bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of an Optimal Tuner Selection Approach for On-Board Self-Tuning Engine Models
Authors: Simon Donald L. , Armstrong Jeffrey B. , Garg Sanjay
Published: January 2012

An enhanced design methodology for minimizing the error in on-line Kalman filter-based aircraft engine performance estimation applications is presented in this paper. It specifically addresses the under-determined estimation problem, in which there are more unknown parameters than available sensor measurements. This work builds upon an existing technique for systematically selecting a model tuning parameter vector of appropriate dimension to enable estimation by a Kalman filter, while minimizing the estimation error in the parameters of interest. While the existing technique was optimized for open-loop engine operation at a fixed design point, in this paper an alternative formulation is presented that enables the technique to be optimized for an engine operating under closed-loop control throughout the flight envelope. The theoretical Kalman filter mean squared estimation error at a steady-state closed-loop operating point is derived, and the tuner selection approach applied to minimize this error is discussed. A technique for constructing a globally optimal tuning parameter vector, which enables full-envelope application of the technology, is also presented, along with design steps for adjusting the dynamic response of the Kalman filter state estimates. Results from the application of the technique to linear and nonlinear aircraft engine simulations are presented and compared to the conventional approach of tuner selection. The new methodology is shown to yield a significant improvement in on-line Kalman filter estimation accuracy.
A Comparative Study of Flamelet and Finite Rate Chemistry LES for a Swirl Stabilized Flame
Authors: Fureby C.
Published: January 2012

Present-day demands on combustion equipment are increasing the need for improved understanding and prediction of turbulent combustion. Large eddy simulation (LES), in which the large-scale flow is resolved on the grid, leaving only the small-scale flow to be modeled, provides a natural framework for combustion simulations as the transient nature of the flow is resolved. In most situations; however, the flame is thinner than the LES grid, and subgrid modeling is required to handle the turbulence-chemistry interaction. Here we examine the predictive capabilities between LES flamelet models, such as the flamelet progress variable (LES-FPV) model, and LES finite rate chemistry models, such as the thickened flame model (LES-TFM), the eddy dissipation concept (LES-EDC) model, and the partially stirred reactor model (LES-PaSR). The different models are here used to examine a swirl-stabilized premixed flame in a laboratory gas turbine combustor, featuring the triple annular research swirler (TARS), for which high-quality experimental data is available. The comparisons include velocity and temperature profiles as well as combustor dynamics and NO formation.
Epithelial Nitration by a Peroxidase/NOX5 System Mediates Mosquito Antiplasmodial Immunity
Authors: Oliveira Giselle de Almeida , Lieberman Joshua , Barillas-Mury Carolina
Published: January 2012

From NO to Complement

To complete their development in the mosquito, ookinetes—reproductive stages of the malaria parasite
Plasmodium
—must traverse the midgut epithelium and avoid being detected and lysed by the mosquito complement system thioester-containing protein 1 (TEP1).

Oliveira
et al.

(p.
856
, published online 26 January) identified mosquito heme peroxidase (HPX2) and a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (NOX5) as key enzymes that are induced in midgut cells during ookinete invasion that, together with nitric oxide synthase, mediate protein nitration. The HPX2-NOX5 system potentiates nitric oxide toxicity and is critical for mosquitoes to mount an effective antiplasmodial response. Epithelial nitration and TEP1-mediated lysis appear to act sequentially in parasite killing, and epithelial nitration may help to promote the mosquito complement cascade.
Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus
Authors: Lee Jeong Ho , Silhavy Jennifer L. , Lee Ji Eun , Al-Gazali Lihadh , Thomas Sophie , Davis Erica E. , Bielas Stephanie L. , Hill Kiley J. , Iannicelli Miriam , Brancati Francesco , Gabriel Stacey B. , Russ Carsten , Logan Clare V. , Sharif Saghira Malik , Bennett Christopher P. , Abe Masumi , Hildebrandt Friedhelm , Diplas Bill H. , Attié-Bitach Tania , Katsanis Nicholas , Rajab Anna , Koul Roshan , Sztriha Laszlo , Waters Elizabeth R. , Ferro-Novick Susan , Woods C. Geoffrey , Johnson Colin A. , Valente Enza Maria , Zaki Maha S. , Gleeson Joseph G.
Published: January 2012

Distinguishing Ciliopathy

Cilia were once thought to be evolutionary remnants, but structural defects reveal their importance in signaling pathways and human disease, such as Joubert syndrome. Either of the genes
TMEM138
and
TMEM216
can be found mutated in phenotypically indistinguishable ciliopathy patients. Interestingly, despite their lack of sequence homology, these genes have always been aligned in head-to-tail configuration during vertebrate evolution. The proteins expressed by these genes mark distinct tethered vesicles, which differentially carry ciliary proteins for assembly.

Lee
et al.

(p.
966
, published online 26 January; see the Perspective by

Chakravarti and Kapoor

) show that the coordinated expression of these adjacent genes depends upon a coevolved regulatory element in the noncoding intergenic region, which thus integrates the roles of both gene products. This discovery explains not only the indistinguishable pathogenesis of the patients' genotypes but also how the evolutionary clustering of genes unrelated in sequence may correlate with coordinated control of expression and function.
Lithium Isotope History of Cenozoic Seawater: Changes in Silicate Weathering and Reverse Weathering
Authors: Misra Sambuddha , Froelich Philip N.
Published: January 2012

Life of Li

Because lithium primarily exists in silicate minerals on continents, the variations of Li isotopes in marine sedimentary rocks reflect the degree of silicate weathering and formation of new sediments on the seafloor, which in turn are largely controlled by climate and tectonic forces over geologic time. By analyzing sedimentary cores from eight drill sites around the world's oceans,
Misra and Froelich
(p.
818
, published online 26 January; see the cover; see the Perspective by

Paytan

) assembled a 68-million-year record of the Li isotope composition of seawater. The record reveals a stepwise change in the Li isotopic ratio, suggesting that several intense episodes of tectonic uplift increased continental weathering rates and delivery of sediments to the oceans. Abrupt swings in the record at specific points in Earth's history, for example, around the time when dinosaurs became extinct, imply major changes in ocean chemistry—but their mechanisms remain enigmatic.
Mountains, Weathering, and Climate
Authors: Paytan Adina
Published: January 2012

Changes in the lithium isotope composition of seawater over the past 70 million years elucidate the links between weathering and climate.
Preparation of polypyrrole by direct electrochemical oxidation of pyrrole on paraffin impregnated graphite electrode
Authors: Filkusová Mária , Oriňáková Renáta , Markušová Kvetoslava , Kovaľ Karol
Published: January 2012

The formation of polypyrrole (PPy) layers by electrochemical polymerisation of pyrrole (Py) on paraffin impregnated graphite electrode (PIGE) was studied. Electrochemical oxidation of Py was studied by means of cyclic voltammetry (CV) and the morphology of the deposited layers was investigated with scanning electron microscope (SEM). The structure and quality of PPy layers on PIGE depends on monomer concentration, pH value, stirring intensity and scan rate during the polymerisation process.
Perceptions of junior doctors in the NHS about their training: results of a regional questionnaire
Authors: Gilbert Alexandra , Hockey Peter , Vaithianathan Rhema , Curzen Nick , Lees Peter
Published: January 2012

Objective

To explore the views of doctors in training about their current roles and their potential value to the National Health Service (NHS) in improving healthcare quality and productivity.

Methods

Online questionnaire sent via email to 3766 junior doctors (foundation year one to specialist trainee year 3+) in the NHS South Central region.

Results

The response rate was 1479/3766 (39.3%). Respondents recognised the importance of leadership (89.7%), team working (89.2%) and professionalism (97%). Only 3.4% of junior doctors stated they have never acted in a leadership capacity. However, respondents reported a lack of receptivity from their organisations: the majority responded that they do not feel valued by managers (83.3%), the chief executive (77.7%), the organisation (77.3%), the NHS (79.3%) and consultants (58.2%). 91.2% of respondents have had ideas for improvement in their workplace; however, only 10.7% have had their ideas for change implemented. Respondents who had been on a NHS South Central leadership development course were significantly more likely to feel valued by all groups of staff in their organisation. They were also significantly more likely to report having their ideas implemented.

Conclusions

Doctors in training have a desire and perceived ability to contribute to improvement in the NHS but do not perceive their working environment as receptive to their skills. Junior doctors who attend leadership training report higher levels of desire and ability to express these skills. This study suggests junior doctors are an untapped NHS resource and that they and their organisations would benefit from more formalised provision of training in leadership.
Graphic medicine: comics as medical narrative
Authors: Williams Ian C M
Published: January 2012

Among the growing number of works of graphic fiction, a number of titles dealing directly with the patient experience of illness or caring for others with an illness are to be found. Thanks in part to theMedical Humanitiesmovement, many medical schools now encourage the reading of classic literature to gain insight into the human condition. Until recently, the medium of comics (the term is used in the plural to refer to both the physical objects and the attendant philosophy and practice surrounding them) has received little attention from healthcare scholars, even though some authors argue that graphic fiction is, in fact, a form of literature. This paper suggests that it is time that the medium was examined by healthcare professionals and studies some acclaimed comic works. Drawing on the principles of narrative medicine, this paper will ask whether comics and graphic novels could be used as a resource for health professionals, patients and carers.
Lobar collapse demystified: the chest radiograph with CT correlation
Authors: Mullett Rebecca , Jain Abhishek , Kotugodella Sripali , Curtis John
Published: January 2012

Collapse of a lobe of a lung is an important indicator of a range of conditions, including malignancy. Clinical symptoms and signs may suggest a diagnosis of lobar collapse; however, it is often diagnosed, and always needs to be confirmed, with radiological examination. The radiological signs may be subtle, difficult to interpret and sometimes confusing to both clinicians and radiologists. Although multidetector CT (MDCT) is now widely in use for confirming and diagnosing lobar collapse, the plain chest radiograph is usually the first imaging modality performed and so recognition on the plain film remains of vital importance. The basics of chest radiograph interpretation are reviewed, concentrating on the concepts of radiographic density and the silhouette sign. MDCT images are used to demonstrate the general radiological signs of collapse, and the signs of collapse that are specific to the different lobes of the lung are reviewed.
Chronic kidney disease in snake envenomed patients with acute kidney injury in Sri Lanka: a descriptive study
Authors: Herath H M N J , Wazil A W M , Abeysekara D T D J , Jeewani N D C , Weerakoon K G A D , Ratnatunga N V I , Bandara E H C K , Kularatne S A M
Published: January 2012

Background

Data on the long-term outcomes of acute kidney injury (AKI) in envenomed patients leading to chronic kidney disease (CKD) are scarce. The aim of the study was to investigate this issue and to determine the predictive factors in developing CKD.

Methods

The records of a series of 54 patients who had AKI following a snakebite during the period 2004–2009 and who had been followed up were reviewed in the nephrology unit, Kandy, Sri Lanka. The primary outcome measure was the failure of renal functions to return to normal within 1 year. The renal histology was studied in seven patients.

Results

The mean age of the group was 50 years (SD 13 years) and 39 (72%) patients were men. The offending snakes were Russell's viper and hump-nosed viper in 15 (28%) and 13 (24%) patients, respectively. At 1 year, 20 patients (37%) had developed CKD (CKD group) and the rest (63%) had recovered (recovered group). The acute stage serum creatinine was high in both groups with no difference (on admission, p=0.134; on discharge, p=0.323), but the CKD group showed significantly high serum creatinine at 2 months after AKI (p=0.004). Mean duration of renal replacement therapy (RRT) of the recovered group and CKD group were 7 (SD 5) and 16 (SD 12) days, respectively (p=0.015). Renal histology of six CKD patients showed predominant glomerular sclerosis and interstitial nephritis.

Conclusions

CKD is an outcome of severe AKI following snake envenoming probably predicted by the length of RRT.
Imaging in pulmonary hypertension, part 2: large vessel diseases
Authors: McCann Caroline , Gopalan Deepa , Sheares Karen , Screaton Nicholas
Published: January 2012

Pulmonary hypertension is defined by physiological parameters but there are numerous causes that differ in their pathogenesis, management and prognosis. Causes include chronic cardiac or pulmonary diseases and diffuse small vessel disease but also a range of large vessel obstructive diseases. The physiological manifestation of all these diseases is increased pulmonary vascular resistance and pulmonary arterial hypertension, and while clinical features may provide a clue to diagnosis, imaging plays a fundamental role in establishing a precise diagnosis and therefore guiding therapy. Chronic thromboembolic pulmonary hypertension (CTEPH) is the most common large vessel cause of pulmonary hypertension. It is increasingly recognised as a major cause of morbidity and mortality which is underdiagnosed and often diagnosed late. The importance of CTEPH is that for patients in whom the distribution of disease lies predominantly in the proximal vasculature there is potential for symptomatic and physiological cure by surgical pulmonary endarterectomy. More distal disease may be suitable for medical management. Increased awareness on behalf of both clinicians and imagers is therefore paramount. However, there are other rare causes or large vessel obstruction/stenosis such as large vessel vasculitis, pulmonary artery tumour, fibrosing mediastinitis, congenital stenosis or extrinsic compression of the pulmonary arteries/veins. Atypical imaging appearance such as unilateral central pulmonary artery obstruction should lead to consideration of a diagnosis other than CTEPH.
EMPIRICAL COPULA-BASED TEMPLATES TO RECOGNIZE SURFACE EMG SIGNALS OF HAND MOTIONS
Authors: JU ZHAOJIE , ZHU XIANGYANG , LIU HONGHAI
Published: January 2012

Current tendency of electromyography (EMG)-based prosthetic hand is to enable the user to perform complex grasps or manipulations with natural muscle movements. In this paper, empirical copula-based templates; including the unified motion template and the state-based motion template, are introduced to identify the naturally contracted surface EMG (sEMG) patterns for hand motion recognition. The unified motion template utilizes a dependence structure as a motion template, which includes one-to-one correlations of the SEMG feature channels with all the sampling points, while the state-based motion template divides the sampling points into different states and takes the union of the dependence structures of the different states. Comparison results have demonstrated that the proposed Empirical Copula-based methods can successfully classify different hand motions from different subjects with better recognition rates than Gaussian mixture models (GMMs). In addition, the state-based motion template has a better performance than the unified motion template especially for the complex hand motions.
THE VISUAL-AUDIO INTEGRATED RECOGNITION METHOD FOR USER AUTHENTICATION SYSTEM OF PARTNER ROBOTS
Authors: CAO JIANGTAO , KUBOTA NAOYUKI , LI PING , LIU HONGHAI
Published: January 2012

Some of noncontact biometric ways have been used for user authentication system of partner robots, such as visual-based recognition methods and speech recognition. However, the methods of visual-based recognition are sensitive to the light noise and speech recognition systems are perturbed to the acoustic environment and sound noise. Inspiring from the human's capability of compensating visual information (looking) with audio information (hearing), a visual-audio integrating method is proposed to deal with the disturbance of light noise and to improve the recognition accuracy. Combining with the PCA-based and 2DPCA-based face recognition, a two-stage speaker recognition algorithm is used to extract useful personal identity information from speech signals. With the statistic properties of visual background noise, the visual-audio integrating method is performed to draw the final decision. The proposed method is evaluated on a public visual-audio dataset VidTIMIT and a partner robot authentication system. The results verified the visual-audio integrating method can obtain satisfied recognition results with strong robustness.
Fabrication of Freestanding Pb(Zr,Ti)O Film Microstructures Using Ge Sacrificial Layer
Authors: Lee Jae-Wung , Kawai Yusuke , Tanaka Shuji , Lin Yu-Ching , Gessner Thomas , Esashi Masayoshi
Published: January 2012

A high quality freestanding Pb(Zr,Ti)O3(PZT) film with various micropatterns was fabricated using a Ge sacrificial layer in order to meet the need of micro-electromechanical system (MEMS) applications. A flat Pt film was released from a Si substrate by etching the Ge layer (∼1 µm) between the Pt film and the Si substrate. After that, PZT was deposited on the freestanding Pt film by low temperature rf-magnetron sputtering and then annealed. The obtained freestanding PZT film showed strong (100) orientation and good ferroelectric property. This might be due to the characteristics of the developed process, for example, the lattice parameter change of the Pt film, a small heat capacity in the annealing process of PZT, and an absence of clamping effect from the substrate.
Comparative Study of Multiplet Structures of Mn4+ in K2SiF6, K2GeF6, and K2TiF6 Based on First-Principles Configuration–Interaction Calculations
Authors: Novita Mega , Ogasawara Kazuyoshi
Published: January 2012

We performed first-principles configuration–interaction calculations of multiplet energies for Mn4+ in K2SiF6, K2GeF6, and K2TiF6 crystals. The results indicate that corrections based on a single-electron calculation are effective for the prediction of 4A2 → 4T2 and 4A2 → 4T1a transition energies, while such corrections are not necessary for the prediction of the 4A2 → 2E transition energy. The cluster size dependence of the multiplet energies is small. However, the 4A2 → 2E transition energy is slightly improved by using larger clusters including K ions. The theoretical multiplet energies are improved further by considering the lattice relaxation effect. As a result, the characteristic multiplet energy shifts depending on the host crystal are well reproduced without using any empirical parameters. Although K2GeF6 and K2TiF6 have lower symmetry than K2SiF6, the results indicate that the variation of the multiplet energy is mainly determined by the Mn–F bond length.
Investigation of Al-Doped ZnO Channel Layer in ZnO-Based Transparent Thin-Film Transistors
Authors: Lee Hsin-Ying , Shien Wen-Ming
Published: January 2012

The enhancement mode and bottom gate Al-doped ZnO transparent thin-film transistors (ZnO:Al TTFTs) were investigated. To provide a suitable amount of free carriers and reduce the associated resistance, the ZnO:Al channel layer with Al imperceptibly doped into the ZnO was deposited using a cosputter system. To investigate the function and optimal thickness of the ZnO:Al channel layer, ZnO:Al layers of various thicknesses were deposited in the TTFTs. The maximum effective field-effect mobility (in the linear region) and the on/off current ratio of the ZnO:Al TTFTs with a 30-nm-thick ZnO:Al channel layer were 32.5 cm2V-1s-1and larger than 107, respectively. In this work, the effective field-effect mobility of 32.5 cm2V-1s-1is larger than the previous published performances of the ZnO TTFTs. To investigate the mechanisms of the optimal 30-nm-thick channel layer, the induced thickness of the channel layer was estimated. The estimated induced thickness is about 27 nm. The other 3-nm-thick ZnO:Al channel layer is used to passivate the induced channel layer.
Frequency and Temperature Characteristics of an Ultrasonic Method for Measuring the Specific Gravity of Lead-Acid Battery Electrolyte
Authors: Liu Jiaxin , Li Guofeng
Published: January 2012

In this paper, we present an ultrasonic method for measuring the specific gravity of lead-acid battery electrolyte and study its frequency and temperature characteristics. This method uses an improved frequency scanning ultrasonic pulse echo reflectometer with a two-transducer configuration. The velocity and attenuation coefficient (1 to 30 MHz) of electrolytes with different specific gravities (1.05 to 1.30) are obtained at 25 °C. It has been shown that the ultrasonic velocity changes little with frequency, and there is low attenuation at approximately 5 MHz. The velocities of several electrolytes with different specific gravities are measured in the temperature range from 10 to 50 °C. The thermal transient of the measurement cell is analyzed, showing 0.1% accuracy in specific gravity measurement for a steady temperature and 0.5% accuracy under thermal gradient conditions after temperature compensation. This method is suitable for the on-line, rapid, and accurate measurement of the specific gravity of a lead-acid battery electrolyte.
ENaCs and ASICs as therapeutic targets
Authors: Qadri Yawar J. , Rooj Arun K. , Fuller Catherine M.
Published: January 2012

The epithelial Na+ channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.
The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model
Authors: Shang Quan , Liu Matthew K. , Saumoy Monica , Holst Jens Juul , Salen Gerald , Xu Guorong
Published: January 2012

Bile acid sequestrants have been shown to reduce glucose levels in patients with type 2 diabetes. We previously reported that the bile acid sequestrant colesevelam HCl (Welchol) (COL) induced the release of glucagon-like peptide (GLP)-1 and improved glycemic control in insulin-resistant rats. In the present study, we tested whether adding sitagliptin (Januvia) (SIT), which prolongs bioactive GLP-1 half life, to COL would further enhance glycemic control. Male Zucker diabetic fatty (ZDF) rats were assigned to four groups: diabetic model without treatment (the model), the model treated with 2% COL or 0.4% (120 mg/day) SIT alone, or with the combination (COL+SIT). After 4 wk of treatment, the glucose area under the curve (AUC) was reduced more in the COL+SIT than the COL although both groups showed decreased glucose AUC with increased AUC of bioactive GLP-1 (GLP-1A) compared with the model group. The above changes were not observed after 8 wk. Increasing the SIT dose by 50% (180 mg SIT/day) in the diet reduced the glucose AUC in the COL+SIT group even after 8 wk but still not in the SIT alone group compared with the model. It was noteworthy that, after 8 wk, insulin levels in the SIT group declined to levels similar to the model. Histological examination of the pancreatic β-cell islets showed that islet sizes were larger, proliferation enhanced, and cell apoptosis reduced in the COL+SIT but not the SIT alone group compared with the model. We hypothesize that the combination of COL with SIT extends the half life of COL-induced GLP-1A and benefits preservation of the islets that delay the development of diabetes and improve glycemic control. This study suggests that the combined therapy (COL+SIT) is more effective than either drug alone for reducing glucose levels in diabetes.
Infrared thermal imaging of rat somatosensory cortex with whisker stimulation
Authors: Suzuki Takashi , Ooi Yasuhiro , Seki Junji
Published: January 2012

The present study aims to validate the applicability of infrared (IR) thermal imaging for the study of brain function through experiments on the rat barrel cortex. Regional changes in neural activity within the brain produce alterations in local thermal equilibrium via increases in metabolic activity and blood flow. We studied the relationship between temperature change and neural activity in anesthetized rats using IR imaging to visualize stimulus-induced changes in the somatosensory cortex of the brain. Sensory stimulation of the vibrissae (whiskers) was given for 10 s using an oscillating whisker vibrator (5-mm deflection at 10, 5, and 1 Hz). The brain temperature in the observational region continued to increase significantly with whisker stimulation. The mean peak recorded temperature changes were 0.048 ± 0.028, 0.054 ± 0.036, and 0.097 ± 0.015°C at 10, 5, and 1 Hz, respectively. We also observed that the temperature increase occurred in a focal spot, radiating to encompass a larger region within the contralateral barrel cortex region during single-whisker stimulation. Whisker stimulation also produced ipsilateral cortex temperature increases, which were localized in the same region as the pial arterioles. Temperature increase in the barrel cortex was also observed in rats treated with a calcium channel blocker (nimodipine), which acts to suppress the hemodynamic response to neural activity. Thus the location and area of temperature increase were found to change in accordance with the region of neural activation. These results indicate that IR thermal imaging is viable as a functional quantitative neuroimaging technique.
Assessment of upper airway dynamics by anterior magnetic phrenic stimulation in conscious sleep apnea patients
Authors: Melo-Silva César Augusto , Borel Jean-Christian , Gakwaya Simon , Sériès Frédéric
Published: January 2012

Phrenic nerve magnetic stimulation (PNMS) performed anterolaterally at the base of the neck (BAMPS) and cervical magnetic stimulation are common techniques for assessing upper airway (UA) mechanical properties in conscious humans. We considered that if NMS performed at the sternal level (a-MS) could induce a similar percentage of flow-limited twitches as BAMPS in conscious subjects, gauging UA dynamic properties by PNMS would be simplified. Instantaneous flow, pharyngeal and esophageal pressures, as well as thoraco-abdominal motion were recorded in 10 conscious sleep apnea patients. BAMPS and a-MS were applied at end expiration. The percentage of flow-limited twitches, maximal tolerated intensity, and minimal stimulator output associated with flow-limited twitches were similar between BAMPS and a-MS. Examining the effects of stimulation site, stimulation intensity and site*intensity interaction on the characteristics of flow-limited twitches, the former was responsible for more negative peak esophageal pressure (BAMPS: −11.5 ± 0.9 cmH2O; a-MS: −6.5 ± 1.1 cmH2O; P = 0.002) and UA closing pressure (BAMPS: −7.7 ± 0.5 cmH2O; a-MS: −5.8 ± 0.6 cmH2O; P = 0.02) as well as for lower mean linear upper airway resistance (UAR) (BAMPS 3.5 ± 0.4 cmH2O·l−1·s−1; a-MS 2.2 ± 0.4 cmH2O·l−1·s−1; P = 0.02). a-MS systematically evoked outward/inward thoracic displacement, although this movement pattern was observed in only 50% of patients when they were subjected to BAMPS. Linear UAR of BAMPS-induced flow-limited twitches was lower in the presence of initial outward thoracic movement (2 ± 0.05 cmH2O·l−1·s−1) than with inward motion (4.3 ± 1.5 cmH2O·l−1·s−1; P = 0.03). We conclude that a-MS represents a practical and functional technique to evaluate UA mechanical properties in conscious sleep apnea patients.
Mechanisms of Fetal Programming in Hypertension
Authors: Jones John Edward , Jurgens Julie A. , Evans Sarah A. , Ennis Riley C. , Villar Van Anthony M. , Jose Pedro A.
Published: January 2012

Events that occur in the early fetal environment have been linked to long-term health and lifespan consequences in the adult. Intrauterine growth restriction (IUGR), which may occur as a result of nutrient insufficiency, exposure to hormones, or disruptions in placental structure or function, may induce the fetus to alter its developmental program in order to adapt to the new conditions. IUGR may result in a decrease in the expression of genes that are responsible for nephrogenesis as nutrients are rerouted to the development of more essential organs. Fetal survival under these conditions often results in low birth weight and a deficit in nephron endowment, which are associated with hypertension in adults. Interestingly, male IUGR offspring appear to be more severely affected than females, suggesting that sex hormones may be involved. The processes of fetal programming of hypertension are complex, and we are only beginning to understand the underlying mechanisms.
Antidepressant Treatment for Acute Bipolar Depression: An Update
Authors: Amit Ben H. , Weizman Abraham
Published: January 2012

While studies in the past have focused more on treatment of the manic phase of bipolar disorder (BD), recent findings demonstrate the depressive phase to be at least as debilitating. However, in contrast to unipolar depression, depression in bipolar patients exhibits a varying response to antidepressants, raising questions regarding their efficacy and tolerability.Methods. We conducted a MEDLINE and Cochrane Collaboration Library search for papers published between 2005 and 2011 on the subject of antidepressant treatment of bipolar depression. Sixty-eight articles were included in the present review.Results. While a few studies did advocate the use of antidepressants, most well-controlled studies failed to show a robust effect of antidepressants in bipolar depression, regardless of antidepressant class or bipolar subtype. There was no significant increase in the rate of manic/hypomanic switch, especially with concurrent use of mood stabilizers. Prescribing guidelines published in recent years rely more on atypical antipsychotics, especially quetiapine, as a first-line therapy.Conclusions. Antidepressants probably have no substantial role in acute bipolar depression. However, in light of conflicting results between studies, more well-designed trials are warranted.
Neurologic Involvement in Scleroderma en Coup de Sabre
Authors: Amaral Tiago Nardi , Marques Neto João Francisco , Lapa Aline Tamires , Peres Fernando Augusto , Guirau Caio Rodrigues , Appenzeller Simone
Published: January 2012

Localized scleroderma is a rare disease, characterized by sclerotic lesions. A variety of presentations have been described, with different clinical characteristics and specific prognosis. In scleroderma en coup de sabre (LScs) the atrophic lesion in frontoparietal area is the disease hallmark. Skin and subcutaneous are the mainly affected tissues, but case reports of muscle, cartilage, and bone involvement are frequent. These cases pose a difficult differential diagnosis with Parry-Romberg syndrome. Once considered an exclusive cutaneous disorder, the neurologic involvement present in LScs has been described in several case reports. Seizures are most frequently observed, but focal neurologic deficits, movement disorders, trigeminal neuralgia, and mimics of hemiplegic migraines have been reported. Computed tomography and magnetic resonance imaging have aided the characterization of central nervous system lesions, and cerebral angiograms have pointed to vasculitis as a part of disease pathogenesis. In this paper we describe the clinical and radiologic aspects of neurologic involvement in LScs.
Tumor-Derived Chemokine CCL5 Enhances TGF-β–Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells
Authors: Chang Li-Yuan , Lin Yung-Chang , Mahalingam Jayashri , Huang Ching-Tai , Chen Ten-Wen , Kang Chiao-Wen , Peng Hui-Min , Chu Yu-Yi , Chiang Jy-Ming , Dutta Avijit , Day Yuan-Ji , Chen Tse-Ching , Yeh Chau-Ting , Lin Chun-Yen
Published: January 2012

Chemokine CCL5/RANTES is highly expressed in cancer where it contributes to inflammation and malignant progression. In this study, we show that CCL5 plays a critical role in immune escape in colorectal cancer. We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (Treg). In mouse cells, RNA interference (RNAi)-mediated knockdown of CCL5 delayed tumor growth in immunocompetent syngeneic hosts but had no effect on tumor growth in immunodeficient hosts. Reduced tumor growth was correlated with a reduction in Treg infiltration and CD8+ T-cell apoptosis in tumors. Notably, we found that CCL5 enhanced the cytotoxicity of Treg against CD8+ T cells. We also found tumor growth to be diminished in mice lacking CCR5, a CCL5 receptor, where a similar decrease in both Treg cell infiltration and CD8+ T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8+ T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-deficient Treg or to enhance their cytotoxic effects against CD8+ T cells. CCR5 signaling blockade also diminished the in vivo suppressive capacity of Treg in inhibiting the antitumor responses of CD8+ T cells, in the same way as CCL5 signaling blockade. Together, our findings establish that CCL5/CCR5 signaling recruits Treg to tumors and enhances their ability to kill antitumor CD8+ T cells, thereby defining a novel mechanism of immune escape in colorectal cancer. Cancer Res; 72(5); 1092–102. ©2012 AACR.
Extracellular Matrix Protein CCN1 Limits Oncolytic Efficacy in Glioma
Authors: Haseley Amy , Boone Sean , Wojton Jeffrey , Yu Lianbo , Yoo Ji Young , Yu Jianhua , Kurozumi Kazuhiko , Glorioso Joseph C. , Caligiuri Michael A. , Kaur Balveen
Published: January 2012

Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. Cysteine rich 61 (CCN1) is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined a hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real-time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Furthermore, they suggest therapeutic interventions to inhibit CCN1–integrin α6 interactions to sensitize gliomas to viral oncolysis. Cancer Res; 72(6); 1353–62. ©2012 AACR.
Leptin Mediates Tumor–Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells
Authors: Barone Ines , Catalano Stefania , Gelsomino Luca , Marsico Stefania , Giordano Cinzia , Panza Salvatore , Bonofiglio Daniela , Bossi Gianluca , Covington Kyle R. , Fuqua Suzanne A.W. , Andò Sebastiano
Published: January 2012

Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type (WT) and K303R mutant estrogen receptor-α (ERα)–expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ERα hyperactive receptor than WT-ERα–expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ERα compared with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and “educated” CAFs that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer–stromal cell communication may represent an effective strategy for targeted therapy of breast cancer. Cancer Res; 72(6); 1416–27. ©2012 AACR.
Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression
Authors: Roth Felix , De La Fuente Adriana C. , Vella Jennifer L. , Zoso Alessia , Inverardi Luca , Serafini Paolo
Published: January 2012

In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloid-derived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-α (IL4Rα or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti–IL4Rα aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumor-infiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra–STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Rα signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Rα signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer. Cancer Res; 72(6); 1373–83. ©2012 AACR.
3′-UTR and Functional Secretor Haplotypes in Mannose-Binding Lectin 2 Are Associated with Increased Colon Cancer Risk in African Americans
Authors: Zanetti Krista A. , Haznadar Majda , Welsh Judith A. , Robles Ana I. , Ryan Bríd M. , McClary Andrew C. , Bowman Elise D. , Goodman Julie E. , Bernig Toralf , Chanock Stephen J. , Harris Curtis C.
Published: January 2012

Because chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here, we report the association of 24 MBL2 single-nucleotide polymorphisms (SNP) and corresponding haplotypes with colon cancer risk in a case–control study. Four SNPs in the 3′-untranslated region (UTR) of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. ORs for homozygous variants versus wild-type ranged from 3.17 [95% confidence interval (CI), 1.57–6.40] to 4.51 (95% CI, 1.94–10.50), whereas the 3′-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42–3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 5′ secretor haplotypes known to correlate with moderate and low MBL serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes, LYPA and LYQC, relative to the referent HYPA haplotype (LYPA: OR, 2.60; 95% CI, 1.33–5.08 and LYQC: OR, 2.28; 95% CI, 1.20–4.30). Similar associations were not observed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans. Cancer Res; 72(6); 1467–77. ©2012 AACR.
Ovarian Cancer Risk Associated with Inherited Inflammation-Related Variants
Authors: White Kristin L. , Schildkraut Joellen M. , Palmieri Rachel T. , Iversen Edwin S. , Berchuck Andrew , Vierkant Robert A. , Rider David N. , Charbonneau Bridget , Cicek Mine S. , Sutphen Rebecca , Birrer Michael J. , Pharoah Paul P.D. , Song Honglin , Tyrer Jonathan , Gayther Simon A. , Ramus Susan J. , Wentzensen Nicolas , Yang Hannah P. , Garcia-Closas Montserrat , Phelan Catherine M. , Cunningham Julie M. , Fridley Brooke L. , Sellers Thomas A. , Goode Ellen L.
Published: January 2012

The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case–control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (Pheterogeneity = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis. Cancer Res; 72(5); 1064–9. ©2012 AACR.
Relationship between 18F-Fluorodeoxyglucose Accumulation and KRAS/BRAF Mutations in Colorectal Cancer
Authors: Kawada Kenji , Nakamoto Yuji , Kawada Mayumi , Hida Koya , Matsumoto Takuya , Murakami Teppei , Hasegawa Suguru , Togashi Kaori , Sakai Yoshiharu
Published: January 2012

Purpose: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been widely used in the management of colorectal cancer (CRC). However, the relationship between FDG accumulation and KRAS/BRAF mutations has not yet been investigated. The purpose of this study was to investigate whether KRAS/BRAF mutations affect FDG accumulation in CRC.

Experimental Design: Retrospective analysis was conducted in 51 patients with CRC who underwent FDG-PET/computed tomographic (CT) scans for staging before primary tumor resection. The maximum standardized uptake value (SUVmax) for the primary tumor and the tumor-to-liver ratio (TLR) were calculated from FDG accumulation and compared between KRAS/BRAF mutated and wild-type groups. Expression levels of glucose transporter-1 (GLUT1) and hexokinase type-II (HXK-II) were assessed by immunohistochemical analysis.

Results: Both SUVmax and TLR were significantly higher in the KRAS/BRAF-mutated group compared with the wild-type group (P = 0.006 and 0.001, respectively). Multivariate analysis indicated that SUVmax and TLR remained significantly associated with KRAS/BRAF mutations (P = 0.016 and 0.01, respectively). KRAS/BRAF status could be predicted with an accuracy of 75% when a SUVmax cutoff value of 13 or 14 was used. GLUT1 expression in cancer cells was positively correlated with FDG accumulation and KRAS/BRAF status whereas HXK-II expression was not.

Conclusion: FDG accumulation was higher in CRC with KRAS/BRAF mutations. FDG-PET/CT scans may be useful for predicting the KRAS/BRAF status of patients with CRC and thus aid in determination of therapeutic strategies for patients with CRC. Clin Cancer Res; 18(6); 1696–703. ©2012 AACR.