosclerosis, respectively. Previous studies have shown that these mechanical quantities are significantly affected by the axial stretch of the vessels. The objective of this study was to measure the physiological axial stretch in the coronary vasculature; i.e., from left anterior descending (LAD) artery tree to coronary sinus vein and to determine its effect on the PDR and hence wall stiffness. Silicone elastomer was perfused through the LAD artery and coronary sinus trees to cast the vessels at the physiologic pressure. The results show that the physiological axial stretch exists for orders 4 to 11 (> 24 μm in diameter) arteries and orders −4 to −12 (>38 μm in diameter) veins but vanishes for the smaller vessels. Statistically, the axial stretch is higher for larger vessels and is higher for arteries than veins. The axial stretch λ z shows a linear variation with the order number ( n) as: λ z = 0.062 n + 0.75 ( R2 = 0.99) for artery and λ z = −0.029 n + 0.89 ( R2 = 0.99) for vein. The mechanical analysis shows that the axial stretch significantly affects the PDR of the larger vessels. The circumferential stretch/strain was found to be significantly higher for the epicardial arteries (orders 9–11), which are free of myocardium constraint, than the intramyocardial arteries (orders 4–8). These findings have fundamental implications for coronary blood vessel mechanics.
Relationships between the lung clearance index and conductive and acinar ventilation heterogeneity
Authors: Verbanck Sylvia , Paiva Manuel , Schuermans Daniel , Hanon Shane , Vincken Walter , Van Muylem Alain
Published: December 2011

The lung clearance index (LCI) derived from a multiple breath washout test has regained considerable popularity in recent years, alternatively being promoted as an early detection tool or a marker of small airways function. In this study, we systematically investigated the link between LCI and indexes of acinar and conductive airways ventilation heterogeneity (Sacin, Scond) to assess potential contributions from both lung zones. Relationships were examined in 55 normal subjects after provocation, where only Scond is known to be markedly increased, and in 55 asthma patients after bronchodilation, in whom both Scond and Sacin ranged between normal and abnormal. LCI was correlated to Scond in both groups ( R = 0.37–0.43; P < 0.01 for both); in the asthma group, LCI was also tightly correlated to Sacin ( R = 0.70; P < 0.001). Potential mechanisms operational at various levels of the bronchial tree were identified by considering washout curvilinearity in addition to LCI to distinguish specific ventilation and dead space effects (also illustrated by simple 2-compartment model simulations). Although the asthma data clearly demonstrate that LCI can reflect very peripheral ventilation heterogeneities, the normal provocation data also convincingly show that LCI increases may be the exclusive result of far more proximal ventilation heterogeneities. Because LCI potentially includes heterogeneities at all length scales, it is suggested that ventilation imaging in combination with LCI measurement at the mouth could identify the scale of relevant ventilation heterogeneities. In the meantime, interpretations of LCI results in the clinic based on washout curves collected at the mouth should be handled with caution.
Beside the point: motor adaptation without feedback-based error correction in task-irrelevant conditions
Authors: Schaefer Sydney Y. , Shelly Iris L. , Thoroughman Kurt A.
Published: December 2011

Adaptation of movement may be driven by the difference between planned and actual motor performance, or the difference between expected and actual sensory consequences of movement. To identify how the nervous system differentially uses these signals, we asked: does motor adaptation occur when movement errors are irrelevant to the task goal? Participants reached on a digitizing tablet from a fixed start location to one of three targets: a point, an arc, or a ray. For the arc, reaches could be in any direction, but to a specific extent. For the ray, reaches could be to any distance, but in a targeted direction. After baseline reaching to the point, the direction or extent of continuous visual feedback was perturbed during training with either a cursor rotation or gain, respectively, while reaching to either the ray (goal = direction) or the arc (goal = extent). The perturbation, therefore, was either relevant or irrelevant to the task goal, depending on target type. During interspersed catch trials, the perturbation was removed and the target switched back to the point, identical to baseline. Although the goal of baseline and catch trials was the same, significant aftereffects in catch trials indicated behavioral adaptation in response to the perturbation. Adaptation occurred regardless of whether the perturbation was relevant to the task, and it was independent of feedback control. The presence of adaptation orthogonal to task demands supports the hypothesis that the nervous system can rely on sensory prediction to drive motor learning that can generalize across tasks.
Electrophysiological recordings in humans reveal reduced location-specific attentional-shift activity prior to recentering saccades
Authors: Krebs Ruth M. , Boehler C. Nicolas , Zhang Helen H. , Schoenfeld Mircea A. , Woldorff Marty G.
Published: December 2011

Being able to effectively explore the visual world is of fundamental importance, and it has been suggested that the straight-ahead gaze position within the egocentric reference frame (“primary position”) might play a special role in this context. In the present study we employed human electroencephalography (EEG) to examine neural activity related to the spatial guidance of saccadic eye movements. Moreover, we sought to investigate whether such activity would be modulated by the spatial relation of saccade direction to the primary gaze position (recentering saccades). Participants executed endogenously cued saccades between five equidistant locations along the horizontal meridian. This design allowed for the comparison of isoamplitude saccades from the same starting position that were oriented either toward the primary position (centripetal) or further away from it (centrifugal). By back-averaging time-locked to the saccade onset on each trial, we identified a parietally distributed, negative-polarity EEG deflection contralateral to the direction of the upcoming saccade. Importantly, this contralateral presaccadic negativity, which appeared to reflect the location-specific attentional guidance of the eye movement, was attenuated for recentering saccades relative to isoamplitude centrifugal saccades. This differential electrophysiological signature was paralleled by faster saccadic reaction times and was substantially more apparent when time-locking the data to the onset of the saccade rather than to the onset of the cue, suggesting a tight temporal association with saccade initiation. The diminished level of this presaccadic component for recentering saccades may reflect the preferential coding of the straight-ahead gaze position, in which both the eye-centered and head-centered reference frames are perfectly aligned and from which the visual world can be effectively explored.
Metronomic Dosing of BH3 Mimetic Small Molecule Yields Robust Antiangiogenic and Antitumor Effects
Authors: Imai Atsushi , Zeitlin Benjamin D. , Visioli Fernanda , Dong Zhihong , Zhang Zhaocheng , Krishnamurthy Sudha , Light Emily , Worden Frank , Wang Shaomeng , Nör Jacques E.
Published: December 2011

Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs. Cancer Res; 72(3); 716–25. ©2011 AACR.
Molecular Pathways: BCR-ABL
Authors: Cilloni Daniela , Saglio Giuseppe
Published: December 2011

Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies. Here, we summarize the molecular pathways that are abnormally activated by the oncoprotein. Such pathways may provide additional opportunities to develop new drugs to overcome the resistance to tyrosine kinase inhibitors. In particular, the phosphoinositide 3-kinase (PI3K)/AKT pathway can be effectively blocked by mTOR inhibitors, and several compounds can hit the RAS pathway and the resulting mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) and MAP kinase activation. Furthermore, mitotic kinases can be blocked by Aurora kinase inhibitors, and Pim kinases can be blocked by selective serine-threonine kinase inhibitors. Finally, the abnormal pathways that sustain the self-renewal of leukemic stem cells are described as possible targets to completely eradicate leukemic clones. Such pathways include the Hedgehog pathway, which can be blocked by Smoothened inhibitors, and the CXCR4/SDF1 axis, which can be targeted by specific antagonists. Clin Cancer Res; 18(4); 930–7. ©2011 AACR.
History and Biological Significance of GPCR Heteromerization in the Neuroendocrine System
Authors: Tadagaki Kenjiro , Jockers Ralf , Kamal Maud
Published: December 2011

G protein-coupled receptors (GPCRs) constitute a large family of seven transmembrane proteins that regulate major cellular functions. The important role of GPCRs in the neuroendocrine system is outlined by the great interest of pharmaceutical companies in developing new drugs targeting these receptors. GPCRs exist as monomers, but can also be organized in oligomeric structures composed of either homo- or heteromers. GPCR heteromerization may play an important role in modulating and fine-tuning GPCR function and signaling. The literature reports many examples of GPCR heteromers in vitro raising the question of the physiological relevance of these complexes in tissues. Considerable efforts are currently being directed towards conclusive evidence for the existence of GPCRs heteromers in vivo, a crucial step for the validation of the concept of GPCR heteromerization and future drug development. The present review will give a brief history of GPCR oligomerization and emphasize the importance and physiological relevance of GPCR heteromerization by discussing key examples of GPCR couples.
Adult Pituitary Stem Cells: From Pituitary Plasticity to Adenoma Development
Authors: Florio Tullio
Published: December 2011

The pituitary needs high plasticity of the hormone-producing cell compartment to generate the continuously changing hormonal signals that govern the key physiological processes it is involved in, as well as homeostatic cell turnover. However, the underlying mechanisms are still poorly understood. It was proposed that adult stem cells direct the generation of newborn cells with a hormonal phenotype according to the physiological requirements. However, only in recent years adult pituitary stem cells have begun to be phenotypically characterized in several studies that identified multiple stem/progenitor cell candidates. Also considering the incompletely defined features of this cell subpopulation, some discrepancies among the different reports are clearly apparent and long-term self-renewal remains to be unequivocally demonstrated. Here, all the recently published evidence is analyzed, trying, when possible, to reconcile the results of the different studies. Finally, with the perspective of shedding light on pituitary tumorigenesis and the development of potentially new pharmacological approaches directed against these cells, very recent evidence on the presence of putative cancer stem cells in human pituitary adenomas is discussed.
Stroke Prediction after Transient Ischemic Attacks in Patients Admitted to a Stroke Unit
Authors: Tari Capone Francesca , Cavallari Michele , Casolla Barbara , Caselli Giulio , Pieroni Alessio , Di Lazzaro Vincenzo , Napolitano Simone , Stanzione Paolo , Puca Emanuele , Toni Danilo , Rasura Maurizia , Orzi Francesco
Published: December 2011

Background: Transient ischemic attacks (TIAs) bear a presumed high risk of early recurrence of stroke. Data in the literature, however, are inconsistent, as recurrence rates range from 9.5 to 20%, at 90 days. Aims: The study was designed to determine the risk of stroke after TIA. Methods: 94 consecutive patients referred to a Stroke Unit for TIA or minor stroke, within 24 h of symptom onset, were recruited. Eleven of the 94 patients (12%, 95% CI: 7–20%) had a relapse within 90 days. The relapse consisted of a TIA for 9 patients (10%, 95% CI: 5–17%), or of a stroke for 2 subjects (1%, 95% CI: 0–8%). More than a quarter of the relapses occurred within 1 week from the first TIA. ABCD2, ABCD2-I and ABCD-E+ scores were similar among people with or without relapse. Conclusions: The data seem to confirm previous reports on the relatively low relapse rate for stroke, when TIA patients are promptly assisted in dedicated structures. The findings stress the potential benefit of early intervention in subjects with TIA.
Fine-Needle Aspiration of Mucin-Producing Thyroid Tumors
Authors: Yang Grace C.H. , Scognamiglio Theresa , Kuhel William I.
Published: December 2011

Objective: Mucin-producing thyroid tumors are extremely rare. Nonetheless, we have encountered three such cases in fine-needle aspiration. We report the cytologic and histologic findings and review the literature. Study Design: Cytologic features were studied on direct smears using Romanovsky stain to detect background substance and Papanicolaou stain to analyze nuclear and cytoplasmic features. The cytologic features were correlated with histology. Mucin was demonstrated by mucicarmine, Alcian Blue/PAS, and Alcian Blue (pH 2.5). Results: The cytologic features related to mucin include: (1) thick luminal mucin globules and signet ring cells aspirated from an 83-year-old woman with a 3-cm signet ring cell follicular adenoma, (2) abundant fluffy mucin containing signet ring cells in cohesive fragments aspirated from a 75-year-old man with the bilateral signet ring cell follicular variant of papillary carcinoma, which is the first case in the English literature, and (3) abundant thin mucoid mucin aspirated from the lymph node of an 86-year-old woman with a 5-cm mucinous poorly differentiated thyroid carcinoma. Conclusion: The occurrence of mucin in thyroid fine-needle aspiration does not necessarily indicate metastasis, and the presence of mucin in cervical lymph nodes does not exclude the thyroid gland as a possible primary.
The Frequency of ‘Atypia of Undetermined Significance’ Interpretations for Thyroid Fine-Needle Aspirations Is Negatively Correlated with Histologically Proven Malignant Outcomes
Authors: VanderLaan Paul A. , Krane Jeffrey F. , Cibas Edmund S.
Published: December 2011

Objective: Cytopathologists’ usage patterns for ‘atypia of undetermined significance’ (AUS) in thyroid fine-needle aspiration (FNA) are not well understood. AUS rates over a 5-year period were analyzed to quantify variability and identify correlations with experience and histologic outcomes. Study Design: A retrospective review of thyroid FNAs from a tertiary-care hospital from 2005 to 2009 was performed. Results were compiled for individual cytopathologists, stratified by year, and correlated with histologic outcomes. Results: Thyroid FNAs (5,327) were evaluated by 7 cytopathologists, with an overall AUS rate of 11.2%. The annual AUS rate remained relatively constant over this time period, though notable inter- and intrapathologist variability was seen. The AUS rate was significantly lower for those with cytopathology boards (10.3%) compared to those without (14.0%). There was no correlation between the AUS rate and cytopathologist experience or thyroid FNA volume. The AUS rate and malignant outcome were inversely related: the higher an individual’s AUS rate was, the lower the rate of malignancy for that AUS cohort was. Conclusions: Individual cytopathologist AUS rates were variable and often exceeded the recommended target of 7%. The application of recently published defined diagnostic criteria, along with directed cytopathologist feedback, may reduce observer variability and appropriately lower AUS utilization.
The Relationship of Cytomorphology of Medullary Thyroid Carcinomas between Family Members with the Same RET Proto-Oncogene Mutation
Authors: Chang Jan-Shun , Chang Chin-Feng , Yang Wei-Shiung , Chang Tien-Chun
Published: December 2011

Objective: To evaluate the relationship of the cytomorphology of medullary thyroid carcinomas (MTC) between family members with the same RET proto-oncogene mutation. Study Design: Review of the fine-needle aspiration slides of 13 cases with MTC proven by surgery and pathology from 5 unrelated families with either multiple endocrine neoplasia (MEN) type 2A or familial MTC (FMTC). Results: Small, round, and abundant large oval-to-polygonal cells were major cytomorphologic findings in 66.7% of family members with exon 11, codon 634 TGC → CGC germline mutation. Small, round cells and only a few or no polygonal cells were found in 66.7% of family members with exon 11, codon 634 TGC → TTC germline mutation and in 100% of family members with codon 634 TGC → TGG germline mutations, as well as in 100% of family members with exon 10, codon 620 TGC → GGC germline mutation. Conclusions: The high rate of similarity of cytomorphology (66.7–100%) in the family members with MEN type 2A or FMTC might be related to the same etiology in the production of MTC in the same family. The relationship of the respective cytomorphology with the long-term prognosis is worth elucidating further.
BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Specimens Enhances the Predictability of Malignancy in Thyroid Follicular Lesions of Undetermined Significance
Authors: Adeniran Adebowale J. , Hui Pei , Chhieng David C. , Prasad Manju L. , Schofield Kevin , Theoharis Constantine
Published: December 2011

Background/Objective: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as ‘indeterminate’ and they are further subclassified into two categories. BRAF mutation occurs in 40–60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. Study Design: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as ‘indeterminate’ were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. Results: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. Conclusions: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.