bluuebunny/crossref_metadata_2025 huggingface dataset:
Sales Growth Rate Forecasting Using Improved PSO and SVM
Authors: Wang Xibin , Wen Junhao , Alam Shafiq , Gao Xiang , Jiang Zhuo , Zeng Jun
Published: June 2014

Accurate forecast of the sales growth rate plays a decisive role in determining the amount of advertising investment. In this study, we present a preclassification and later regression based method optimized by improved particle swarm optimization (IPSO) for sales growth rate forecasting. We use support vector machine (SVM) as a classification model. The nonlinear relationship in sales growth rate forecasting is efficiently represented by SVM, while IPSO is optimizing the training parameters of SVM. IPSO addresses issues of traditional PSO, such as relapsing into local optimum, slow convergence speed, and low convergence precision in the later evolution. We performed two experiments; firstly, three classic benchmark functions are used to verify the validity of the IPSO algorithm against PSO. Having shown IPSO outperform PSO in convergence speed, precision, and escaping local optima, in our second experiment, we apply IPSO to the proposed model. The sales growth rate forecasting cases are used to testify the forecasting performance of proposed model. According to the requirements and industry knowledge, the sample data was first classified to obtain types of the test samples. Next, the values of the test samples were forecast using the SVM regression algorithm. The experimental results demonstrate that the proposed model has good forecasting performance.
A Structural Equation Modeling on Factors of How Experienced Teachers Affect the Students’ Science and Mathematics Achievements
Authors: Kocakaya Serhat , Kocakaya Ferit
Published: June 2014

The main purpose of this study was to propose a model for how elementary school students’ science and mathematics achievements in their schools and in Level Determination Exam (SBS) depend on the number of teachers and expert teachers in their schools. The sample of the study was 5672 elementary students for the purpose of the study, the number of teachers and expert teachers who worked in sample schools has been defined as independent variables, and students’ science and mathematics achievements in their schools and in SBS exam have been defined as dependent variables. The data obtained from school administrations were analyzed using structural equation modeling to analyze relations among students’ science and mathematics grades in their schools and science and mathematics achievements in SBS exam and the number of teachers and expert teachers in their school. As a result of the analysis, it has been observed that established model has acceptable fit indices and an increasing number of teachers and expert teachers have positive effects on students' science and mathematics achievements.
Moving State Marine SINS Initial Alignment Based on High Degree CKF
Authors: Zhang Yong-Gang , Huang Yu-Long , Wu Zhe-Min , Li Ning
Published: June 2014

A new moving state marine initial alignment method of strap‐down inertial navigation system (SINS) is proposed based on high‐degree cubature Kalman filter (CKF), which can capture higher order Taylor expansion terms of nonlinear alignment model than the existing third‐degree CKF, unscented Kalman filter and central difference Kalman filter, and improve the accuracy of initial alignment under large heading misalignment angle condition. Simulation results show the efficiency and advantage of the proposed initial alignment method as compared with existing initial alignment methods for the moving state SINS initial alignment with large heading misalignment angle.
One-Dimensional Nonequilibrium Radiation-Transport Equation under Diffusion Approximation and Its Discrete Scheme
Authors: Gao Qi , Zhang Chuanfei , Zhou Lin , Li Zhenghong , Wu Zeqing , Lei Yu , Zhang Chunlai , Zu Xiaotao
Published: June 2014

Based on the nonlocal thermodynamic equilibrium state and large optical thickness of plasma, we establish one-dimensional nonequilibrium radiation-transport equation from diffusion approximation. Through finite volume method, the discrete scheme of radiation-transport equation and the conditions for its definite solution are proposed. The reliability of radiation-transport equation and its discrete scheme is validated.
Suppression of the Oncogenic Transcription Factor FOXM1 by Proteasome Inhibitors
Authors: Gartel Andrei L.
Published: June 2014

The oncogenic transcription factor FOXM1 is one of the key regulators of tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone nucleophosmin. We also determined that FOXM1 is negatively regulated by the tumor suppressor p53. We identified the thiazole antibiotics Siomycin A and thiostrepton as inhibitors of transcriptional activity and FOXM1 expression via proteasome inhibition. In addition, we found that all tested proteasome inhibitors target FOXM1. We showed synergy between thiostrepton and bortezomib in different human cancer cell lines andin vivo.We generated isogenic human cancer cell lines of different origin with wild-type p53 or p53 knockdown and we demonstrated that proteasome inhibitors induce p53-independent apoptosis in these cells. Using RNA-interference or proteasome inhibitors to inhibit FOXM1 we found that suppression of FOXM1 sensitized human cancer cells to apoptosis induced by DNA-damaging agents or oxidative stress. We encapsulated thiostrepton into micelle-nanoparticles and after injection we detected accumulation of nanoparticles in tumors and in the livers of treated mice. This treatment led to inhibition of human xenograft tumor growth in nude mice. Our data indicate that targeting FOXM1 increases apoptosis and inhibits tumor growth.
An Improved Dispatch Strategy of a Grid‐Connected Hybrid Energy System with High Penetration Level of Renewable Energy
Authors: Zhang Yan , Meng Jie , Guo Bo , Zhang Tao
Published: June 2014

As more and more renewable energy sources (RES) integrated into the conventional distribution system, how to make the current electric grid more reliable and efficient is becoming an important topic the world must face. In order to achieve these goals, grid‐connected hybrid energy systems (HES) which contain battery energy storage systems (BESS) and many other advanced technologies have been developed and applied. Many benefits of BESS, such as high density of energy and power, have fast response in energy time‐shift, frequency regulation, and so on. This paper focuses on the fluctuation alleviation and power quality improvement of grid‐connected HES with high penetration level of RES. A multistage dispatch strategy of BESS for HES is proposed in this paper to mitigate the randomness and intermittence of the power flowed in HES because of high penetration level of RES integration. Four other conventional strategies are also discussed for evaluating the performance of the method proposed in this paper. Detailed cases and corresponding discussions are implemented, and the results show that the method proposed in this paper is more effective and robust than the other conventional strategies.
Improvement in Brightness Uniformity by Compensating for the Threshold Voltages of Both the Driving Thin-Film Transistor and the Organic Light-Emitting Diode for Active-Matrix Organic Light-Emitting Diode Displays
Authors: Fan Ching-Lin , Chen Hao-Wei , Lai Hui-Lung , Guo Bo-Liang , Huang Bohr-Ran
Published: June 2014

This paper proposes a novel pixel circuit design and driving method for active-matrix organic light-emitting diode (AM-OLED) displays that use low-temperature polycrystalline-silicon thin-film transistors (LTPS-TFTs) as driving element. The automatic integrated circuit modeling simulation program with integrated circuit emphasis (AIM-SPICE) simulator was used to verify that the proposed pixel circuit, which comprises five transistors and one capacitor, can supply uniform output current. The voltage programming method of the proposed pixel circuit comprises three periods: reset, compensation with data input, and emission periods. The simulated results reflected excellent performance. For instance, whenΔVTH=±0.33 V, the average error rate of the OLED current variation was low (<0.8%), and whenΔVTH_OLED=+0.33 V, the error rate of the OLED current variation was 4.7%. Moreover, when theI×R(current × resistance) drop voltage of a power line was 0.3 V, the error rate of the OLED current variation was 5.8%. The simulated results indicated that the proposed pixel circuit exhibits high immunity to the threshold voltage deviation of both the driving poly-Si TFTs and OLEDs, and simultaneously compensates for theI×Rdrop voltage of a power line.
Design of a Practical and Compact mm-Wave MIMO System with Optimized Capacity and Phased Arrays
Authors: Cella Tommaso , Orten Pål , Ekman Torbjörn
Published: June 2014

In this paper we evaluate the feasibility of short range outdoor mm-wave MIMO links in the 70 GHz portion of the E-band (71–76 GHz). We use phased arrays in order to strongly reduce the impact of the multipath components, thus making the channel mainly line-of-sight (LOS). We design the array using a simple patch as a single element and simulate the performances for a 200 m link and a MIMO system with equal element spacing at the transmitter and the receiver. Each node of the MIMO system consists of a uniform rectangular array (URA) where the single element is a patch antenna, in order to achieve higher gains and narrow beams. Such configuration is much more compact compared to the antennas currently employed for the same bandwidth. We optimize the interelement distances at the transmitter and the receiver and evaluate the capacity achievable with different array sizes. The results show that, for the proposed link budget, capacity up to 29 bit/s/Hz is achievable at a range of 200 m, with practical dimensions. We also show that the beamforming capabilities make the design much more flexible than the single reflector antenna systems. In the last part of the paper, we verify that our antenna can also operate in rainy conditions and longer ranges.
Immunopathological Aspects of ExperimentalTrypanosoma cruziReinfections
Authors: Reis Machado Juliana , Silva Marcos Vinícius , Borges Diego Costa , da Silva Crislaine Aparecida , Ramirez Luis Eduardo , dos Reis Marlene Antônia , Castellano Lúcio Roberto , Rodrigues Virmondes , Rodrigues Denise Bertulucci Rocha
Published: June 2014

Chagas disease is caused byTrypanosoma cruziinfection. Besides the host-related factors, such as immune response and genetic background, the parasite, strain, and occurrences of reinfection episodes, may influence disease outcome. Our results demonstrate that both the primary infection and the reinfection with the Colombiana strain are connected with lower survival rate of the mice. After reinfection, parasitaemia is approximately ten times lower than in primary infected animals. Only Colombiana, Colombiana/Colombiana, and Y/Colombiana groups presented amastigote nests in cardiac tissue. Moreover, the mice infected and/or reinfected with the Colombiana strain had moreT. cruzinests, more intense inflammatory infiltrate, and higherin situexpression of TNF-αand IFN-γthan Y strain. Antigen-stimulated spleen cells from infected and/or reinfected animals produced higher levels of TNF-α, IFN-γ, and IL-10. Our results reinforce the idea that Chagas disease outcome is influenced by the strain of the infective parasite, being differentially modulated during reinfection episodes. It highlights the need of control strategies involving parasite strain characterization in endemic areas for Chagas disease.
Clinical and Imaging Resolution of Neonatal Hemochromatosis following Treatment
Authors: Machtei Ayelet , Klinger Gil , Shapiro Rivka , Konen Osnat , Sirota Lea
Published: June 2014

Neonatal hemochromatosis (NH) is an acute liver disease associated with both hepatic and extrahepatic iron deposition and is a leading cause of neonatal liver transplantation. The concept that NH is an alloimmune disease has led to the emergence of a new treatment approach utilizing exchange transfusion and intravenous immunoglobulin therapy. We present a two-day old neonate with progressive liver dysfunction who was diagnosed with NH. Magnetic resonance imaging confirmed tissue iron overload. Treatment with intravenous immunoglobulins and exchange transfusion led to rapid improvement in liver function. Follow-up physical examination at the age of 8 months showed normal development and near normal liver function. A repeat abdominal magnetic resonance scan at 8 months showed no signs of iron deposition in the liver, pancreas, or adrenal glands. The present report provides further support for the use of exchange transfusion and immunoglobulin therapy in NH and is the first to document resolution of typical iron deposition by magnetic resonance imaging.
The Effect of Surfactants on the Diameter and Morphology of Electrospun Ultrafine Nanofiber
Authors: Zheng Jian-Yi , Zhuang Ming-Feng , Yu Zhao-Jie , Zheng Gao-Feng , Zhao Yang , Wang Han , Sun Dao-Heng
Published: June 2014

Different surfactants are introduced to study the diameter and morphology transformation characteristics of electrospun nanofiber. Surfactants increase the net charge density and instability motion of charged jet. The instability motion provides a good way to stretch the charged jets into finer ones, by which the beaded structures are also prevented. Ultrafine nanofiber with average diameter less than 65 nm can be fabricated. The nanofiber diameter decreases with the increase of surfactant concentration in polymer solution. The nanofibers with anionic surfactant sodium dodecyl sulfate (SDS) have the smallest diameter. The cationic surfactant hexadecyl trimethyl ammonium bromide (HTAB) plays the best role to prevent the formation of beaded structures in nanofibers, and helps to increase the uniformity of electrospun nanofiber. The effects of surfactants on the nanofiber diameter and morphology have been studied, which would promote the industrial application of ultrafine polymeric nanofibers.
Methane Steam Reforming over an Ni-YSZ Solid Oxide Fuel Cell Anode in Stack Configuration
Authors: Mogensen D. , Grunwaldt J.-D. , Hendriksen P. V. , Nielsen J. U. , Dam-Johansen K.
Published: June 2014

The kinetics of catalytic steam reforming of methane over an Ni-YSZ anode of a solid oxide fuel cell (SOFC) have been investigated with the cell placed in a stack configuration. In order to decrease the degree of conversion, a single cell stack with reduced area was used. Measurements were performed in the temperature range 600–800°C and the partial pressures of all reactants and products were varied. The obtained rates could be well fitted with a power law expression (r ∝PCH40.7). A simple model is presented which is capable of predicting the methane conversion in a stack configuration from intrinsic kinetics of the anode support material. The predictions are compared with the stack measurements presented here, and good agreement is observed.
Spontaneous Uterine Perforation of Pyometra Presenting as Acute Abdomen
Authors: Kitai Toshihiro , Okuno Kentaro , Ugaki Hiromi , Komoto Yoshiko , Fujimi Satoshi , Takemura Masahiko
Published: June 2014

Pyometra is the accumulation of pus in the uterine cavity, and spontaneous perforation of pyometra resulting in generalized diffuse peritonitis is extremely uncommon. We report a rare case of diffuse peritonitis caused by spontaneous perforation of pyometra. A 66-year-old postmenopausal woman with diffuse abdominal pain and vomiting was admitted to our institution. She had a history of mixed connective-tissue disease and had been taking steroids for 20 years. Under a diagnosis of generalized peritonitis secondary to perforation of the gastrointestinal tract or uterus, supravaginal hysterectomy and bilateral salpingo-oophorectomy were performed. Unfortunately, wound dehiscence and infection occurred during the postoperative course, which were exacerbated by her immunocompromised state. Despite intensive care and a course of antibiotics, the patient died of multiple organ failure resulting from sepsis on the 36th postoperative day. Although correct diagnosis, early intervention, and proper treatment can reduce morbidity and mortality of spontaneous perforation of pyometra, if severe infection occurs, this disease can be life threatening for immunocompromised hosts.
The Behavior of an SVIR Epidemic Model with Stochastic Perturbation
Authors: Zhao Yanan , Jiang Daqing
Published: June 2014

We discuss a stochastic SIR epidemic model with vaccination. We investigate the asymptotic behavior according to the perturbation and the reproduction numberR0. We deduce the globally asymptotic stability of the disease-free equilibrium whenR0≤ 1and the perturbation is small, which means that the disease will die out. WhenR0>1, we derive that the disease will prevail, which is measured through the difference between the solution and the endemic equilibrium of the deterministic model in time average. The key to our analysis is choosing appropriate Lyapunov functions.
Incidence of Otolaryngological Symptoms in Patients with Temporomandibular Joint Dysfunctions
Authors: Ferendiuk E. , Zajdel K. , Pihut M.
Published: June 2014

The functional disorders of the masticatory organ are the third stomatological disease to be considered a populational disease due to its chronicity and widespread prevalence. Otolaryngological symptoms are a less common group of dysfunction symptoms, including sudden hearing impairment or loss, ear plugging sensation and earache, sore and burning throat, difficulties in swallowing, tinnitus, and vertigo. The diagnostic and therapeutic problems encountered in patients with the functional disorders of the masticatory organ triggered our interest in conducting retrospective studies with the objective of assessing the incidence of otolaryngological symptoms in patients subjected to prosthetic treatment of the functional disorders of masticatory organ on the basis of the analysis of medical documentation containing data collected in medical interviews.Material and Methods. Retrospective study was conducted by analyzing the results of medical interviews of 1208 patients, who had reported for prosthetic treatment at the Functional Disorders Clinic of the Department of Dental Prosthetics of Jagiellonian University Medical College in Cracow between 2008 and March 14, 2014.Results. Otolaryngological symptoms were observed in 141 patients. The most common symptoms in the study group were earache and sudden hearing impairment; no cases of sudden hearing loss were experienced.
Topical Anesthesia for Cataract Surgery: The Patients' Perspective
Authors: Apil Aytekin , Kartal Baki , Ekinci Metin , Cagatay Halil Huseyin , Keles Sadullah , Ceylan Erdinc , Cakici Ozgur
Published: June 2014

Purpose. To evaluate the analgesic efficacy of 0.5% propacaine hydrochloride as topical anesthesia during phacoemulsification surgery. Methods. Intraoperative pain intensity was assessed using a 5-category verbal rating scale during each of three surgical stages. Pain scores from each surgical stage and total pain scores were compared for the factors of patient age, gender, cataract laterality, and type. Results. In comparison of cataract type subgroups, the mean total pain scores and mean stage 2 pain scores in both white mature cataract (WMC) and corticonuclear plus posterior subcapsular cataract (CN + PSC) groups were significantly higher than in the PSC-only (PSC) group P<0.05. Conclusion. Phacoemulsification with topical anesthesia is not a completely painless procedure. Pain intensity varies with cataract type and stage of surgery.
Nanocomposite Thin Film of Poly(3-aminobenzoic acid) and Multiwalled Carbon Nanotubes Fabricated through an Electrochemical Method
Authors: Netsuwan Paphawadee , Chaisu Wirat , Phanichphant Sukon , Sriwichai Saengrawee
Published: June 2014

The composite thin films of poly(3-aminobenzoic acid) (PABA) and multiwalled carbon nanotubes (MWNTs) are successfully fabricated through an electrochemical method. The composite mixtures containing 50 mM of 3-aminobenzoic acid with various concentrations of MWNTs (1.0, 2.5, 5.0, 7.5, and 10 mg/mL) in 0.5 M H2SO4were prepared and used in this study. Cyclic voltammetry (CV) was used for fabrication and monitoring the electropolymerization of the composite thin films with potential range of 0 to 1100 mV for 5 cycles at scan rate of 20 mV/s on indium tin oxide- (ITO)-coated glass substrate. UV-vis absorption spectroscopy, atomic force microscopy (AFM), and scanning electron microscopy (SEM) techniques were employed to characterize the obtained composite thin films. It was found that MWNTs can enhance the peak current of CV traces of the PABA/MWNTs composite thin films without affecting the UV-vis absorption spectra. The surface morphology of the thin films can be studied using AFM and SEM techniques.
Fault Detection for Wireless Networked Control Systems with Stochastic Switching Topology and Time Delay
Authors: Guo Pengfei , Zhang Jie , Karimi Hamid Reza , Liu Yurong , Wang Yunji , Bo Yuming
Published: June 2014

This paper deals with the fault detection problem for a class of discrete-time wireless networked control systems described by switching topology with uncertainties and disturbances. System states of each individual node are affected not only by its own measurements, but also by other nodes’ measurements according to a certain network topology. As the topology of system can be switched in a stochastic way, we aim to designH∞fault detection observers for nodes in the dynamic time-delay systems. By using the Lyapunov method and stochastic analysis techniques, sufficient conditions are acquired to guarantee the existence of the filters satisfying theH∞performance constraint, and observer gains are derived by solving linear matrix inequalities. Finally, an illustrated example is provided to verify the effectiveness of the theoretical results.
Matrix Metalloproteinases and Their Multiple Roles in Alzheimer’s Disease
Authors: Wang Xiang-Xiang , Tan Meng-Shan , Yu Jin-Tai , Tan Lan
Published: June 2014

Alzheimer’s disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include amyloid-β(Aβ) plaques and neurofibrillary tangles (NFTs), as well as neuronal death and synaptic loss. Matrix metalloproteinases (MMPs) play an important role as inflammatory components in the pathogenesis of AD. MMP-2 might be assumed to have a protective role in AD and is the major MMP which is directly linked to Aβin the brain. Synthesis of MMP-9 can be induced by Aβ, and the enzymes appear to exert multiple effects in AD in senile plaque homoeostasis. The proaggregatory influence on tau oligomer formation in strategic brain regions may be a potential neurotoxic side effect of MMP-9. MMP-3 levels are correlated to the duration of AD and correlate with the CSF T-tau and P-tau levels in the elderly controls. Elevated brain levels of MMP-3 might result in increased MMP-9 activity and indirectly facilitate tau aggregation. At present, the clinical utility of these proteins, particularly in plasma or serum, as potential early diagnostic biomarkers for AD remains to be established. More research is needed to understand the diverse roles of these proteases to design specific drugs and devise therapeutic strategies for AD.
Antitumor Effects in Hepatocarcinoma of Isoform-Selective Inhibition of HDAC2
Authors: Lee Yun-Han , Seo Daekwan , Choi Kyung-Ju , Andersen Jesper B. , Won Min-Ah , Kitade Mitsuteru , Gómez-Quiroz Luis E. , Judge Adam D. , Marquardt Jens U. , Raggi Chiara , Conner Elizabeth A. , MacLachlan Ian , Factor Valentina M. , Thorgeirsson Snorri S.
Published: June 2014

Histone deacetylase 2 (HDAC2) is a chromatin modifier involved in epigenetic regulation of cell cycle, apoptosis, and differentiation that is upregulated commonly in human hepatocellular carcinoma (HCC). In this study, we show that specific targeting of this HDAC isoform is sufficient to inhibit HCC progression. siRNA-mediated silencing of HDAC inhibited HCC cell growth by blocking cell-cycle progression and inducing apoptosis. These effects were associated with deregulation of HDAC-regulated genes that control cell cycle, apoptosis, and lipid metabolism, specifically, by upregulation of p27 and acetylated p53 and by downregulation of CDK6 and BCL2. We found that HDAC2 silencing in HCC cells also strongly inhibited PPARγ signaling and other regulators of glycolysis (ChREBPα and GLUT4) and lipogenesis (SREBP1C and FAS), eliciting a marked decrease in fat accumulation. Notably, systemic delivery of HDAC2 siRNA encapsulated in lipid nanoparticles was sufficient to blunt the growth of human HCC in a murine xenograft model. Our findings offer preclinical proof-of-concept for HDAC2 blockade as a systemic therapy for liver cancer. Cancer Res; 74(17); 4752–61. ©2014 AACR.
A Multiparametric Serum Marker Panel as a Complementary Test to Mammography for the Diagnosis of Node-Negative Early-Stage Breast Cancer and DCIS in Young Women
Authors: Lacombe Jérôme , Mangé Alain , Bougnoux Anne-Claire , Prassas Ioannis , Solassol Jérôme
Published: June 2014

Background: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging.

Methods: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2). Circulating autoantibody levels were measured in a cohort of 396 serum samples from histologically confirmed DCIS (n = 87) or T1N0 PBC (n = 153) and healthy controls (n = 156).

Results: Individually, antibodies against CCNB1, FKBP52, GAL3, PAK2, PRDX2, PPIA, P53, and MUC1 demonstrated discriminatory power between breast cancer and healthy control groups. At 90% sensitivity, the overall combined specificity of the autoantibody serum screening test was 42%. Adjustment for higher sensitivities of 95% and 99% resulted in 30% and 21% specificities, respectively (33% and 18% in T1N0 PBC and 28% and 21% in DCIS). Finally, in patients with node-negative early-stage breast cancer younger than 50 years, the autoantibody assay exhibited 59% specificity with a fixed sensitivity at 90%.

Conclusions: Our autoantibody panel allows accurate detection of early breast cancer and DCIS, notably in younger patients.

Impact: Clinical assessment of this autoantibody panel displays a potential to facilitate clinical management of early-stage breast cancer detection in cases of inconclusive mammogram. Cancer Epidemiol Biomarkers Prev; 23(9); 1834–42. ©2014 AACR.
Molecular Basis of the ‘Anti-Aging' Effect of Spermidine and Other Natural Polyamines - A Mini-Review
Authors: Minois Nadège
Published: June 2014

Background: Spermidine, a naturally occurring polyamine, has recently emerged as exhibiting anti-aging properties. Its supplementation increases lifespan and resistance to stress, and decreases the occurrence of age-related pathology and loss of locomotor ability. Its mechanisms of action are just beginning to be understood. Objectives: An up-to-date overview of the so far identified mechanisms of action of spermidine and other polyamines on aging is presented. Methods: Studies of aging and of the molecular effects of polyamines in general and spermidine in particular are used to synthesize our knowledge on what molecular mechanisms spermidine and other polyamines trigger to positively affect aging. Results: Autophagy is the main mechanism of action of spermidine at the molecular level. However, recent research shows that spermidine can act via other mechanisms, namely inflammation reduction, lipid metabolism and regulation of cell growth, proliferation and death. It is suggested that the main pathway used by spermidine to trigger its effects is the MAPK pathway. Conclusions: Given that polyamines can interact with many molecules, it is not surprising that they affect aging via several mechanisms. Many of these mechanisms discovered so far have already been linked with aging and by acting on all of these mechanisms, polyamines may be strong regulators of aging.
Sarcopenia, Cachexia and Aging: Diagnosis, Mechanisms and Therapeutic Options - A Mini-Review
Authors: Ali Sumbul , Garcia Jose M.
Published: June 2014

By the year 2050, individuals over the age of 65 years will comprise 20% of the US population. Loss of muscle mass and strength is common in this age group and it is associated with increased dependence, frailty and mortality. Sarcopenia, defined as the loss of muscle mass and function associated with aging, and cachexia, defined as weight loss due to an underlying illness, are muscle wasting disorders of particular relevance in the aging population, but they go largely unrecognized. In this review we highlight the common pathophysiological mechanisms underlying muscle loss in sarcopenia and cachexia, the factors unique to each condition and means of diagnosing and differentiating them clinically. Therapeutic options including exercise, nutritional therapy, androgens and growth hormone as well as their practical limitations are discussed. We also shed light on newer agents being developed as potential therapeutic options for wasting diseases.
Have Biologics Changed the Natural History of Crohn's Disease?
Authors: Mandel Michael D. , Miheller Pal , Müllner Katalin , Golovics Petra A. , Lakatos Peter L.
Published: June 2014

Crohn's disease (CD) is a progressive condition, with most patients developing a penetrating or stricturing phenotype over time. The introduction of anti-tumor necrosis factor (TNF) therapies over the past 10-15 years, which was supported by accumulating evidence both from trials and clinical practice, has led to a significant change in patient management, monitoring, and treatment algorithms. Anti-TNF therapy was demonstrated to be effective for both luminal and fistulizing disease. Regular therapy with both infliximab and adalimumab was shown to increase the likelihood of clinical remission and mucosal healing, as well as to reduce the need for surgery and hospitalization in both clinical trials and clinical practice, especially in patients with pediatric-onset CD, shorter disease duration, and when used in combination with immunosuppressives. This has led to new treatment goals and to the use of early aggressive medical therapy in a selected group of patients with a worse prognosis. Exploratory clinical trials are underway to determine if further optimization of therapies and treatment beyond clinical remission leads to superior disease outcomes. However, more long-term clinical data are needed to assess whether an early, aggressive therapeutic strategy employing anti-TNF, alone or in combination with biologicals, can further improve long-term disease outcomes in both pediatric patients and young adults.
Have We Changed the Natural History of Pediatric Crohn's Disease with Biologics?
Authors: Dubinsky Marla
Published: June 2014

Considerable debate exists as to whether the risk of complications and need for surgery has truly decreased in Crohn's disease (CD) over time. A recent systematic review and meta-analysis reported that after the year 2000, the surgical rates at 1, 5 and 10 years have significantly decreased. It is unclear whether this decrease can be solely attributable to the introduction of biologics, the more effective use of thiopurine dosing with monitoring or perhaps earlier disease recognition and early use of effective interventions. Uncontrolled observational studies confirmed that scheduled maintenance treatment with anti-TNF as compared to episodic or discontinued use of anti-TNF resulted in fewer surgeries. Recent population-based studies have shown similar improved disease outcomes with early immunomodulator use. There is a dearth of pediatric-specific natural history studies for both short and long term. Multiple pediatric observational cohort studies have reported that up to one third of pediatric-onset CD patients progress to surgery within 5 years. This is a slightly higher proportion than that of adult patients followed in the same time frame. This discrepancy may be explained by less early biologic use in pediatric patients. More data are needed to follow all CD patients for longer follow-up periods with an emphasis on pediatric onset to better gauge whether our proposed treatment strategies are actually altering the natural history of disease and what role biologics play in this regard.
Are We Under- or Mistreating Patients at the Time of Presentation?
Authors: Fish Samantha , Baldassano Robert
Published: June 2014

Treatment goals in Crohn's disease (CD) are evolving beyond the control of symptoms towards deep remission, which encompasses clinical remission and mucosal healing. The ultimate goals are to prevent bowel damage, reduce long-term disability, and maintain normal quality of life. Until recently, goals of CD management focused on induction and maintenance of a symptomatic response, and little attention was paid to the delay or even prevention of disease progression. A very different approach is taken with other chronic diseases, such as hypertension, diabetes, and rheumatoid arthritis. This more comprehensive approach is often referred to as ‘treat-to-target' strategy. The treat-to-target strategy defines a new treatment objective that aims to achieve and sustain both clinical remission and control of inflammation. With our new understanding of the etiopathophysiology of inflammatory bowel disease, are we mistreating our patients? The most convincing concept at this time is that of a defective mucosal barrier due to inappropriate recognition of the luminal flora or a defective defense against those bacteria. These recent theories indicate that the paradigm of immune suppression may not be the optimal concept. Therefore, a variety of approaches to improve the barrier function or to modulate luminal components have to be considered. We still have much to learn about these concepts in order to achieve the treatment goals of avoiding structural damage and complications.
Is Rifaximin Effective in Maintaining Remission in Crohn's Disease?
Authors: Jigaranu Anca Olivia , Nedelciuc Otilia , Blaj Andreea , Badea Mircea , Mihai Catalina , Diculescu Mircea , Cijevschi-Prelipcean Cristina
Published: June 2014

Background: Recent studies indicate that persistent intestinal inflammation in patients with Crohn's disease (CD) might be caused by abnormal intestinal microbiota. This hypothesis may suggest a beneficial effect of antibiotics in CD therapy. So far, guidelines do not recommend antibiotics except in the treatment of complicated CD, and there are few studies on the effects of rifaximin in these patients. Methods: Between December 2011 and December 2012, we performed a blinded randomized trial in 168 patients with a previous history of moderately active CD concerning the efficacy of rifaximin. All the patients had previously achieved remission with standard therapy (prednisone/budesonide). Data from patients receiving 800 mg of rifaximin (83 patients) twice a day for 12 weeks were compared with those from patients who received placebo (83 patients). The primary endpoint was maintaining remission during the follow-up. Results: All the patients (100%; 83/83) on 800 mg of rifaximin were in remission after 12 weeks of treatment in comparison with 84% (70/83) of the placebo group. This significant difference was also persistent at the 24-week follow-up [78% (65/83) vs. 41% (34/83), respectively]. The last evaluation performed at 48 weeks revealed disease activity in 45% (38/83) of the patients of the rifaximin group, i.e. a significant decrease compared with the placebo group [75% (63 of 83)]. Conclusions: Remission previously obtained with standard treatment can be sustained in patients with moderately active CD after the administration of 800 mg of rifaximin.
Should We Be Treating the Bugs instead of Cytokines and T Cells?
Authors: Wine Eytan
Published: June 2014

Background/Aim: It is now clear that intestinal microbes are involved in many aspects of inflammatory bowel diseases (IBD) and that understanding how microbes lead to disease could present novel opportunities for diagnosis and treatment. Microbes are linked to most disease-associated genetic polymorphisms and are critical mediators of environmental effects (through food, hygiene, and infection). This paper reviews recent findings and future implications for targeting microbes in IBD. Methods: A comprehensive review of the literature is presented, with specific focus on how treating microbes could alter patient care in the future. Results: Human and animal-based research supports the central role of microbes in IBD pathogenesis at multiple levels. Antibiotics, probiotics, diet, and potentially fecal transplantation are all potential treatments for IBD. Animal models of IBD only develop in the presence of microbes and co-housing mice genetically susceptible to gut inflammation with normal mice can lead to the development of bowel injury. Key papers have used microbial sequencing and metagenomics to study the role of microbes in IBD and we are now on the cusp of expanding into clinically relevant fields, such as diagnosis and therapeutics. However, many challenges still remain in understanding how microbes can be manipulated to prevent or treat disease. Conclusions: In the future, we may be able to predict risk of disease, define biological subtypes, establish tools for prevention, and even cure IBD using microbes or their products. A broad spectrum of therapeutic tools, spanning from fecal transplantation, probiotics, prebiotics, microbial products to microbe-tailored diets, may replace current IBD treatments.
Managing Intractable Proctitis and the Problematic Pouch
Authors: Kent Alex , Keshav Satish
Published: June 2014

Proctitis accounts for a significant proportion of cases of ulcerative colitis (UC), and some patients subsequently develop more extensive disease. However, most patients continue to have limited inflammation, although the changes in the distal colon and rectum can occasionally be severe, and symptoms of increased frequency, rectal bleeding and urgency can be as disabling as they are for patients with more extensive colitis. Furthermore, although symptoms are typically well controlled with standard medications, medically refractory proctitis poses particular problems. Patients generally are not systemically unwell, and there is no added fear of cancer. Therefore, the prospect of colectomy for such limited disease is resisted by patients, physicians and surgeons alike. Unusual therapies, often delivered locally by enema or suppository, have been tested in small case series without definitive outcomes. The pathogenesis of such limited, yet intractable inflammation remains unclear, and the differential diagnosis should be carefully reviewed to ensure that local disease, whether it is infectious, vascular, or a result of injury or degeneration, is not overlooked. Ileo-anal pouch formation is the surgery of choice for about 20% of patients with UC who undergo colectomy. In the majority of cases, this surgery results in an acceptable quality of life and freedom from a stoma. However, in a sizeable minority of cases, pouch dysfunction can cause intractable problems. The causes of pouch dysfunction are varied and must all be considered carefully, particularly in refractory cases. Pouchitis is a common issue and is usually transient and easily treated. However, refractory and chronic pouchitis can be challenging. Ischaemia, injury, infection and Crohn's disease can all cause refractory pouch dysfunction. In a minority of cases, there appears to be no apparent organic pathology, and the presumptive diagnosis is that of a functional pouch disorder. Although it is much rarer, neoplastic changes in the pouch must also be considered, and the risk managed appropriately. The management of both intractable proctitis and the problematic pouch is made more challenging by the wide differential diagnosis that must be considered and by the paucity of high-quality clinical trials to support any one therapy. Key strategies to overcoming these limitations include methodical and systematic investigation and review, and a willingness to tailor therapy to the individual patient. Clinical trials of new treatments should be supported, and data from the experience with small cohorts of patients should be meticulously collected, critically analysed and widely disseminated.
Physiological Intermolecular Modification Spectroscopy for the Prediction of Response to Anti-Tumor Necrosis Factor Therapy in Patients with Inflammatory Bowel Diseases
Authors: Eftekhari Pierre , Glaubitz Lisa , Breidert Matthias , Neurath Markus Friedrich , Atreya Raja
Published: June 2014

Background/Aims: Anti-tumor necrosis factor (TNF) antibodies have clinical efficiency only in a subgroup of patients with inflammatory bowel diseases (IBD). Prediction of clinical response is a critical clinical problem. Physiological intermolecular modification spectroscopy (PIMS) is a label-free technology performed in physiological conditions. PIMS enables real-time monitoring of dynamic molecular resonance of entire proteins and macromolecules of an individual. The aim of this study was to explore the capacity of PIMS to discriminate IBD patients regarding response to anti-TNF treatment. Methods: Protein extracts of peripheral blood mononuclear cells (PBMC) from 30 outpatients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) and treated with infliximab were subjected to PIMS analysis in a blinded transversal study. Total protein from each patient's PBMCs was challenged with infliximab. Dynamic changes in macromolecular interaction were registered while the temperature rose from -37 to 37°C. Individual macromolecular volume and molecular elasticity were determined for each patient. Results: Clinical data revealed that 67% of UC and 79% of CD patients responded to infliximab therapy during the 3-month study period based on their respective clinical activity score. These results confirm that PIMS data predicted response to anti-TNF therapy with an accuracy of 96%. Conclusion: PIMS stratified IBD patients into two groups, responders and nonresponders, which correlated with the clinical efficacy of anti-TNF therapy. PIMS seems to be a powerful technology to adapt IBD treatment to the individual patient. Further studies with PIMS might enable to predict clinical response to biological treatment in IBD patients before the therapy is initiated.
Future Methods for the Diagnosis of Inflammatory Bowel Disease
Authors: Aggio Raphael , Probert Chris
Published: June 2014

The diagnosis of inflammatory bowel disease (IBD) remains a challenge for clinicians, and patients. Clinical suspicion of these disorders leads to a diagnostic pathway that may include stool testing, colonoscopy, radiological tests and capsule examinations. This workup is unpleasant, embarrassing, painful and occasionally dangerous. Alternative means of diagnosing IBD are being explored. Genetic testing and serology have not been found to be sufficiently specific or sensitive to be used for diagnosis. Faecal markers, however, have demonstrated some potential. Faecal lactoferrin and calprotectin may be used to differentiate IBD from non-inflammatory disorders and these tests are now commonly used, with support from the National Institute for Health and Care Excellence. Recent research has focused upon volatile organic compounds emitted from bodily fluids, including faeces, urine and breath. Headspace gas from faeces or urine may be analysed by gas chromatography/mass spectrometry. Models have been built based on these compounds to enable Crohn's disease and ulcerative colitis to be distinguished from irritable bowel syndrome (IBS) and from healthy controls. Similar work has found that headspace gases from urine may be used to diagnose IBS. Faecal samples are relatively easy to obtain, but patients dislike collecting samples, so a urinary test is an attractive alternative. Early data from breath samples also show potential and will be presented. Non-invasive diagnosis of IBD is becoming a reality that will save patients from discomfort, embarrassment and risk, and may mean significant savings for healthcare providers.
Phase II Trial of Cetuximab plus Irinotecan for Oxaliplatin- and Irinotecan-Based Chemotherapy-Refractory Patients with Advanced and/or Metastatic Colorectal Cancer: Evaluation of Efficacy and Safety Based on KRAS Mutation Status (T-CORE0801)
Authors: Soeda Hiroshi , Shimodaira Hideki , Gamoh Makio , Ando Hideaki , Isobe Hideki , Suto Takeshi , Takahashi Shin , Kakudo Yuichi , Amagai Kenji , Mori Takahiro , Watanabe Mika , Yamaguchi Takuhiro , Kato Shunsuke , Ishioka Chikashi
Published: June 2014

Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. Methods: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. Results:KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. Conclusion: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.
Recombinant Human Erythropoietin Augments Angiogenic Responses in a Neonatal Rat Model of Cerebral Unilateral Hypoxia-Ischemia
Authors: Zhu Lihua , Bai Xiang , Wang Shiyu , Hu Yan , Wang Ting , Qian Lijuan , Jiang Li
Published: June 2014

Background: Recombinant human erythropoietin (rh-EPO) has been used as a drug to treat premature infant anemia for over a decade. In addition to its erythropoietic effect, rh-EPO has also been reported to have protective effects against brain injury. Objectives: Our aim was to evaluate the levels of angiogenesis-related cells (CD34+ cells) and angiogenic factors (vascular endothelial growth factor, VEGF, and angiopoietin-1, Ang-1) in a neonatal rat model of cerebral unilateral hypoxia-ischemia (HI) and to identify the effects of rh-EPO on angiogenic responses. Methods: Postnatal day 3 (PD3) rats underwent permanent ligation of the right common carotid artery followed by 6% O2 for 4 h (HI) or sham operation and normoxic exposure (sham). Immediately after HI, the rats received a single intraperitoneal injection of rh-EPO (5 U/g) or saline. Angiogenesis-related cells (CD34+ cells) and angiogenic factors (VEGF and Ang-1) were examined on PD5, 7, 10 and 14. Results: Compared with the sham rats, the number of CD34+ cells in HI rats increased from PD5 to 7 but decreased from PD10 to 14. VEGF and Ang-1 mRNA levels both increased from PD5 to 14. CD34+ cells, VEGF and Ang-1 were all upregulated in rh-EPO-treated rats compared with HI rats. Conclusions: In the present study, we show the angiogenic effects of rh-EPO in a rat model of neonatal cerebral unilateral HI. Our results highlight the powerful therapeutic potential of rh-EPO treatment of HI premature brain for the enhancement of angiogenic responses.