bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Crohn'z meanz Heinz’: foreign body inflammatory mass mimicking Crohn’s disease
Authors: Visagan R , Grossman R , Dimitriadis P A , Desai A
Published: June 2013

The authors present a patient with a presumed diagnosis of Crohn's disease for 6 years turning out to be an unusual inflammatory mass caused by ileal perforation due to a foreign body. When surgical intervention became necessary for admissions with recurrent obstruction, laparoscopy revealed an inflammatory mass in the terminal ileum, exposing two pieces of plastic bearing the word ‘Heinz’. Resection of the inflammatory mass led to the complete resolution of symptoms. Histology from the operative specimen showed no features of Crohn's disease. There were no granulomas and no fissuring ulcers. This case highlights that an inflammatory mass in the small intestine caused by the perforation of ingested foreign body can mimic Crohn's disease. To our knowledge, this is the first report of a synthetic plastic packaging causing ileo-caecal junctional perforation mimicking Crohn’s disease.
Immunoglobulin G4-related disease with scant tissue IgG4
Authors: Makiishi Tetsuya , Shirase Tomoyuki , Hieda Nobuhiro , Maeda Sayako
Published: June 2013

A 56-year-old man was admitted to our hospital for renal dysfunction and symmetrical swelling of submandibular glands. Laboratory and imaging findings were consistent with immunoglobulin G4-related disease (IgG4RD). Histological findings of the submandibular gland and the kidney were also consistent with IgG4RD. However, the patient did not have elevated serum or tissue IgG4 levels. Oral prednisolone therapy, initially 50 mg/day and gradually tapered over 12 months, improved his laboratory abnormalities and the swelling of his affected organs. These findings prompted our final diagnosis of IgG4RD. IgG4RD is a newly recognised disease with an unknown aetiology. This case suggests that IgG4 antibodies do not play a primary role in the aetiology of IgG4RD. Furthermore, clinicians should not exclude the diagnosis of IgG4RD in patients lacking elevated IgG4 levels in their affected tissues, particularly if they have other features of IgG4RD. Steroid therapy should be considered for such patients.
Rapid resolution of pulmonary Langerhans cell histiocytosis
Authors: Chong Sy Giin , Samaha Mario , Samaha Georges , Casserly Brian
Published: June 2013

A 38-year-old woman with a long-term history of smoking presented to the lung cancer clinic with weight loss and recurrent lower respiratory tract infections. A diagnosis of Langerhans cell histiocytosis was made by specimen samples taken from video-assisted thoracoscopic surgery.  She was advised to stop smoking, which she adhered to. She was followed up in the respiratory clinic with pulmonary function tests every 6 months, which were all normal. Follow-up chest x-ray showed complete resolution of the multifocal interstitial infiltrates, and with smoking cessation, the patient has sustained an excellent quality of life.
Solid variant of papillary thyroid carcinoma in a 14-year-old girl
Authors: Wan Abdul Rahman Wan Faiziah , Md Hashim Mohd Nizam , Win Thin Thin , Bakrin Ikmal Hisyam
Published: June 2013

Solid variant of papillary thyroid carcinoma (PTC) is a rare, poorly characterised variant and predominantly reported in children with a history of radiation exposure. This variant has a high propensity for extra-thyroidal extension and cervical lymph node metastases. A 14-year-old Malay girl who had no history of radiation exposure, presented with multiple cervical lymphadenopathy and it was clinically suspicious for tuberculosis or lymphoma. An incisional biopsy revealed a metastatic PTC. The patient underwent total thyroidectomy with bilateral lateral neck dissection and histopathology report was solid variant of PTC. Whole-body I131scan was performed which revealed an intense tracer uptake in the neck. She was planned for radioactive iodine ablation and now on regular follow-up for monitoring of possible tumour metastasis.
An unexpected difficult intubation in a patient with myasthenia gravis undergoing video-assisted transcervical thymectomy
Authors: Grasso Nadia , Celestre Chiara , Borrata Francesco , Migliore Marcello
Published: June 2013

Although there are different methods to evaluate predictive parameters of difficult intubation in apparently normal patients, sometimes this event is unpredictable.We herein report a clinical case of difficult intubation during anaesthesia for video-assisted thymectomy in non-thymomatous myasthenia gravis.
Syncope caused by coronary artery spasm without chest pain leading to ventricular fibrillation
Authors: Kawasaki Yusuke , Kato Takao , Minamino Eri , Inoko Moriaki
Published: June 2013

We present a case of syncope caused by coronary artery spasm without chest pain leading to ventricular fibrillation despite of vasodilator therapy with a calcium channel blocker (CCB). A 68-year-old man presented with two episodes of syncope without chest pain. Ergonovine provocation test induced a diffuse spasm in the right coronary artery (RCA) and subsequently, ventricular fibrillation. Under the therapy with multiple vasodilators including two CCBs, a second ergonovine provocation induced a spasm of the proximal RCA resulting in complete obstruction. Owing to drug-resistant coronary spasm complicated by ventricular fibrillation, an implantable cardioverter defibrillator (ICD) was implanted. This case report highlights the occurrence of syncope caused by coronary artery spasm without chest pain that was refractory to single CCB therapy and needed ICD implantation. Therapy with multiple vasodilators, including two or more CCBs, along with ICD implantation may be required to treat such refractory coronary artery spasms leading to lethal arrhythmia.
Restoration of fractured anterior permanent teeth using reference guide technique
Authors: Nayak Ullal Anand , Khandelwal Vishal , Nayak Prathibha Anand , Thakur Jandel S
Published: June 2013

The most common consequence of traumatic dental injury is uncomplicated crown fracture. The main techniques for reconstructing fractured teeth include the use of direct adhesive restorative materials. However, this type of treatment is time consuming and requires a skilled operator. An alternative to the direct restorative technique is the use of a reference guide. The advantage is that the restorative procedure can be carried out in two short clinical sessions with a drastic reduction in chair time. The size, shape and inclination of the teeth are determined in advance, which reduces the need for eventual adjustments. In addition, the use of a reference guide makes it possible for two or more teeth to be restored simultaneously; in contrast, with the conventional technique. This paper offers a step-by-step description, of a reference guide technique for restoration of permanent maxillary incisors fractured through trauma.
Huddling for high reliability and situation awareness
Authors: Goldenhar Linda M , Brady Patrick W , Sutcliffe Kathleen M , Muething Stephen E
Published: June 2013

Background

Studies show that implementing huddles in healthcare can improve a variety of outcomes. Yet little is known about the mechanisms through which huddles exert their effects. To help remedy this gap, our study objectives were to explore hospital administrator and frontline staff perspectives on the benefits and challenges of implementing a tiered huddle system; and propose a model based on our findings depicting the mediating pathways through which implementing a huddle system may reduce patient harm.

Methods

Using qualitative methods, we conducted semi-structured interviews and focus groups to obtain a deeper understanding of the huddle system and its outcomes as implemented in an academic tertiary care children's hospital with 539 inpatient beds. We recruited healthcare providers representing all levels using a snowball sampling technique (10 interviews), and emails, flyers, and paper invitations (six focus groups). We transcribed recordings and analysed the data using established techniques.

Results

Five themes emerged and provided the foundational constructs of our model. Specifically we propose that huddle implementation leads to improved efficiencies and quality of information sharing, increased levels of accountability, empowerment, and sense of community, which together create a culture of collaboration and collegiality that increases the staff's quality of collective awareness and enhanced capacity for eliminating patient harm.

Conclusions

While each construct in the proposed model is itself a beneficial outcome of implementing huddles, conceptualising the pathways by which they may work allows us to design ways to evaluate other huddle implementation efforts designed to help reduce failures and eliminate patient harm.
Reduction of unnecessary use of indwelling urinary catheters
Authors: Janzen Jolien , Buurman Bianca M , Spanjaard Lodewijk , de Reijke Theo M , Goossens Astrid , Geerlings Suzanne E
Published: June 2013

Background

The most effective way to reduce catheter-associated urinary tract infections (CA-UTIs) is to avoid unnecessary urinary catheterisation and to minimise the duration of catheterisation.

Aim

To implement and assess the effect of an intervention to reduce the duration of urinary tract catheterisation.

Methods

This quality improvement project was set up as a before–after comparison consisting of a 2-month pre-intervention period, a period in which the intervention was implemented and a 2-month post-intervention period. The intervention included educational sessions to increase physicians' awareness and the daily reassessment of catheter use. The primary endpoint was the duration of catheterisation. Secondary endpoints were the catheter utilisation ratio, the length of hospital stay, the number of hospital-acquired symptomatic CA-UTIs and the number of appropriate indications for catheterisation.

Results

During the total study period, 149 patients (18.3%) were catheterised at some time during their hospital stay. There was a statistically significant decrease in the duration of catheterisation (median 7 vs 5 days; p<0.01), length of hospital stay (median 13 vs 9 days; p<0.01), and number of hospital-acquired CA-UTIs (4 vs 0, p=0.04) in the pre-intervention versus post-intervention period.

Conclusions

An intervention to raise more awareness of the risks of inappropriate catheterisation can reduce the duration of catheterisation along with the length of hospital stay and the number of hospital-acquired symptomatic CA- UTIs, even in a short period of time.
Global epidemiology ofTrichomonas vaginalis
Authors: Poole Danielle N , McClelland R Scott
Published: June 2013

Despite having the highest prevalence of any sexually transmitted infection (STI) globally, there is a dearth of data describingTrichomonas vaginalis(TV) incidence and prevalence in the general population. The lack of basic epidemiological data is an obstacle to addressing the epidemic. Once considered a nuisance infection, the morbidities associated with TV have been increasingly recognised over the past decade, highlighting the importance of this pathogen as a public health problem. Recent developments in TV diagnostics and molecular biology have improved our understanding of TV epidemiology. Improved characterisation of the natural history of TV infection has allowed us to hypothesise possible explanations for observed variations in TV prevalence with age. Direct and indirect hormonal effects on the female genital tract provide a likely explanation for the greater burden of persistent TV infection among women compared with men. Further characterisation of the global epidemiology of TV could enhance our ability to respond to the TV epidemic.
DIMENSIONALITY REDUCTION FOR SENSORY DATASETS BASED ON MASTER–SLAVE SYNCHRONIZATION OF LORENZ SYSTEM
Authors: GHAFFARI REZA , GROSU IOAN , ILIESCU DACIANA , HINES EVOR , LEESON MARK
Published: June 2013

In this study, we propose a novel method for reducing the attributes of sensory datasets using Master–Slave Synchronization of chaotic Lorenz Systems (DPSMS). As part of the performance testing, three benchmark datasets and one Electronic Nose (EN) sensory dataset with 3 to 13 attributes were presented to our algorithm to be projected into two attributes. The DPSMS-processed datasets were then used as input vector to four artificial intelligence classifiers, namely Feed-Forward Artificial Neural Networks (FFANN), Multilayer Perceptron (MLP), Decision Tree (DT) and K-Nearest Neighbor (KNN). The performance of the classifiers was then evaluated using the original and reduced datasets. Classification rate of 94.5%, 89%, 94.5% and 82% were achieved when reduced Fishers iris, crab gender, breast cancer and electronic nose test datasets were presented to the above classifiers.
CHAOS ENTANGLEMENT: A NEW APPROACH TO GENERATE CHAOS
Authors: ZHANG HONGTAO , LIU XINZHI , SHEN XUEMIN , LIU JUN
Published: June 2013

A new approach to generate chaotic phenomenon, called chaos entanglement, is proposed in this paper. The basic principle is to entangle two or multiple stable linear subsystems by entanglement functions to form an artificial chaotic system such that each of them evolves in a chaotic manner. Firstly, a new attractor, entangling a two-dimensional linear subsystem and a one-dimensional one by sine function, is presented as an example. Dynamical analysis shows that both entangled subsystems are bounded and all equilibra are unstable saddle points when chaos entanglement is achieved. Also, numerical computation shows that this system has one positive Lyapunov exponent, which implies chaos. Furthermore, two conditions are given to achieve chaos entanglement. Along this way, by different linear subsystems and different entanglement functions, a variety of novel chaotic attractors have been created and abundant complex dynamics are exhibited. Our discovery indicates that it is not difficult any more to construct new artificial chaotic systems/networks for engineering applications such as chaos-based secure communication. Finally, a possible circuit is given to realize these new chaotic attractors.
EXPANDABLE CIRCUITS OF MUTATOR-BASED MEMCAPACITOR EMULATOR
Authors: SAH MAHESHWAR PD. , BUDHATHOKI RAM KAJI , YANG CHANGJU , KIM HYONGSUK
Published: June 2013

An efficient method to build the expandable circuits of memcapacitor (MC) emulator in various configurations is proposed using our expandable memristor (MR) emulator. Most of the previous studies succeeded in designing only a stand-alone memcapacitor emulator. In this study, the expandable architecture of memcapacitor emulator is addressed, where the connectivity and interoperability are the main concern. It is shown that the memcapacitor circuits can be built only with memristors together with a single mutator, which is connected after each input source. Examples of serial, parallel and hybrid memcapacitor circuits are demonstrated in this paper. Also, it is shown that complicated circuits of Wye (Y) and Delta (Δ) memcapacitor connections with multiple input sources can be built with the proposed memcapacitor emulator. Various simulation results showing the proper operations of the proposed mutator-based expandable memcapacitor emulators are included in this paper.
SPIRAL DYNAMICS IN EXCITABLE MEDIUM INDUCED BY EXTERNAL PERIODIC MODULATION
Authors: QIAN YU , LI WEI , HUANG XIAODONG , ZHANG ZHAOYANG , MI YUANYUAN
Published: June 2013

Spatiotemporal dynamics of spiral tip and the evolution of spiral wave induced by external periodic modulation has been investigated in a generic excitable model. Tip dynamics of spiral wave depending on the frequency and strength of the external modulation is revealed by the meandering size variable Rx of the tip trajectory. Different effects of frequency and strength on spiral dynamics are observed and the corresponding mechanisms are explained. Finally, we can eliminate spiral wave out of the boundary successfully by suitably choosing the frequency and the strength of the external periodic modulation.
CONTROL AND SYNCHRONIZATION OF JULIA SETS OF THE COMPLEX PERTURBED RATIONAL MAPS
Authors: ZHANG YONGPING
Published: June 2013

The dynamical and fractal behaviors of the complex perturbed rational maps [Formula: see text] are discussed in this paper. And the optimal control function method is taken on the Julia set of this system. In this control method, infinity is regarded as a fixed point to be controlled. By substituting the driving item for an item in the optimal control function, synchronization of Julia sets of two such different systems is also studied.
CHAOS ON HYPERSPACE
Authors: BERAN ZDENĚK , ČELIKOVSKÝ SERGEJ
Published: June 2013

In this paper, the chaotic behavior of a set-valued mapping F : X → 2X, where X is a compact space, is investigated. The existence of the generalized shadowing property in the hyperspace 2X is proved. Based on the generalized shadowing property of the set-valued mappings F and the assumption of the existence of an unstable chain recurrent point of the mapping F, it is shown that the Bernoulli system of bi-directional shifts is embedded in the sense of semiconjugacy into the image of mapping F, i.e. Smale's chaos in the set-valued system F is thereby proved.
ASYMMETRIC PERIODIC MOTIONS WITH CHAOS IN A SOFTENING DUFFING OSCILLATOR
Authors: LUO ALBERT C. J. , HUANG JIANZHE
Published: June 2013

In this paper, asymmetric periodic motions in a periodically forced, softening Duffing oscillator are presented analytically through the generalized harmonic balance method. For the softening Duffing oscillator, the symmetric periodic motions with jumping phenomena were understood very well. However, asymmetric periodic motions in the softening Duffing oscillators are not investigated analytically yet, and such asymmetric periodic motions possess much richer dynamics than the symmetric motions in the softening Duffing oscillator. For asymmetric motions, the bifurcation tree from asymmetric period-1 motions to chaos is discussed comprehensively. The corresponding, unstable and stable, asymmetric and symmetric, periodic motions in the softening Duffing oscillator are presented, and numerical illustrations of stable and unstable periodic motions are completed. This investigation provides a better picture of complex motion in the softening Duffing oscillator.
TRAVELING WAVE SOLUTIONS OF THE GREEN–NAGHDI SYSTEM
Authors: DENG SHENGFU , GUO BOLING , WANG TINGCHUN
Published: June 2013

We investigate the traveling wave solutions of the Green–Naghdi system. Using the qualitative analysis methods of planar autonomous systems, we show not only its phase portraits but also the exact expressions of some bounded wave solutions. These results are a complement of the work by Deng et al. [2011], which studied the traveling wave solutions of its equivalent system under some conditions.
STEADY STATE SYMMETRY BREAKING IN PERIODICALLY EXCITED SYSTEMS INVOLVING TIME DELAY BY HARMONIC HOMOTOPY
Authors: LEUNG A. Y. T. , GUO ZHONGJIN
Published: June 2013

Symmetry breaking is a ubiquitous and important phenomenon arising in a wide range of physical systems. We propose the use of the harmonic balance in combination with homotopy continuation to investigate symmetry breaking occurrence in the periodically excited systems involving time delay. Two numerical examples are given to show the details. When the Hopfield neural network is subject to external excitation, we investigate the relation of the magnitude of excitation versus the amplitude of the bias term and analyze the effect of time delay on the steady state response. The second example concerns the delayed feedback control of a nonlinear beam subject to moving load. The relationship of the position feedback gain, external excitation frequency and time delay versus the amplitudes of steady state responses are studied analytically. The symmetry breaking points are accurately predicted. In addition, the Runge–Kutta numerical simulation results are used to cross-check the efficiency and accuracy.
SMOOTH AND NONSMOOTH BIFURCATIONS IN MULTI-STRUCTURE MULTI-OPERATING-MODE HYBRID POWER SYSTEMS
Authors: XIONG XIAOLING , TSE CHI K. , RUAN XINBO
Published: June 2013

Hybrid renewable power generation systems have been developed rapidly in recent years. Due to the inherent fluctuation of availability of energy from renewable sources, systems that are designed to capture energy from such sources and deliver it in loads have to cope with the difficult challenges of maintaining stability under all possible operating conditions. As a result, the structures and operating modes of such hybrid systems are inherently time-varying. Due to their multiple structures and operating-modes, hybrid systems have rather complex dynamic behavior and the design for stable operation requires thorough consideration of the effects of variation in parameters on the operating modes and corresponding stability statuses. This paper presents a formal system description for such systems and a general procedure for analyzing the change of dynamical behavior under parameter variations (i.e. bifurcation) of this kind of systems. A hybrid power system consisting of dual-input buck converters is taken as an example for illustrating the possible complex behavior. We reveal smooth and nonsmooth bifurcation phenomena in this system. Under certain conditions, nonsmooth bifurcations have been observed and verified with full-circuit simulations. Moreover, a detailed analysis based on an averaged model is performed to identify two specific types of bifurcation and evaluate the stability boundaries of the system.
Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis
Authors: Zhao Lishan , Chang Wei-chen , Xiao Youli , Liu Hung-wen , Liu Pinghua
Published: June 2013

Isoprenoids are a class of natural products with more than 55,000 members. All isoprenoids are constructed from two precursors, isopentenyl diphosphate and its isomer dimethylallyl diphosphate. Two of the most important discoveries in isoprenoid biosynthetic studies in recent years are the elucidation of a second isoprenoid biosynthetic pathway [the methylerythritol phosphate (MEP) pathway] and a modified mevalonic acid (MVA) pathway. In this review, we summarize mechanistic insights on the MEP pathway enzymes. Because many isoprenoids have important biological activities, the need to produce them in sufficient quantities for downstream research efforts or commercial application is apparent. Recent advances in both MVA and MEP pathway–based synthetic biology are also illustrated by reviewing the landmark work of artemisinic acid and taxadien-5α-ol production through microbial fermentations.
Correlating Structure and Energetics in Protein-Ligand Interactions: Paradigms and Paradoxes
Authors: Martin Stephen F. , Clements John H.
Published: June 2013

Predicting protein-binding affinities of small molecules, even closely related ones, is a formidable challenge in biomolecular recognition and medicinal chemistry. A thermodynamic approach to optimizing affinity in protein-ligand interactions requires knowledge and understanding of how altering the structure of a small molecule will be manifested in protein-binding enthalpy and entropy changes; however, there is a relative paucity of such detailed information. In this review, we examine two strategies commonly used to increase ligand potency. The first of these involves introducing a cyclic constraint to preorganize a small molecule in its biologically active conformation, and the second entails adding nonpolar groups to a molecule to increase the amount of hydrophobic surface that is buried upon binding. Both of these approaches are motivated by paradigms suggesting that protein-binding entropy changes should become more favorable, but paradoxes can emerge that defy conventional wisdom.
Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling
Authors: Yamamoto Shuji , Nakase Hiroshi , Matsuura Minoru , Honzawa Yusuke , Matsumura Kayoko , Uza Norimitsu , Yamaguchi Yu , Mizoguchi Emiko , Chiba Tsutomu
Published: June 2013

Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.
Regulated traffic of anion transporters in mammalian Brunner's glands: a role for water and fluid transport
Authors: Collaco Anne M. , Jakab Robert L. , Hoekstra Nadia E. , Mitchell Kisha A. , Brooks Amos , Ameen Nadia A.
Published: June 2013

The Brunner's glands of the proximal duodenum exert barrier functions through secretion of glycoproteins and antimicrobial peptides. However, ion transporter localization, function, and regulation in the glands are less clear. Mapping the subcellular distribution of transporters is an important step toward elucidating trafficking mechanisms of fluid transport in the gland. The present study examined 1) changes in the distribution of intestinal anion transporters and the aquaporin 5 (AQP5) water channel in rat Brunner's glands following second messenger activation and 2) anion transporter distribution in Brunner's glands from healthy and disease-affected human tissues. Cystic fibrosis transmembrane conductance regulator (CFTR), AQP5, sodium-potassium-coupled chloride cotransporter 1 (NKCC1), sodium-bicarbonate cotransporter (NBCe1), and the proton pump vacuolar ATPase (V-ATPase) were localized to distinct membrane domains and in endosomes at steady state. Carbachol and cAMP redistributed CFTR to the apical membrane. cAMP-dependent recruitment of CFTR to the apical membrane was accompanied by recruitment of AQP5 that was reversed by a PKA inhibitor. cAMP also induced apical trafficking of V-ATPase and redistribution of NKCC1 and NBCe1 to the basolateral membranes. The steady-state distribution of AQP5, CFTR, NBCe1, NKCC1, and V-ATPase in human Brunner's glands from healthy controls, cystic fibrosis, and celiac disease resembled that of rat; however, the distribution profiles were markedly attenuated in the disease-affected duodenum. These data support functional transport of chloride, bicarbonate, water, and protons by second messenger-regulated traffic in mammalian Brunner's glands under physiological and pathophysiological conditions.
Registration-based assessment of regional lung function via volumetric CT images of normal subjects vs. severe asthmatics
Authors: Choi Sanghun , Hoffman Eric A. , Wenzel Sally E. , Tawhai Merryn H. , Yin Youbing , Castro Mario , Lin Ching-Long
Published: June 2013

The purpose of this work was to explore the use of image registration-derived variables associated with computed tomographic (CT) imaging of the lung acquired at multiple volumes. As an evaluation of the utility of such an imaging approach, we explored two groups at the extremes of population ranging from normal subjects to severe asthmatics. A mass-preserving image registration technique was employed to match CT images at total lung capacity (TLC) and functional residual capacity (FRC) for assessment of regional air volume change and lung deformation between the two states. Fourteen normal subjects and thirty severe asthmatics were analyzed via image registration-derived metrics together with their pulmonary function test (PFT) and CT-based air-trapping. Relative to the normal group, the severely asthmatic group demonstrated reduced air volume change (consistent with air trapping) and more isotropic deformation in the basal lung regions while demonstrating increased air volume change associated with increased anisotropic deformation in the apical lung regions. These differences were found despite the fact that both PFT-derived TLC and FRC in the two groups were nearly 100% of predicted values. Data suggest that reduced basal-lung air volume change in severe asthmatics was compensated by increased apical-lung air volume change and that relative increase in apical-lung air volume change in severe asthmatics was accompanied by enhanced anisotropic deformation. These data suggest that CT-based deformation, assessed via inspiration vs. expiration scans, provides a tool for distinguishing differences in lung mechanics when applied to the extreme ends of a population range.
Does hypercapnia-induced impairment of cerebral autoregulation affect neurovascular coupling? A functional TCD study
Authors: Maggio Paola , Salinet Angela S. M. , Panerai Ronney B. , Robinson Thompson G.
Published: June 2013

Neurovascular coupling (NVC) and dynamic cerebral autoregulation (dCA) are both impaired in the acute phase of ischemic stroke, but their reciprocal interactions are difficult to predict. To clarify these aspects, the present study explored NVC in a healthy volunteer population during a surrogate state of impaired dCA induced by hypercapnia. This study aimed to test whether hypercapnia leads to a depression of NVC through an impairment of dCA. Continuous recordings of middle cerebral arteries cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end-tidal CO2 were performed in 19 right-handed subjects (aged >45 yr) before, during, and after 60 s of a passive paradigm during normocapnia and hypercapnia. The CBFv response was broken down into subcomponents describing the relative contributions of BP (VBP), critical closing pressure (VCrCP), and resistance area product (VRAP). VRAP reflects myogenic activity in response to BP changes, whereas VCrCP is more indicative of metabolic control. The results revealed that hypercapnia significantly affected NVC, with significant reductions in the relative contribution of VCrCP to the paradigm-induced increase in CBFv. The present study suggests that hypercapnia impairs both dCA and NVC, probably acting through an impairment of the metabolic component of CBF control.
Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms
Authors: Stanhewicz Anna E. , Alexander Lacy M. , Kenney W. Larry
Published: June 2013

Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 ± 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer's solution, 2) 10 mM BH4, and 3) 20 mM NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1°C rise in oral temperature, mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (%CVCmax 28 mM sodium nitroprusside and local heat 43°C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 ± 2 pmol/ml vs. 3 h: 43.8 ± 3 pmol/ml; P < 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 ± 1 %CVCmax vs. sapropterin: 25 ± 4 %CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 ± 1 %CVCmax vs. BH4-treated: 24 ± 3 %CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans.
IL-10 Promotes Tumor Aggressiveness via Upregulation of CIP2A Transcription in Lung Adenocarcinoma
Authors: Sung Wen-Wei , Wang Yao-Chen , Lin Po-Lin , Cheng Ya-Wen , Chen Chih-Yi , Wu Tzu-Chin , Lee Huei
Published: June 2013

Purpose: Interleukin-10 (IL-10) determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial.

Experimental Design: To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10–mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were conducted. IL-10 and CIP2A mRNA levels in lung tumors from patients with lung cancer were determined by real-time reverse transcription PCR. The prognostic value of both molecules on survival was estimated by Cox regression model.

Results: Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6 knockdown TL1 cells and increased in E6- overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of cAMP response element-binding protein (CREB) and C/enhancer-binding protein β (C/EBPβ) via phosphoinositide 3-kinase (PI3K) signaling pathway. IL-10–mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors.

Conclusion: IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients’ outcome and life quality. Clin Cancer Res; 19(15); 4092–103. ©2013 AACR.
A New Alpha in Line Between KRAS and NF-κB Activation?
Authors: Pak Chorom , Miyamoto Shigeki
Published: June 2013

Summary: Bang and colleagues report a novel role for GSK-3α, rather than the well-studied GSK-3β, as the link between oncogenic KRAS and the canonical and noncanonical activation pathways of NF-κB in pancreatic cancer. Although the mechanism through which it promotes noncanonical activation remains unclear, the authors show that GSK-3α binds and stabilizes TAK1-TAB complexes to constitutively activate canonical NF-κB signaling. Consequently, the inhibition of GSK-3α retards pancreatic cancer growth in vitro and in vivo, thereby revealing this relatively less-studied kinase as a potential therapeutic target for treatment of KRAS-positive pancreatic cancer. Cancer Discov; 3(6); 613–5. ©2013 AACR.

See related article by Bang et al., p. 690
Performing Radical Cystectomy and Urinary Diversion in Regional Anesthesia: Potential Risk Reduction in the Treatment of Bladder Cancer
Authors: Friedrich-Freksa M. , Schulz E. , Nitzke T. , Wenzel O. , Popken G.
Published: June 2013

Objective: To assess the feasibility and performance of radical cystectomy with urinary diversion using exclusively regional anesthesia (i.e. combined spinal thoracic epidural anesthesia, CSTEA), avoiding the adverse effects of general anesthesia. Materials and Methods: In our hospital, radical cystectomy with extended pelvic and iliac lymphadenectomy and urinary diversion was performed on 28 patients using CSTEA without applying general anesthesia, in 2011 and 2012. Under maintained spontaneous breathing, the patients were awake and responsive during the entire procedure. Outcome measurements included operative time, blood loss, start of oral nutrition, start of mobilization, postoperative pain levels using numerical and visual analog scales (NAS/VAS), postoperative complications according to the Clavien-Dindo classification and length of hospital stay. Results: All surgical procedures were performed without any complications and caused no anesthesiologically or surgically untoward effects. We observed no more severe complications than grade 1 according to the Clavien-Dindo classification. Conclusions: Our data show that CSTEA is an effective and safe technique for radical cystectomy, whereby spontaneous breathing and reduced interference with the cardiopulmonary system potentially lower the perioperative risks, especially for high-risk patients. We recommend practice of CSTEA for radical cystectomy to further evaluate and monitor the safety, efficacy, outcomes and complications of CSTEA.
Schistosoma Antigens Downmodulate the in vitro Inflammatory Response in Individuals Infected with Human T Cell Lymphotropic Virus Type 1
Authors: Lima Luciane Mota , Santos Silvane Braga , Oliveira Ricardo Riccio , Cardoso Luciana Santos , Oliveira Sérgio Costa , Góes Alfredo Miranda , Loukas Alex , Carvalho Edgar M. , Araújo Maria Ilma
Published: June 2013

Human T cell lymphotropic virus type 1 (HTLV-1) is the causal agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While the immune response to HTLV-1 infection is polarized to the Th1-type, chronic helminth infections drive the Th2- and T regulatory-type, and are able to downregulate the inflammatory response in some autoimmune diseases. Objective: To evaluate whether Schistosoma spp. antigens alter the in vitro cytokine response in HTLV-1 infection. Methods: The recombinant Schistosoma antigens Sm29 and ShTSP2 (tetraspanin) and PIII, a fraction of the Schistosoma mansoni adult worm antigen were added to peripheral blood mononuclear cell (PBMC) cultures of HTLV-1-infected individuals and the levels of interferon (IFN)-γ and interleukin (IL)-10 in the supernatants were measured using the ELISA sandwich technique. Results: Compared to the levels of cytokine in nonstimulated cultures, the levels of IFN-γ were reduced in 50, 47 and 50% of patients by the presence of Sm29, ShTsp2 and PIII, respectively. The downregulation of IFN-γ production in the presence of Sm29 antigen was observed mainly in subjects who had lower basal levels of this cytokine. The levels of IL-10, however, increased by the addition of the three antigens in the cultures in 74, 62 and 44% of individuals, respectively. In addition, there was a decrease in the ratio of IFN-γ/IL-10 levels in cultures stimulated with Sm29 and ShTSP2 when compared to nonstimulated ones. Conclusions: The Schistosoma spp. antigens used in this study were able to downmodulate IFN-γ production in vitro in HTLV-1 infection. This may be associated with the increased levels of IL-10 induced by the antigens.
Viewpoint: Mismatch between the European and American guidelines on oral antiplatelet P2Y12 inhibitors after acute coronary syndromes
Authors: DiNicolantonio James , Serebruany Victor
Published: June 2013

Recent European Society of Cardiology (ESC) Guidelines declare superiority of prasugrel and ticagrelor over clopidogrel in non-ST segment elevation myocardial infarction (NSTEMI) and STEMI patients with acute coronary syndromes (ACS). The recommendations for NSTEMI and especially STEMI are based on a subgroup analyses yielded from a single trial with either prasugrel (TRITON), or ticagrelor (PLATO). In contrast, the United States (US) Guidelines present a more balanced, conservative, and evidence-based outlook suggesting no proven extra benefit of one P2Y12 antagonist over the other(s). It was the purpose of this study to scrutinise the evidence leading to the current ESC ACS Guidelines on oral antiplatelet agents and compare them with US recommendations. Matching the evidence from TRITON and PLATO primary publications with the data reported in the Food and Drug Administration (FDA) official reviews in light of their impact on current regional ACS Guidelines on antiplatelet P2Y12 inhibitors. The available body of evidence on the efficacy and safety of the new oral P2Y12 inhibitors challenge the ESC Guidelines, and supports the US recommendations. Some of the pivotal data with regard to the newer P2Y12 inhibitors (prasugrel and ticagrelor) on event definition, adjudication, questionable efficacy, and serious safety concerns were ignored by the European Task Force Members, while the other “beneficial” findings were exaggerated to a disproportional extent. We conclude that current ESC Guidelines, with regard to their recommendation of superiority of prasugrel or ticagrelor over clopidogrel, in contrast to the US, are overoptimistic, and not evidence based. Low clinical utilisation of prasugrel and especially ticagrelor worldwide in general, and Europe in particular suggests mismatch of prescription habits with issued ESC recommendations.
Liver-Specific Cholesteryl Ester Hydrolase Deficiency Attenuates Sterol Elimination in the Feces and Increases Atherosclerosis in
Ldlr
−/−
Mice
Authors: Bie Jinghua , Wang Jing , Marqueen Kathryn E. , Osborne Rachel , Kakiyama Genta , Korzun William , Ghosh Siddhartha S. , Ghosh Shobha
Published: June 2013

Objective—

Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CEs) is essential to generate the free cholesterol required for this process. Earlier, we demonstrated that overexpression of human CE hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis.

Approach and Results—

Liver-specific Ces3 knockout mice (Ces3-LKO) were generated, and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and free cholesterol or bile acid transport. The effects of Ces3 deficiency on the development of Western diet–induced atherosclerosis were examined in low density lipoprotein receptor knock out
−/−
mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in low density lipoprotein receptor knock out
−/−
Ces3-LKO mice along with a significant decrease in the bile acid content of bile. Ces3 deficiency significantly reduced the flux of cholesterol from [
3
H]-CE–labeled high-density lipoproteins to feces (as free cholesterol and bile acids) and decreased total fecal sterol elimination.

Conclusions—

Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CEs and thereby regulates free cholesterol and bile acid secretion into the feces. Therefore, its deficiency results in reduced cholesterol elimination from the body, leading to significant increase in atherosclerosis. Collectively, these data establish the antiatherogenic role of hepatic CE hydrolysis.
Circulating p53-Responsive MicroRNAs Are Predictive Indicators of Heart Failure After Acute Myocardial Infarction
Authors: Matsumoto Sen , Sakata Yasuhiko , Suna Shinichiro , Nakatani Daisaku , Usami Masaya , Hara Masahiko , Kitamura Tetsuhisa , Hamasaki Toshimitsu , Nanto Shinsuke , Kawahara Yukio , Komuro Issei
Published: June 2013

Rationale:

Despite a recent decline of in-hospital mortality attributable to acute myocardial infarction (AMI), the incidence of ischemic heart failure (HF) in post-AMI patients is increasing. Although various microRNAs have been proposed as diagnostic indicators for AMI, no microRNAs have been established as predictors of ischemic HF that develops after AMI.

Objective:

We attempted to identify circulating microRNAs that can serve as reliable predictors of ischemic HF in post-AMI patients.

Methods and Results:

Using sera collected a median of 18 days after AMI onset, we screened microRNAs in 21 patients who experienced development of HF within 1 year after AMI and in 65 matched controls without subsequent cardiovascular events after discharge. Among the 377 examined microRNAs, the serum level of only miR-192 was significantly upregulated in AMI patients with development of ischemic HF. Because miR-192 is reported to be p53-responsive, the serum levels of 2 other p53-responsive microRNAs, miR-194 and miR-34a, also were investigated. Interestingly, both microRNAs were coordinately increased with miR-192, particularly in exosomes, suggesting that these microRNAs function as circulating regulators of HF development via the p53 pathway. Furthermore, miR-194 and miR-34a expression levels were significantly correlated with left ventricular end-diastolic dimension 1 year after AMI.

Conclusions:

In the sera of post-AMI patients who experienced development of de-novo HF within 1 year of AMI onset, the levels of 3 p53-responsive microRNAs had been elevated by the early convalescent stage of AMI. Further investigations are warranted to confirm the usefulness of these circulating microRNAs for predicting the risk of development of ischemic HF after AMI.
HCN4 Dynamically Marks the First Heart Field and Conduction System Precursors
Authors: Liang Xingqun , Wang Gang , Lin Lizhu , Lowe Jennifer , Zhang Qingquan , Bu Lei , Chen Yihan , Chen Ju , Sun Yunfu , Evans Sylvia M.
Published: June 2013

Rationale:

To date, there has been no specific marker of the first heart field to facilitate understanding of contributions of the first heart field to cardiac lineages. Cardiac arrhythmia is a leading cause of death, often resulting from abnormalities in the cardiac conduction system (CCS). Understanding origins and identifying markers of CCS lineages are essential steps toward modeling diseases of the CCS and for development of biological pacemakers.

Objective:

To investigate HCN4 as a marker for the first heart field and for precursors of distinct components of the CCS, and to gain insight into contributions of first and second heart lineages to the CCS.

Methods and Results:

HCN4CreERT2, -nuclear LacZ, and -H2BGFP mouse lines were generated. HCN4 expression was examined by means of immunostaining with HCN4 antibody and reporter gene expression. Lineage studies were performed using HCN4CreERT2, Isl1Cre, Nkx2.5Cre, and Tbx18Cre, coupled to coimmunostaining with CCS markers. Results demonstrated that, at cardiac crescent stages, HCN4 marks the first heart field, with HCN4CreERT2 allowing assessment of cell fates adopted by first heart field myocytes. Throughout embryonic development, HCN4 expression marked distinct CCS precursors at distinct stages, marking the entire CCS by late fetal stages. We also noted expression of HCN4 in distinct subsets of endothelium at specific developmental stages.

Conclusions:

This study provides insight into contributions of first and second heart lineages to the CCS and highlights the potential use of HCN4 in conjunction with other markers for optimization of protocols for generation and isolation of specific conduction system precursors.