bluuebunny/crossref_metadata_2025 huggingface dataset:
Lag Synchronization in Coupled Multistable van der Pol-Duffing Oscillators
Authors: Dudkowski Dawid , Kuzma Patrycja , Kapitaniak Tomasz
Published: April 2014

We consider the system of externally excited identical van der Pol-Duffing oscillators unidirectionally coupled in a ring. When the coupling is introduced, each of the oscillator’s trajectories is on different attractor. We study the changes in the dynamics due to the increase in the coupling coefficient. Studying the phase of the oscillators, we calculate the parameter value for which we obtain the antiphase lag synchronization of the system and also the bifurcation values for which we observe qualitative changes in the dynamics of already synchronized system. We give evidence that lag synchronization is typical for coupled multistable systems.
Transjugular Intrahepatic Portosystemic Shunt for the Treatment of Portal Hypertension in Noncirrhotic Patients with Portal Cavernoma
Authors: Luo Xuefeng , Nie Ling , Zhou Biao , Yao Denghua , Ma Huaiyuan , Jiang Mingshan , Zhang Hailong , Li Xiao
Published: April 2014

Background. The purpose of this study was to evaluate the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) placement in the management of portal hypertension in noncirrhotic patients with portal cavernoma.Methods. We conducted a single institution retrospective analysis of 15 noncirrhotic patients with portal cavernoma treated with TIPS placement. 15 patients (4 women and 11 men) were evaluated via the technical success of TIPS placement, procedural complications, and follow-up shunt patency.Results. TIPS placement was technically successful in 11 out of 15 patients (73.3%). Procedure-related complications were limited to a single instance of hepatic encephalopathy in one patient. In patients with successful shunt placement, the portal pressure gradient decreased from25.8±5.7to9.5±4.2 mmHg (P<0.001). TIPS dysfunction occurred in two patients during a median follow-up time of 45.2 months. Revision was not performed in one patient due to inadequate inflow. The other patient died of massive gastrointestinal bleeding in a local hospital. The remaining nine patients maintained functioning shunts through their last evaluation.Conclusions. TIPS is a safe and effective therapeutic treatment for noncirrhotic patients with symptomatic portal hypertension secondary to portal cavernoma.
Nuclear Distribution of RNA Polymerase II and mRNA Processing Machinery in Early Mammalian Embryos
Authors: Bogolyubova Irina O. , Bogolyubov Dmitry S.
Published: April 2014

Spatial distribution of components of nuclear metabolism provides a significant impact on regulation of the processes of gene expression. While distribution of the key nuclear antigens and their association with the defined nuclear domains were thoroughly traced in mammalian somatic cells, similar data for the preimplantation embryos are scanty and fragmental. However, the period of cleavage is characterized by the most drastic and dynamic nuclear reorganizations accompanying zygotic gene activation. In this minireview, we try to summarize the results of studies concerning distribution of major factors involved in RNA polymerase II-dependent transcription, pre-mRNA splicing mRNA export that have been carried out on early embryos of mammals.
Dynamic Surface Control and Its Application to Lateral Vehicle Control
Authors: Song Bongsob , Hedrick J. Karl , Kang Yeonsik
Published: April 2014

This paper extends the design and analysis methodology of dynamic surface control (DSC) in Song and Hedrick, 2011, for a more general class of nonlinear systems. When rotational mechanical systems such as lateral vehicle control and robot control are considered for applications, sinusoidal functions are easily included in the equation of motions. If such a sinusoidal function is used as a forcing term for DSC, the stability analysis faces the difficulty due to highly nonlinear functions resulting from the low‐pass filter dynamics. With modification of input variables to the filter dynamics, the burden of mathematical analysis can be reduced and stability conditions in linear matrix inequality form to guarantee the quadratic stability via DSC are derived for the given class of nonlinear systems. Finally, the proposed design and analysis approach are applied to lateral vehicle control for forward automated driving and backward parallel parking at a low speed as well as an illustrative example.
Conception of Biologic System: Basis Functional Elements and Metric Properties
Authors: Davydyan Garri
Published: April 2014

A notion of biologic system or just a system implies a functional wholeness of comprising system components. Positive and negative feedback are the examples of how the idea to unite anatomical elements in the whole functional structure was successfully used in practice to explain regulatory mechanisms in biology and medicine. There are numerous examples of functional and metabolic pathways which are not regulated by feedback loops and have a structure of reciprocal relationships. Expressed in the matrix form positive feedback, negative feedback, and reciprocal links represent three basis elements of a Lie algebra sl(2,ℝ) of a special linear group SL(2,ℝ). It is proposed that the mathematical group structure can be realized through the three regulatory elements playing a role of a functional basis of biologic systems. The structure of the basis elements endows the space of biological variables with indefinite metric. Metric structure resembles Minkowski's space-time (+, −, −) making the carrier spaces of biologic variables and the space of transformations inhomogeneous. It endows biologic systems with a rich functional structure, giving the regulatory elements special differentiating features to form steady autonomous subsystems reducible to one-dimensional components.
Rail Vehicle Vibrations Control Using Parameters Adaptive PID Controller
Authors: Metin Muzaffer , Guclu Rahmi
Published: April 2014

In this study, vertical rail vehicle vibrations are controlled by the use of conventional PID and parameters which are adaptive to PID controllers. A parameters adaptive PID controller is designed to improve the passenger comfort by intuitional usage of this method that renews the parameters online and sensitively under variable track inputs. Sinusoidal vertical rail misalignment and measured real rail irregularity are considered as two different disruptive effects of the system. Active vibration control is applied to the system through the secondary suspension. The active suspension application of rail vehicle is examined by using 5‐DOF quarter‐rail vehicle model by using Manchester benchmark dynamic parameters. The new parameters of adaptive controller are optimized by means of genetic algorithm toolbox of MATLAB. Simulations are performed at maximum urban transportation speed (90 km/h) of the rail vehicle with ±5% load changes of rail vehicle body to test the robustness of controllers. As a result, superior performance of parameters of adaptive controller is determined in time and frequency domain.
Real-Time Extended Interface Automata for Software Testing Cases Generation
Authors: Yang Shunkun , Xu Jiaqi , Man Tianlong , Liu Bin
Published: April 2014

Testing and verification of the interface between software components are particularly important due to the large number of complex interactions, which requires the traditional modeling languages to overcome the existing shortcomings in the aspects of temporal information description and software testing input controlling. This paper presents the real-time extended interface automata (RTEIA) which adds clearer and more detailed temporal information description by the application of time words. We also establish the input interface automaton for every input in order to solve the problems of input controlling and interface covering nimbly when applied in the software testing field. Detailed definitions of the RTEIA and the testing cases generation algorithm are provided in this paper. The feasibility and efficiency of this method have been verified in the testing of one real aircraft braking system.
Biodegradable Polyphosphazene Biomaterials for Tissue Engineering and Delivery of Therapeutics
Authors: Baillargeon Amanda L. , Mequanint Kibret
Published: April 2014

Degradable biomaterials continue to play a major role in tissue engineering and regenerative medicine as well as for delivering therapeutic agents. Although the chemistry of polyphosphazenes has been studied extensively, a systematic review of their applications for a wide range of biomedical applications is lacking. Polyphosphazenes are synthesized through a relatively well-known two-step reaction scheme which involves the substitution of the initial linear precursor with a wide range of nucleophiles. The ease of substitution has led to the development of a broad class of materials that have been studied for numerous biomedical applications including as scaffold materials for tissue engineering and regenerative medicine. The objective of this review is to discuss the suitability of poly(amino acid ester)phosphazene biomaterials in regard to their unique stimuli responsive properties, tunable degradation rates and mechanical properties, as well asin vitroandin vivobiocompatibility. The application of these materials in areas such as tissue engineering and drug delivery is discussed systematically. Lastly, the utility of polyphosphazenes is further extended as they are being employed in blend materials for new applications and as another method of tailoring material properties.
Contemporary Hearing Rehabilitation Options in Patients with Aural Atresia
Authors: Lo Jacky F. W. , Tsang Willis S. S. , Yu Joannie Y. K. , Ho Osan Y. M. , Ku Peter K. M. , Tong Michael C. F.
Published: April 2014

Congenital aural atresia is the failure of development of the external auditory canal. It usually occurs in conjunction with microtia, which is the malformation of the auricle due to a failure of development of the external ear. Aural atresia, with or without microtia, may significantly affect the hearing and social life of the patients. It is important for every medical practitioner to be aware of the possible treatment options for hearing rehabilitation in this group of patients. In the era of modern technology, new choices, including Bone-Anchored Hearing Aid (BAHA) (Cochlear Ltd. and Oticon Medical), Vibrant Soundbridge (VSB) (MED-EL, Innsbruck, Austria), and Bonebridge system (BB) (MED-EL, Innsbruck, Austria), provide high-end alternatives to traditional Bone Conduction Hearing Aid and Auditory Canal Reconstruction. All these options have advantages and disadvantages, and they are appropriate for different patients and/or at different ages. This paper aims to provide an overview of the management of hearing rehabilitation in congenital aural atresia patients and a discussion of each treatment option.
Solvability of Third-Order Three-Point Boundary Value Problems
Authors: Liu Dongyuan , Ouyang Zigen
Published: April 2014

We are interested in the existence theorems for a third-order three-point boundary value problem. In the nonresonant case, using the Krasnosel’skii fixed point theorem, we obtain some sufficient conditions for the existence of the positive solutions. In addition, we focus on the resonant case, the boundary value problem being transformed into an integral equation with an undetermined parameter, and the existence conditions being obtained by the Intermediate Value Theorem.
Successful Same-Cycle Blastocyst Transfer following Laparoscopic Ovarian Detorsion: A Report of Two Cases and Literature Review
Authors: Irani Mohamad , Tal Reshef , Seifer David B. , Grazi Richard V.
Published: April 2014

Ovarian stimulation increases the risk of ovarian torsion. During an in vitro fertilization (IVF) cycle, the effects of ovarian torsion on retrieved oocytes and subsequent pregnancy chances are not clear. Moreover, no cases of ovarian torsion occurring following oocyte retrieval but prior to same-cycle embryo transfer have been reported. Such cases present a clinical dilemma with respect to optimal timing of embryo transfer. We report two cases of a 41-year-old and a 32-year-old infertility patients undergoing IVF who were diagnosed with ovarian torsion within several days following oocyte retrieval. Both patients were treated by early laparoscopic evaluation and detorsion followed by day five embryo transfer, resulting in successful pregnancies. Therefore, after prompt laparoscopic ovarian untwisting of a torsed ovary following egg retrieval, embryo transfer may be performed as originally scheduled during the concurrent cycle leading to favorable pregnancy outcomes.
The Biosynthesis of the Molybdenum Cofactor inEscherichia coliand Its Connection to FeS Cluster Assembly and the Thiolation of tRNA
Authors: Leimkühler Silke
Published: April 2014

The thiolation of biomolecules is a complex process that involves the activation of sulfur. The L-cysteine desulfurase IscS is the main sulfur mobilizing protein inEscherichia colithat provides the sulfur from L-cysteine to several important biomolecules in the cell such as iron sulfur (FeS) clusters, molybdopterin (MPT), thiamine, and thionucleosides of tRNA. Various proteins mediate the transfer of sulfur from IscS to various biomolecules using different interaction partners. A direct connection between the sulfur-containing molecules FeS clusters, thiolated tRNA, and the molybdenum cofactor (Moco) has been identified. The first step of Moco biosynthesis involves the conversion of 5′GTP to cyclic pyranopterin monophosphate (cPMP), a reaction catalyzed by a FeS cluster containing protein. Formed cPMP is further converted to MPT by insertion of two sulfur atoms. The sulfur for this reaction is provided by the L-cysteine desulfurase IscS in addition to the involvement of the TusA protein. TusA is also involved in the sulfur transfer for the thiolation of tRNA. This review will describe the biosynthesis of Moco inE. coliin detail and dissects the sulfur transfer pathways for Moco and tRNA and their connection to FeS cluster biosynthesis.
Numerical Investigation of Wave Slamming of Flat Bottom Body during Water Entry Process
Authors: Hu Xiaozhou , Liu Shaojun
Published: April 2014

A numerical wave load model based on two‐phase (water‐air) Reynolds‐averaged Navier‐Stokes (RANS) type equations is used to evaluate hydrodynamic forces exerted on flat bottom body while entering ocean waves of deploying process. The discretization of the RANS equations is achieved by a finite volume (FV) approach. The volume of fluid (VOF) method is employed to track the complicated free surface. A numerical wave tank is built to generate the ocean waves which are suitable for deploying offshore structures. A typical deploying condition is employed to reflect the process of flat bottom body impacting waves, and the pressure distribution of bottom is also presented. Four different lowering velocities are applied to obtain the relationship between slamming force and wave parameters. The numerical results clearly demonstrated the characteristics of flat bottom body impacting ocean waves.
Long Term Followup of Photorefractive Keratectomy with Adjuvant Use of Mitomycin C
Authors: Diakonis Vasilios F. , Kankariya Vardhaman P. , Kymionis George D. , Kounis Georgios , Kontadakis George , Gkenos Eirineos , Grentzelos Michael A. , Hajithanasis George , Yoo Sonia H. , Pallikaris Ioannis G.
Published: April 2014

Purpose.To study the long term refractive and visual outcomes of photorefractive keratectomy (PRK) with intraoperative application of mitomycin C (MMC).Methods.This study included 37 eyes who received myopic PRK; after photoablation, a sponge soaked in 0.02% MMC solution was applied in all corneas for 2 minutes. Efficacy, safety, predictability, and stability of PRK MMC were evaluated. Endothelial cell density was evaluated at the last postoperative interval.Results.Mean preoperative spherical equivalent (SEQ) was−6.03±1.87 D (diopters) and reduced to−0.09±0.53 D at the last postoperative examination. Mean followup was44.73±18.24months. All the eyes were in the ±1.00 D of attempted versus achieved SEQ at the one-year follow-up interval. Furthermore, 95% of the eyes did not lose lines or gained 1 to 2 lines of CDVA, while 5% lost 1 line. At the third postoperative month, 89% of the eyes either were clear or had trace haze, while 4 eyes had mild haze; by the 12-month postoperative interval, none of the eyes demonstrated haze. Mean endothelial cell density (ECD) at the last postoperative interval was2658±153 cells/mm2.Conclusions.PRK, with intraoperative use of MMC, demonstrates stable refractive and visual outcomes up to 44 months after surgery.
Solvability of a Quadratic Integral Equation of Fredholm Type with Supremum in Hölder Spaces
Authors: Caballero Mena J. , Nalepa R. , Sadarangani K.
Published: April 2014

Using the classical Schauder fixed point theorem, we prove the existence of solutions of a quadratic integral equation of Fredholm type with supremum in the space of functions satisfying the Hölder condition.
Heat Treatment in High Chromium White Cast Iron Ti Alloy
Authors: Ibrahim Khaled M. , Ibrahim Mervat M.
Published: April 2014

The influence of heat treatment on microstructure and mechanical properties of high chromium white cast iron alloyed with titanium was investigated. The austenitizing temperatures of 980°C and 1150°C for 1 hour each followed by tempering at 260°C for 2 hours have been performed and the effect of these treatments on wear resistance/impact toughness combination is reported. The microstructure of irons austenitized at 1150°C showed a fine precipitate of secondary carbides (M6C23) in a matrix of eutectic austenite and eutectic carbides (M7C3). At 980°C, the structure consisted of spheroidal martensite matrix, small amounts of fine secondary carbides, and eutectic carbides. Titanium carbides (TiC) particles with cuboidal morphology were uniformly distributed in both matrices. Irons austenitized at 980°C showed relatively higher tensile strength compared to those austenitized at 1150°C, while the latter showed higher impact toughness. For both cases, optimum tensile strength was reported for the irons alloyed with 1.31% Ti, whereas maximum impact toughness was obtained for the irons without Ti-addition. Higher wear resistance was obtained for the samples austenitized at 980°C compared to the irons treated at 1150°C. For both treatments, optimum wear resistance was obtained with 1.3% Ti.
Phytochemical Screening, Physicochemical Properties, Acute Toxicity Testing and Screening of Hypoglycaemic Activity of Extracts ofEremurus himalaicusBaker in Normoglycaemic Wistar Strain Albino Rats
Authors: Mushtaq Ahlam , Akbar Seema , Zargar Mohammad A. , Wali Adil F. , Malik Akhtar H. , Dar Mohammad Y. , Hamid Rabia , Ganai Bashir A.
Published: April 2014

In the present study EtOAc, MeOH, and aqueous extracts ofEremurus himalaicuswere evaluated for hypoglycaemic effect in normal rats using both oral glucose tolerance test and 14-day oral administration study. Phytochemical and physicochemical screening was also done. In oral glucose tolerance test the aqueous and MeOH extracts ofEremurus himalaicusat a dose level of 500 mg/kg body weight prior to glucose load resulted in a significant fall in blood glucose level within 150 min. of glucose administration. The aqueous extract at a dose level of 250 mg/kg body weight and 500 mg/kg body weight also showed good hypoglycaemic response (P< 0.001); this was followed by MeOH extract at a dose level of 500 mg/kg body weight (P< 0.05), while MeOH extract at dose level of 250 mg/kg body weight and ethyl acetate extract at dose level of 250 mg/kg body weight and 500 mg/kg body weight exhibited insignificant effect. Phytochemical screening of extracts revealed the presence of alkaloids, terpenoids, phenolics, tannins, saponins, cardiac glycosides, and flavonoids. The results indicate that aqueous extract possess significant hypoglycaemic activity in normoglycaemic rats which may be attributed to the above-mentioned chemical constituents.
State Estimation for Discrete‐Time Fuzzy Cellular Neural Networks with Mixed Time Delays
Authors: Geng Lijie , Li Haiying , Zhao Bingchen , Su Guang
Published: April 2014

This paper is concerned with the exponential state estimation problem for a class of discrete‐time fuzzy cellular neural networks with mixed time delays. The main purpose is to estimate the neuron states through available output measurements such that the dynamics of the estimation error is globally exponentially stable. By constructing a novel Lyapunov‐Krasovskii functional which contains a triple summation term, some sufficient conditions are derived to guarantee the existence of the state estimator. The linear matrix inequality approach is employed for the first time to deal with the fuzzy cellular neural networks in the discrete‐time case. Compared with the present conditions in the form of M‐matrix, the results obtained in this paper are less conservative and can be checked readily by the MATLAB toolbox. Finally, some numerical examples are given to demonstrate the effectiveness of the proposed results.
A Novel Artificial Bee Colony Algorithm Based on Internal-Feedback Strategy for Image Template Matching
Authors: Li Bai , Gong Li-Gang , Li Ya
Published: April 2014

Image template matching refers to the technique of locating a given reference image over a source image such that they are the most similar. It is a fundamental mission in the field of visual target recognition. In general, there are two critical aspects of a template matching scheme. One is similarity measurement and the other is best-match location search. In this work, we choose the well-known normalized cross correlation model as a similarity criterion. The searching procedure for the best-match location is carried out through an internal-feedback artificial bee colony (IF-ABC) algorithm. IF-ABC algorithm is highlighted by its effort to fight against premature convergence. This purpose is achieved through discarding the conventional roulette selection procedure in the ABC algorithm so as to provide each employed bee an equal chance to be followed by the onlooker bees in the local search phase. Besides that, we also suggest efficiently utilizing the internal convergence states as feedback guidance for searching intensity in the subsequent cycles of iteration. We have investigated four ideal template matching cases as well as four actual cases using different searching algorithms. Our simulation results show that the IF-ABC algorithm is more effective and robust for this template matching mission than the conventional ABC and two state-of-the-art modified ABC algorithms do.
Exogenous Pulmonary Surfactant as a Vehicle for Antimicrobials: Assessment of Surfactant-Antibacterial InteractionsIn Vitro
Authors: Birkun Alexei
Published: April 2014

Owing to its unique surface-active properties, an exogenous pulmonary surfactant may become a promising drug delivery agent, in particular, acting as a vehicle for antibiotics in topical treatment of pneumonia. The purpose of this study was to assess a mutual influence of natural surfactant preparation and three antibiotics (amikacin, cefepime, and colistimethate sodium)in vitroand to identify appropriate combination(s) for subsequentin vivoinvestigations of experimental surfactant/antibiotic mixtures. Influence of antibiotics on surface-active properties of exogenous surfactant was assessed using the modified Pattle method. Effects of exogenous surfactant on antibacterial activity of antimicrobials againstStaphylococcus aureus,Klebsiella pneumoniae, andPseudomonas aeruginosawere evaluated using conventional microbiologic procedures. Addition of amikacin or cefepime to surfactant had no significant influence on surface-active properties of the latter. Obvious reduction of surface-active properties was confirmed for surfactant/colistimethate composition. When suspended with antibiotics, surfactant either had no impact on their antimicrobial activity (amikacin) or exerted mild to moderate influence (reduction of cefepime bactericidal activity and increase of colistimethate bacteriostatic activity againstS. aureusandP. aeruginosa). Considering favorable compatibility profile, the surfactant/amikacin combination is advisable for subsequent investigation of joint surfactant/antibacterial therapy in animals with bacterial pneumonia.
Advances in Microelectronics for Implantable Medical Devices
Authors: Demosthenous Andreas
Published: April 2014

Implantable medical devices provide therapy to treat numerous health conditions as well as monitoring and diagnosis. Over the years, the development of these devices has seen remarkable progress thanks to tremendous advances in microelectronics, electrode technology, packaging and signal processing techniques. Many of today’s implantable devices use wireless technology to supply power and provide communication. There are many challenges when creating an implantable device. Issues such as reliable and fast bidirectional data communication, efficient power delivery to the implantable circuits, low noise and low power for the recording part of the system, and delivery of safe stimulation to avoid tissue and electrode damage are some of the challenges faced by the microelectronics circuit designer. This paper provides a review of advances in microelectronics over the last decade or so for implantable medical devices and systems. The focus is on neural recording and stimulation circuits suitable for fabrication in modern silicon process technologies and biotelemetry methods for power and data transfer, with particular emphasis on methods employing radio frequency inductive coupling. The paper concludes by highlighting some of the issues that will drive future research in the field.
Botnet Detection Using Support Vector Machines with Artificial Fish Swarm Algorithm
Authors: Lin Kuan-Cheng , Chen Sih-Yang , Hung Jason C.
Published: April 2014

Because of the advances in Internet technology, the applications of the Internet of Things have become a crucial topic. The number of mobile devices used globally substantially increases daily; therefore, information security concerns are increasingly vital. The botnet virus is a major threat to both personal computers and mobile devices; therefore, a method of botnet feature characterization is proposed in this study. The proposed method is a classified model in which an artificial fish swarm algorithm and a support vector machine are combined. A LAN environment with several computers which has infected by the botnet virus was simulated for testing this model; the packet data of network flow was also collected. The proposed method was used to identify the critical features that determine the pattern of botnet. The experimental results indicated that the method can be used for identifying the essential botnet features and that the performance of the proposed method was superior to that of genetic algorithms.
Elimination of IL-10–Inducing T-Helper Epitopes from an IGFBP-2 Vaccine Ensures Potent Antitumor Activity
Authors: Cecil Denise L. , Holt Gregory E. , Park Kyong Hwa , Gad Ekram , Rastetter Lauren , Childs Jennifer , Higgins Doreen , Disis Mary L.
Published: April 2014

Immunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4+ T-helper (TH1) and CD8+ cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor–binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN-γ and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-γ (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N-terminus epitope–specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naïve T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N-terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P < 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C-terminus with the N-terminus vaccine abrogated the antitumor response of the N-terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self-tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes. Cancer Res; 74(10); 2710–8. ©2014 AACR.
Releasing Pressure in Tumors: What Do We Know So Far and Where Do We Go from Here? A Review
Authors: Ariffin Arlizan B. , Forde Patrick F. , Jahangeer Saleem , Soden Declan M. , Hinchion John
Published: April 2014

Tumor interstitial pressure is a fundamental feature of cancer biology. Elevation in tumor pressure affects the efficacy of cancer treatment. It causes heterogenous intratumoral distribution of drugs and macromolecules. It also causes the development of hypoxia within tumor bulk, leading to reduced efficacy of therapeutic drugs and radiotherapy. Tumor pressure has been associated with increased metastatic potential and poor prognosis in some tumors. The formation of increased pressure in solid tumors is multifactorial. Factors known to affect tumor pressure include hyperpermeable tortuous tumor vasculatures, the lack of functional intratumoral lymphatic vessels, abnormal tumor microenvironment, and the solid stress exerted by proliferating tumor cells. Reducing this pressure is known to enhance the uptake and homogenous distribution of many therapies. Pharmacologic and biologic agents have been shown to reduce tumor pressure. These include antiangiogenic therapy, vasodilatory agents, antilymphogenic therapy, and proteolytic enzymes. Physical manipulation has been shown to cause reduction in tumor pressure. These include irradiation, hyperbaric oxygen therapy, hyper- or hypothermic therapy, and photodynamic therapy. This review explores the methods to reduce tumor pressure that may open up new avenues in cancer treatment. Cancer Res; 74(10); 2655–62. ©2014 AACR.
A Nasally Applied Cellulose Powder in Seasonal Allergic Rhinitis in Adults with Grass Pollen Allergy: A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study
Authors: Åberg Nils , Ospanova S. Tetjana , Nikitin Nikolai P. , Emberlin Jean , Dahl Åslog
Published: April 2014

Background: A nasally applied cellulose powder is increasingly used in many countries as a remedy for allergic rhinitis. In 2009, a 4-week study in birch pollen-allergic children showed a reduction in nasal symptoms. The best effect occurred on days with lower pollen counts. The present study in grass pollen-allergic adults used the same basic design. Methods: In May 2013, a double-blind, placebo-controlled study was conducted in 108 patients with allergic rhinitis due to grass pollen (18-40 years of age). SMS on mobile phones were used as reminders of treatment and reporting of symptom scores. Results: We found significant reductions in severity scores for sneezing, runny nose, stuffy nose and symptoms from eyes and lower airways, both separately and together (all p < 0.001). Reflective opinion of effect and guess on treatment at follow-up visits (both p < 0.001) confirmed a high efficacy. No clinically significant adverse effects were reported. Conclusions: The product provided significant protection against all seasonal allergic rhinitis symptoms from both upper and lower airways during the grass pollen season in an adult population. The magnitude and scope of efficacy support the use of the product as an early choice in the treatment of allergic rhinitis.
Clinical Studies in Oral Allergen-Specific Immunotherapy: Differences among Allergens
Authors: Sato Sakura , Yanagida Noriyuki , Ogura Kiyotake , Imai Takanori , Utsunomiya Tomohiro , Iikura Katsuhito , Goto Makiko , Asaumi Tomoyuki , Okada Yu , Koike Yumi , Syukuya Akinori , Ebisawa Motohiro
Published: April 2014

Oral immunotherapy (OIT) is a significant focus of treatment of food allergy. OIT appears to be effective in inducing desensitization, however, patients receiving OIT frequently developmild/moderate symptoms during the therapy. It has not been clearly established whether the clinical tolerance induced by OIT resembles natural tolerance. According to our data, the efficacy of OIT is different among food antigens, and it is comparatively difficult to achieve the clinical tolerance in milk OIT. Moreover, the definitive evidence of efficacy and safety with long-term therapy is limited. Further studies need to be offered to patients in clinical practice. Recently, novel treatments for food allergy, sublingual and epicutaneous immunotherapy, and combination treatment with an anti-IgE monoclonal antibody (omalizumab), have been examined in some studies. OIT combined with omalizumab increased the threshold doses of food without adverse reactions and may be of benefit in food allergy treatment. More studies are needed to demonstrate long-term safety and treatment benefits in a larger patient cohort.
Healthy Lifestyle Change and Subclinical Atherosclerosis in Young Adults
Authors: Spring Bonnie , Moller Arlen C. , Colangelo Laura A. , Siddique Juned , Roehrig Megan , Daviglus Martha L. , Polak Joseph F. , Reis Jared P. , Sidney Stephen , Liu Kiang
Published: April 2014

Background—

The benefits of healthy habits are well established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk.

Methods and Results—

The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n=3538) assessed 5 healthy lifestyle factors (HLFs) among young adults aged 18 to 30 years (year 0 baseline) and 20 years later (year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from year 0 to 20 in a continuous composite HLF score (HLF change; range, −5 to +5) is associated with subclinical atherosclerosis (coronary artery calcification and carotid intima-media thickness) at year 20, after adjustment for demographics, medications, and baseline HLFs. By year 20, 25.3% of the sample improved (HLF change ≥+1); 40.4% deteriorated (had fewer HLFs); 34.4% stayed the same; and 19.2% had coronary artery calcification (>0). Each increase in HLFs was associated with reduced odds of detectable coronary artery calcification (odds ratio=0.85; 95% confidence interval, 0.74–0.98) and lower intima-media thickness (carotid bulb β=−0.024,
P
=0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of coronary artery calcification (odds ratio=1.17; 95% confidence interval, 1.02–1.33) and greater intima-media thickness (β=+0.020,
P
<0.01).

Conclusions—

Healthy lifestyle changes during young adulthood are associated with decreased risk and unhealthy lifestyle changes are associated with increased risk for subclinical atherosclerosis in middle age.
Adverse Childhood Experiences Are Associated With Detrimental Hemodynamics and Elevated Circulating Endothelin-1 in Adolescents and Young Adults
Authors: Su Shaoyong , Wang Xiaoling , Kapuku Gaston K. , Treiber Frank A. , Pollock David M. , Harshfield Gregory A. , McCall W. Vaughn , Pollock Jennifer S.
Published: April 2014

Growing evidence suggests that adverse childhood experiences (ACEs) increase the risks for coronary heart disease and hypertension in mid and late adulthood. We previously reported that early life stress induces a hyperreactive endothelin-dependent cardiovascular phenotype in a rat model. In the present study, we evaluated whether exposure to ACEs is associated with greater peripheral resistance, arterial stiffness, blood pressure, or elevated circulating endothelin-1 levels in humans. In 221 healthy adolescents and young adults (mean age, 21 years; range, 13–29 years), we found a graded association of ACE exposure with plasma endothelin-1 levels, of which on average 18% and 24% were higher in participants with 1 ACE and ≥2 ACEs, respectively, compared with those with no ACEs (
P
=0.001). Participants with moderate/severe exposure to ACEs (≥2 ACEs) had significantly higher total peripheral resistance index (+12%), diastolic blood pressure (+5%), and pulse wave velocity (+9%) compared with those who were not exposed. These associations were independent of age, race, sex, body mass index, and childhood socioeconomic status. Our results indicate that early life stress promotes cardiovascular disease risk, specifically detrimental vascular and cardiac function, detectable in young adulthood.
Caspase Recruitment Domain 6 Protects Against Cardiac Hypertrophy in Response to Pressure Overload
Authors: Li Liangpeng , Chen Wen , Zhu Yifan , Wang Xiaodi , Jiang Ding-Sheng , Huang Fuhua , Wang Liming , Xiang Fei , Qin Wei , Wang Qiang , Zhang Rui , Zhu Xueyong , Li Hongliang , Chen Xin
Published: April 2014

Caspase recruitment domain 6 (CARD6), a crucial member of the CARD family, was initially shown to be involved in the immune system and oncogenesis. However, the role of CARD6 in chronic pressure overload–induced cardiac hypertrophy remains unexplored. To evaluate the impact of CARD6 on pathological cardiac hypertrophy, cardiac-specific CARD6 knockout mice and transgenic mice with cardiac-specific CARD6 overexpression were generated and subjected to aortic banding for 4 weeks. Our results demonstrated that CARD6-deficient mice aggravated aortic banding–triggered cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, as measured by echocardiography, immunostaining, and molecular/biochemical analyses. Conversely, CARD6-overexpressing mice exhibited an attenuated hypertrophic response to chronic pressure overload. Similarly, using cultured neonatal rat cardiomyocytes, we found that adenovirus vector–driven overexpression of CARD6 dramatically limited angiotensin II–induced myocyte hypertrophy, whereas knockdown of CARD6 by AdshCARD6 (adenoviral short hairpin CARD6) exhibited the opposite phenotypes. Furthermore, analysis of the signaling events in vitro and in vivo revealed that CARD6-mediated protection against cardiac hypertrophy was attributed to the interruption of mitogen-activated protein kinase kinase (MEK) kinase-1–dependent MEK-extracellular signal-regulated protein kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 (JNK1/2) activation. Altogether, these data indicated that CARD6 serves as a novel cardioprotective factor via negative regulation of MEK kinase-1–dependent MEK-ERK1/2 and JNK1/2 signaling. Thus, our study suggests that CARD6 may be a novel target for the treatment of pathological cardiac hypertrophy and failure.
Cell-Autonomous Role of Endothelial GTP Cyclohydrolase 1 and Tetrahydrobiopterin in Blood Pressure Regulation
Authors: Chuaiphichai Surawee , McNeill Eileen , Douglas Gillian , Crabtree Mark J. , Bendall Jennifer K. , Hale Ashley B. , Alp Nicholas J. , Channon Keith M.
Published: April 2014

Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and NO generation. Augmentation of BH4 levels can prevent eNOS uncoupling and can improve endothelial dysfunction in vascular disease states. However, the physiological requirement for de novo endothelial cell BH4 biosynthesis in eNOS function remains unclear. We generated a novel mouse model with endothelial cell–specific deletion of
GCH1
, encoding GTP cyclohydrolase 1, an essential enzyme for BH4 biosynthesis, to test the cell-autonomous requirement for endothelial BH4 biosynthesis in vivo. Mice with a floxed
GCH1
allele (
GCH1

fl/fl

) were crossed with Tie2cre mice to delete
GCH1
in endothelial cells.
GCH1

fl/fl

Tie2cre mice demonstrated virtually absent endothelial NO bioactivity and significantly greater O
2
•–
production.
GCH1

fl/fl

Tie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium-dependent vasodilatations to acetylcholine and SLIGRL. Endothelium-dependent vasodilatations in
GCH1

fl/fl

Tie2cre aortas were, in part, mediated by eNOS-derived hydrogen peroxide (H
2
O
2
), which mediated vasodilatation through soluble guanylate cyclase. Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished eNOS-derived H
2
O
2
production in
GCH1

fl/fl

Tie2cre aortas.
GCH1

fl/fl

Tie2cre mice had higher systemic blood pressure than wild-type littermates, which was normalized by NOS inhibitor, NG-nitro-L-arginine methyl ester. Taken together, these studies reveal an endothelial cell-autonomous requirement for
GCH1
and BH4 in regulation of vascular tone and blood pressure and identify endothelial cell BH4 as a pivotal regulator of NO versus H
2
O
2
as alternative eNOS-derived endothelial-derived relaxing factors.
Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase
Authors: Caligiuri Stephanie P.B. , Aukema Harold M. , Ravandi Amir , Guzman Randy , Dibrov Elena , Pierce Grant N.
Published: April 2014

In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (−10 mm Hg) and diastolic (−7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid. Plasma α-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography–mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10- and 12,13-dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase–derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [95% confidence interval], −7.97 [−14.4 to −1.50] mm Hg) versus those who exhibited increased plasma soluble epoxide hydrolase–derived oxylipins (+3.17 [−4.78 to 11.13] mm Hg). These data suggest that a flaxseed bioactive may have decreased blood pressure via soluble epoxide hydrolase inhibition. Using a soluble epoxide hydrolase inhibitor screening assay, increasing concentrations of α-linolenic acid decreased soluble epoxide hydrolase activity (
P
=0.0048; ρ=−0.94). In conclusion, α-linolenic acid in flaxseed may have inhibited soluble epoxide hydrolase, which altered oxylipin concentrations that contributed to the antihypertensive effects in patients with peripheral arterial disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00781950
Urinary Angiotensinogen Excretion Is Associated With Blood Pressure Independent of the Circulating Renin–Angiotensin System in a Group of African Ancestry
Authors: Michel Frederic S. , Norton Gavin R. , Maseko Muzi J. , Majane Olebogeng H.I. , Sareli Pinhas , Woodiwiss Angela J.
Published: April 2014

Although the circulating renin–angiotensin system (RAS) is suppressed in salt-sensitive populations, the role of the intrarenal RAS in blood pressure (BP) control in these groups independent of the circulating RAS is uncertain. We evaluated the relationship between 24-hour urinary angiotensinogen excretion and either office (mean of 5 measurements; n=425) or 24-hour ambulatory (n=340) BP independent of the circulating RAS in a community-based sample of African descent that had never received antihypertensive drug therapy. Circulating RAS activity was determined from plasma renin and angiotensinogen and serum aldosterone concentrations. Urinary angiotensinogen to creatinine ratio (angiotensinogen/creat) was correlated with plasma angiotensinogen concentrations (
P
<0.0005) but not with indexes of salt intake. However, urinary angiotensinogen/creat was independently associated with office systolic BP (partial
r
=0.16;
P
<0.001), whereas plasma angiotensinogen (partial
r
=0.07;
P
=0.14) was not independently associated with office systolic BP. Urinary angiotensinogen/creat was also associated with 24-hour systolic BP (partial
r
=0.11;
P
<0.05). The relationships between urinary angiotensinogen/creat and BP survived further adjustments for plasma angiotensinogen and serum aldosterone concentrations, plasma renin concentrations, estimated glomerular filtration rate, urinary Na
+
/K
+
, or 24-hour urinary Na
+
excretion rates (
P
<0.005 for all). Participants with the highest compared with the lowest quartile of urinary angiotensinogen/creat showed an 8.2-mm Hg higher office (
P
<0.005) and 4.6-mm Hg higher 24-hour (
P
=0.01) systolic BP. In conclusion, independent of the systemic RAS, including plasma angiotensinogen concentrations, urinary angiotensinogen excretion is associated with BP in a salt-sensitive, low-renin group of African descent. These data lend further support for a role of the RAS in BP control in salt-sensitive groups of African ancestry.
Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation
Authors: Ishigami Tomoaki , Kino Tabito , Chen Lin , Minegishi Shintaro , Araki Naomi , Umemura Masanari , Abe Kaito , Sasaki Rie , Yamana Hisako , Umemura Satoshi
Published: April 2014

Renin belongs to a family of aspartyl proteases and is the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II. Processing of renal renin has been extensively investigated in juxtaglomerular granular cells, in which prorenin and active renin are present in secretory condensed granules. Previous studies demonstrated alternative renin transcription in rat adrenal glands. Different studies reported novel intracellular forms of renin deduced from novel 5′ variants derived from renin mRNA in both mice and humans. Comprehensive detailed studies in genetically engineered mice showed that both a secreted and an intracellular form of renin plays divergent mechanism regulating fluid intake and metabolism by the brain renin–angiotensin system; however, the presence, regulation, and functions of these renin isoforms in kidney and adrenal gland are not fully understood in mice. To investigate the characteristics of renin isoforms in mice, we performed a systematic inventory of renin transcripts of mice with and without a duplication of the renin gene alternatively from previous studies. We discovered a novel isoform of renin of the
Ren2
gene, which conserved functionally important residues of the prosegment and incomplete isoforms of the
Ren1C/D
gene lacking a pre-pro segment. In situ hybridization assays revealed alternative renin isoforms expressed along cortical tubules. Newly generated transgenic mice with systemic overexpression of alternative renin transcript showed enhanced local angiotensin II generation without elevation of plasma renin activity and systemic insulin resistance in vivo, providing new pathophysiological insights into insulin resistance exaggerated by bona fide renin isoform.