bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of T Helper (TH)17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation
Authors: Hemdan Nasr Y. A. , Abu El-Saad Ahmed M. , Sack Ulrich
Published: September 2013

Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, theTH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the “superstar” at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights intoTH17’s contributions to autoimmunity.
A Case of Primary Submandibular Gland Oncocytic Carcinoma
Authors: Tokashiki Kunihiko , Tsukahara Kiyoaki , Motohashi Ray , Nakamura Kazuhiro , Suzuki Mamoru
Published: September 2013

Primary submandibular gland oncocytic carcinoma is a rare pathology, with only 10 cases being reported to date. We encountered a case of primary submandibular gland oncocytic carcinoma and report it herein. The patient was a 69-year-old man who came to our hospital with right submandibular cancer as the main complaint. Based on the results of computed tomography and magnetic resonance imaging, submandibular gland tumor was diagnosed. Preoperative cytodiagnosis suggested class III oncocytic carcinoma. Resection of the right submandibular tumor was performed along with right neck dissection. Postoperative histopathological diagnosis was oncocytic carcinoma. As of 3 years following surgery, no recurrence has been identified.
Comprehensive Models for Evaluating Rockmass Stability Based on Statistical Comparisons of Multiple Classifiers
Authors: Dong Longjun , Li Xibing
Published: September 2013

The relationships between geological features and rockmass behaviors under complex geological environments were investigated based on multiple intelligence classifiers. Random forest, support vector machine, bayes' classifier, fisher's classifier, logistic regression, and neural networks were used to establish models for evaluating the rockmass stability of slope. Samples of both circular failure mechanism and wedge failure mechanism were considered to establish and calibrate the comprehensive models. The classification performances of different modeling approaches were analyzed and compared by receiver operating characteristic (ROC) curves systematically. Results show that the proposed random forest model has the highest accuracy for evaluating slope stability of circular failure mechanism, while the support vector Machine model has the highest accuracy for evaluating slope stability of wedge failure mechanism. It is demonstrated that the established random forest and the support vector machine models are effective and efficient approaches to evaluate the rockmass stability of slope.
Cumulative Effect of Depression on Dementia Risk
Authors: Olazarán J. , Trincado R. , Bermejo-Pareja F.
Published: September 2013

Objective. To analyze a potential cumulative effect of life-time depression on dementia and Alzheimer’s disease (AD), with control of vascular factors (VFs).Methods. This study was a subanalysis of the Neurological Disorders in Central Spain (NEDICES) study. Past and present depression, VFs, dementia status, and dementia due to AD were documented at study inception. Dementia status was also documented after three years. Four groups were created according to baseline data: never depression (nD), past depression (pD), present depression (prD), and present and past depression (prpD). Logistic regression was used.Results. Data of 1,807 subjects were investigated at baseline (mean age 74.3, 59.3% women), and 1,376 (81.6%) subjects were evaluated after three years. The prevalence of dementia at baseline was 6.7%, and dementia incidence was 6.3%. An effect of depression was observed on dementia prevalence (OR [CI 95%] 1.84 [1.01–3.35] for prD and 2.73 [1.08–6.87] for prpD), and on dementia due to AD (OR 1.98 [0.98–3.99] for prD and OR 3.98 [1.48–10.71] for prpD) (fully adjusted models, nD as reference). Depression did not influence dementia incidence.Conclusions. Present depression and, particularly, present and past depression are associated with dementia at old age. Multiple mechanisms, including toxic effect of depression on hippocampal neurons, plausibly explain these associations.
Seroprevalence of Dengue IgG Antibodies among Healthy Adult Population in Lahore, Pakistan
Authors: Mahmood Shahid , Nabeel Hiba , Hafeez Saadia , Zahra Urooj , Nazeer Hammad
Published: September 2013

Background. Dengue is a mosquito-borne flavivirus infection prevalent in tropical and subtropical regions around the world. Aim of this study was to determine seroprevalence of anti-dengue IgG antibodies in healthy adult population of Lahore and also describe risk factors in relation to dengue seropositivity. Methods. In this cross-sectional study, 274 healthy adult individuals aged 15 years and above were randomly selected using multistage sampling technique. These individuals were interviewed between July–September 2012, using a semistructured questionnaire, followed by drawing 3 mL of their venous blood for dengue IgG test. Nova Tech ELISA kit with sensitivity and specificity of 96.5% and 97.5%, respectively, was used for serology. Results. Out of 274 participants, 184 (67.2%) were found to be positive for dengue IgG antibodies. Seroprevalence was higher among individuals with poor awareness about potential breeding sites for dengue mosquito (63.6%), followed by the subjects who had poor knowledge about dengue signs/symptoms and complications (52.2% and 68.5%, resp.). Conclusion. About two-third of healthy population of Lahore was also seropositive for anti-dengue IgG during July–September 2012, indicating a considerable burden of subclinical dengue infection in the city. Males were predominantly affected than the females. We found no statistical association between dengue IgG seropositivity and socioeconomic status, occupation, and knowledge about the disease.
The Solubility of Hydrocarbon Gases in Glassy Polymers: Fractal Modeling
Authors: Kozlov Georgii V. , Cruz-Morales Jorge A. , Vargas Joel , Tlenkopatchev Mikhail A.
Published: September 2013

This work describes the fractal modeling of the solubility ofn-alkanes,n-alkenes, methylacetylene, allene, ethylacetylene, and butadiene hydrocarbon gases in glassy poly(vinyltrimethylsilane) (PVTMS). The proposed equation represents satisfactorily the solubility coefficients of the hydrocarbon gases in glassy PVTMS as a function of the fractal dimension of the polymer and the effective diameter of a gas penetrant molecule. It is found that the calculated solubility coefficients have a good correlation with the experimental data. The proposed model can predict the solubility of hydrocarbon gases in glassy polymers.
Allergy or Tolerance: Reduced Inflammatory Cytokine Response and Concomitant IL-10 Production of Lymphocytes and Monocytes in Symptom-Free Titanium Dental Implant Patients
Authors: Thomas Peter , Iglhaut Gerhard , Wollenberg Andreas , Cadosch Dieter , Summer Burkhard
Published: September 2013

Hypersensitivity reactions to titanium (Ti) are very rare. Thus, we assessed the proinflammatory response and also potential tolerance favoringin vitroreactivity of human blood lymphocytes and monocytes (PBMC) to Ti in healthy individuals (14 without, 6 with complication-free dental Ti implants). The proliferation index (SI) in lymphocyte transformation test (LTT) and production of cytokines linked to innate immune response (IL-1β, IL-6, and TNFα) or immune regulation (IL-10) were assessed in response to TiO2particles or Ti discs. In both groups, the Ti-LTT reactivity was not enhanced (e.g.,SI<3). The control antigen tetanus toxoid (TT) gave adequate reactivity (median SI individuals without/with implant:20.6±5.97/19.58±2.99). Individuals without implant showed higher cytokine response to Ti materials than individuals with symptom-free implants; for example, TiO2rutile particle induced increase of IL-1β70.27-fold/8.49-fold versus control medium culture. PBMC of 5 of the 6 individuals with complication-free Ti implants showed anex vivoongoing production of IL-10 (mean4.18±2.98 pg/mL)-but none of the 14 controls showed such IL-10 production. Thusin vitroIL-1β-, IL-6-, and TNF-αproduction reflects “normal” unspecific immune response to Ti. This might be reduced by production of tolerogenic IL-10 in individuals with symptom-free Ti dental implants.
Study on Immune Relevant Vector Machine Based Intelligent Fault Detection and Diagnosis Algorithm
Authors: Miao Zhong-hua , Zhou Guang-xing , Wang Xiao-hua , He Chuang-xin
Published: September 2013

An immune relevant vector machine (IRVM) based intelligent classification method is proposed by combining the random real-valued negative selection (RRNS) algorithm and the relevant vector machine (RVM) algorithm. The method proposed is aimed to handle the training problem of missing or incomplete fault sampling data and is inspired by the “self/nonself” recognition principle in the artificial immune systems. The detectors, generated by the RRNS, are treated as the “nonself” training samples and used to train the RVM model together with the “self” training samples. After the training succeeds, the “nonself” detection model, which requires only the “self” training samples, is obtained for the fault detection and diagnosis. It provides a general way solving the problems of this type and can be applied for both fault detection and fault diagnosis. The standard Fisher's Iris flower dataset is used to experimentally testify the proposed method, and the results are compared with those from the support vector data description (SVDD) method. Experimental results have shown the validity and practicability of the proposed method.
Influence of Metallic Molar Ratio on the Electron Spin Resonance and Thermal Diffusivity of Zn–Al Layered Double Hydroxide
Authors: Ahmed Abdullah Ahmed Ali , Talib Zainal Abidin , Hussein Mohd Zobir
Published: September 2013

The coprecipitation method was used to prepare Zn–Al layered double hydroxide (Zn–Al–NO3‐LDH) at pH 7.5 and different Zn2+/Al3+ molar ratios of 2, 3, 4, 5, and 6. The elemental, structural, and textural properties of prepared samples were studied. The crystallinity of prepared LDH nanostructure decreases as Zn2+/Al3+ molar ratio increases. The electron spin resonance (ESR) spectroscopy of different LDH samples showed new ESR spectra. These spectra were produced due to the presence of different phases with formed LDH such as ZnO phase and ZnAl2O4 spinel. At low Zn2+/Al3+ molar ratio, the ESR signals were produced from the presence of free nitrate anions in the LDH interlayer. Above Zn2+/Al3+ = 2, the ESR signals were attributed to the existence of ZnO phase and ZnAl2O4 spinel in the samples. Because the nuclear magnetic moment of 67Zn is lower than 27Al, the increasing in Zn2+/Al3+ molar ratio causes a reduction of the magnetic activity of ZnAl2O4 spinel. Thermal diffusivity versus in situ temperature showed nonlinear relation for different samples due to the changing in the water content of LDH as temperature increases. The dc conductivity of samples decreased as Zn2+/Al3+ molar ratio.
Takotsubo Cardiomyopathy in Two Patients without Any Cardiac Symptom on Maintenance Hemodialysis
Authors: Muratsu Jun , Morishima Atsuyuki , Ueda Hiroyasu , Hiraoka Hisatoyo , Sakaguchi Katsuhiko
Published: September 2013

Takotsubo cardiomyopathy is a disorder characterized by left ventricular apical ballooning and electrocardiographic changes in the absence of coronary artery disease. While reversible in many cases, the mechanism of this disorder remains unclear. The most frequent clinical symptoms of takotsubo cardiomyopathy on admission are chest pain and dyspnea, resembling acute myocardial infarction. Here, we describe two cases of takotsubo cardiomyopathy without chest pain or dyspnea in patients on maintenance hemodialysis. The asymptomatic nature of these two cases may be due to the patients being on hemodialysis. Periodic electrocardiograms (ECG) may be helpful in screening this population for asymptomatic takotsubo cardiomyopathy and in evaluating its incidence.
Characterization of C-S Lyase fromC. diphtheriae: A Possible Target for New Antimicrobial Drugs
Authors: Astegno Alessandra , Giorgetti Alejandro , Allegrini Alessandra , Cellini Barbara , Dominici Paola
Published: September 2013

The emergence of antibiotic resistance in microbial pathogens requires the identification of new antibacterial drugs. The biosynthesis of methionine is an attractive target because of its central importance in cellular metabolism. Moreover, most of the steps in methionine biosynthesis pathway are absent in mammals, lowering the probability of unwanted side effects. Herein, detailed biochemical characterization of one enzyme required for methionine biosynthesis, a pyridoxal-5′-phosphate (PLP-) dependent C-S lyase fromCorynebacterium diphtheriae, a pathogenic bacterium that causes diphtheria, has been performed. We overexpressed the protein inE. coliand analyzed substrate specificity, pH dependence of steady state kinetic parameters, and ligand-induced spectral transitions of the protein. Structural comparison of the enzyme with cystalysin fromTreponema denticolaindicates a similarity in overall folding. We used site-directed mutagenesis to highlight the importance of active site residues Tyr55, Tyr114, and Arg351, analyzing the effects of amino acid replacement on catalytic properties of enzyme. Better understanding of the active site ofC. diphtheriaeC-S lyase and the determinants of substrate and reaction specificity from this work will facilitate the design of novel inhibitors as antibacterial therapeutics.
Characterization of the Boreal Summer Upwelling at the Northern Coast of the Gulf of Guinea Based on the PROPAO In Situ Measurements Network and Satellite Data
Authors: Kouadio Yves K. , Djakouré Sandrine , Aman Angora , Ali K. Eugène , Koné Vamara , Toualy Elisée
Published: September 2013

The boreal summer upwelling along the northern coast of the Gulf of Guinea (GG) is characterized using new in situ sea surface temperature (SST) from onset sensor and satellite TRMM Microwave Imager (TMI) datasets. This study aims to encourage intensive in situ SST measurements at the northern coast of the Gulf of Guinea. It shows good agreement between daily in situ SST and TMI SST and similar coastal upwelling onset date, end date, and durations calculated using both datasets. Interannual evolution of the onset date at four stations along the northern coast of GG indicates that the upwelling can be initiated at one cape or simultaneously at both the cape of palms and the cape of three points. It can be also initiated eastward towards Cotonou or globally off all the northern coasts of GG. Nonsignificant trend is found on upwelling onset date and end date variability. Moreover, this study shows that SST is significantly warm or cold some years. Ocean conditions during these years are related to known physical processes.
Effectively Improved SiO2-TiO2Composite Films Applied in Commercial Multicrystalline Silicon Solar Cells
Authors: Yang Chih-Hsiang , Lien Shui-Yang , Chu Chia-Ho , Kung Chung-Yuan , Cheng Tieh-Fei , Chen Pai-Tsun
Published: September 2013

Composite silicon dioxide-titanium dioxide (SiO2-TiO2) films are deposited on a large area of 15.6 × 15.6 cm2textured multicrystalline silicon solar cells to increase the incident light trapped within the device. For further improvement of the antireflective coatings (ARCs) quality, dimethylformamide (DMF) solution is added to the original SiO2-TiO2solutions. DMF solution solves the cracking problem, thus effectively decreasing reflectance as well as surface recombination. The ARCs prepared by sol-gel process and plasma-enhanced chemical vapor deposition (PECVD) on multicrystalline silicon substrate are compared. The average efficiency of the devices with improved sol-gel ARCs is 16.3%, only 0.5% lower than that of devices with PECVD ARCs (16.8%). However, from equipment depreciation point of view (the expiration date of equipment is generally considered as 5 years), the running cost (USD/watt) of sol-gel technique is 80% lower than that of PECVD method for the first five years and 66% lower than that of PECVD method from the start of the sixth year. This result proves that sol-gel-deposited ARCs process has potential applications in manufacturing low-cost, large-area solar cells.
Oscillation on a Class of Differential Equations of Fractional Order
Authors: Liu Tongbo , Zheng Bin , Meng Fanwei
Published: September 2013

Based on Riccati transformation and certain inequality technique, some new oscillatory criteria are established for the solutions of a class of sequential differential equations with fractional order defined in the modified Riemann-Liouville derivative. The oscillatory criteria established are of new forms compared with the existing results so far in the literature. For illustrating the validity of the results established, we present some examples for them.
Fault Tolerant Control for Interval Fractional-Order Systems with Sensor Failures
Authors: Song Xiaona , Shen Hao
Published: September 2013

The problem of robust fault tolerant control for continuous-time fractional-order (FO) systems with interval parameters and sensor faults of0<α<2has been investigated. By establishing sensor fault model and state observer, an observer-based FO output feedback controller is developed such that the closed-loop FO system is asymptotically stable, not only when all sensor components are working well, but also in the presence of sensor components failures. Finally, numerical simulation examples are given to illustrate the application of the proposed design method.
Pituitary Tumor-Transforming Gene 1 Is Expressed in Primary Ductal Breast Carcinoma, Lymph Node Infiltration, and Distant Metastases
Authors: Grizzi Fabio , Di Biccari Sonia , Fiamengo Barbara , Štifter Sanja , Colombo Piergiuseppe
Published: September 2013

Despite the advances that have been made in the fields of molecular and cell biology, there is still considerable debate explaining how the breast cancer cells progress through carcinogenesis and acquire their metastatic ability. The lack of preventive methods and effective therapies underlines the pressing need to identify new biomarkers that can aid early diagnosis and may be targets for effective therapeutic strategies. In this study we explore the pituitary tumor-transforming gene 1 (PTTG1) expression in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. Three human cell lines, 184B5 derived from normal mammary epithelium, HCC70 from a primary ductal carcinoma, and MDA-MB-361 from a breast metastasis, were used for quantifying PTTG1 mRNA expression. The PTTG1 immunohistochemical expression was carried out on specimens taken from eight patients with invasive ductal breast cancer who underwent surgical treatment and followup for five years retrospectively selected. The study demonstrated that PTTG1 is expressed gradually in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. Our findings suggest that the immunohistochemical evaluation of PTTG1 expression might be a powerful biomarker of recognition and quantification of the breast cancer cells in routine pathological specimens and a potential target for developing an effective immunotherapeutic strategy for primary and metastatic breast cancer.
Evaluation of the Antioxidative Properties of N‐Acylamino‐Substituted Tricyclic Imides
Authors: Gul Melek , Kulu Irem , Peksel Aysegul , Ocal Nuket
Published: September 2013

New N‐acylamino‐substituted tricyclic imides have been screened for scavenging ability against the free radical 2,2‐diphenyl‐1‐picryl‐hydrazyl (DPPH•), chelating activity on ferrous ions, and reductive potential. The results were compared with synthetic antioxidants BHT, BHA, and Trolox. The compounds exhibited different levels of antioxidant activity in all tests.
Exergy, Energy, and Dynamic Parameter Analysis of Indigenously Developed Low-Concentration Photovoltaic System
Authors: Yadav Pankaj , Tripathi Brijesh , Kumar Manoj
Published: September 2013

Piecewise linear parabolic trough collector (PLPTC) is designed and developed to concentrate solar radiation on monocrystalline silicon based photovoltaic module. A theoretical model is used to perform electrical energy and exergy analysis of low-concentration photovoltaic (LCPV) system working under actual test conditions (ATC). The exergy efficiency of LCPV system is in the range from 5.1% to 4.82% with increasing rate of input exergy rate from 30.81 W to 96.12 W, when concentration ratio changes from 1.85 to 5.17 Sun. Short-circuit current shows increasing trend with increasing input exergy rate of≈0.011 A/W. Power conversion efficiency decreases from 7.07 to 5.66%, and open-circuit voltage decreases from 9.86 to 8.24 V with temperature coefficient of voltage≈-0.021 V/K under ATC. The results confirm that the commercially available silicon solar PV module performs satisfactorily under low concentration.
Prediction the Vapor-Liquid Equilibria of CO2-Containing Binary Refrigerant Mixtures Using Artificial Neural Networks
Authors: Azari Ahmad , Atashrouz Saeid , Mirshekar Hamed
Published: September 2013

Artificial neural network (ANN) technique has been applied for estimation of vapor-liquid equilibria (VLE) for eight binary refrigerant systems. The refrigerants include difluoromethane (R32), propane (R290), 1,1-difluoroethane (R152a), hexafluoroethane (R116), decafluorobutane (R610), 2,2-dichloro-1,1,1-trifluoroethane (R123), 1-chloro-1,2,2,2-tetrafluoroethane (R124), and 1,1,1,2-tetrafluoroethane (R134a). The related experimental data of open literature have been used to construct the model. Furthermore, some new experimental data (not applied in ANN training) have been used to examine the reliability of the model. The results confirm that there is a reasonable conformity between the predicted values and the experimental data. Additionally, the ability of the ANN model is examined by comparison with the conventional thermodynamic models. Moreover, the presented model is capable of predicting the azeotropic condition.
The Assessment ofProteus mirabilisSusceptibility to Ceftazidime and Ciprofloxacin and the Impact of These Antibiotics at Subinhibitory Concentrations onProteus mirabilisBiofilms
Authors: Kwiecińska-Piróg Joanna , Skowron Krzysztof , Zniszczol Katarzyna , Gospodarek Eugenia
Published: September 2013

Rods of theProteusgenus are commonly isolated from patients, especially from the urinary tracts of the catheterised patients. The infections associated with biomaterials are crucial therapeutic obstacles, due to the bactericidal resistance of the biofilm. The aim of this study was to assess the susceptibility ofP. mirabilisplanktonic forms to ciprofloxacin and ceftazidime, the ability to form biofilm, and the impact of chosen sub-MIC concentrations of these antibiotics on biofilm at different stages of its formation. The research included 50P. mirabilisstrains isolated from wounds and the urinary tracts from patients of the University Hospital No. 1 in Bydgoszcz. The assessment of susceptibility to ciprofloxacin and ceftazidime was conducted using micromethods. The impact of sub-MIC concentrations of the chosen antibiotics on the biofilm was measured using the TTC method. The resistance to ciprofloxacin was confirmed for 20 strains (40.0%) while to ceftazidime for 32 (64.0%) of the testedP. mirabilisstrains. All of the tested strains formed biofilm: 24.0% weakly, 26.0% moderately, and 50.0% strongly. It was determined that ciprofloxacin and ceftazidime caused eradication of the biofilm. Moreover, the connection between origin of the strains, biofilm maturity level, and resistance to antibiotics was proved.
A Heuristic Approach to Flow Shop Scheduling Problem in Which Processing Times Are Associated with Their Respective Probabilities with No-Idle Constraint
Authors: Gupta Deepak , Singh Harminder
Published: September 2013

This paper is an attempt to study general flow shop scheduling problem in which processing time of jobs is associated with probabilities under no-idle constraint. The objective of this paper is to develop a heuristic algorithm to flowshop scheduling so that no machine remains idle during working for any given sequence of jobs. The proposed algorithm is simple, and easy to understand and provides an important tool in many practical situations for minimizing the expected hiring cost of the machines for a fixed sequence of job processing. A numerical illustration is also given to justify the proposed algorithm.
Effect of Laser Irradiation at Different Wavelengths (940, 808, and 658 nm) on Pressure Ulcer Healing: Results from a Clinical Study
Authors: Taradaj J. , Halski T. , Kucharzewski M. , Urbanek T. , Halska U. , Kucio C.
Published: September 2013

The aim of the study was to assess the efficacy of laser therapy (at different wavelengths: 940, 808, and 658 nm) for treating pressure ulcers. The primary endpoint in this trial included both the percentage reduction of the ulcer surface area and the percentage of completely healed wounds after one month of therapy (ulcer healing rate). The secondary endpoint was the ulcer healing rate at the follow-up evaluation (3 months after the end of the study). In total, 72 patients with stage II and III pressure ulcers received laser therapy once daily, 5 times per week for 1 month using a (GaAlAs) diode laser with a maximum output power of 50 mW and continuous radiation emission. Three separate wavelengths were used for the laser treatment: 940 nm (group I), 808 nm (group II), and 658 nm (group III). An average dose of 4 J/cm2was applied. In group IV, a placebo was applied (laser device was turned off). The laser therapy at a wavelength of 658 nm appeared to be effective at healing pressure ulcers. The wavelengths of 808 and 940 nm did not have any effect in our study.
N-Terminal proBNP Levels and Tissue Doppler Echocardiography in Acute Rheumatic Carditis
Authors: Kotby Alyaa A. , El-Shahed Ghada S. , Elmasry Ola A. , El-Hadidi Iman S. , El Shafey Rowaida N. S.
Published: September 2013

Background. Rheumatic heart disease (RHD) is a leading cause of heart failure in children and young adults worldwide. B-type natriuretic peptide (BNP) is a useful marker of critical pediatric heart disease, and its N-terminal peptide, NT-proBNP, is elevated in congenital and acquired heart disease in children.Aim. To measure NT-proBNP levels as a marker of carditis in children with acute rheumatic carditis, as compared to children with quiescent RHD and healthy controls.Methods. 16 children with acute rheumatic carditis, 33 children with quiescent RHD, and a cohort of 30 healthy children were studied. Transthoracic echocardiography was performed to assess valve and cardiac function. Tissue Doppler echocardiography was performed forE/E′(ratio between mitral inflowEwave and lateral mitral annulusE′wave) and systolic strain.Results. NT-proBNP levels were significantly higher in children with acute rheumatic carditis and dropped with its resolution. Strain andE/E′values were comparable among the three groups.Conclusion. NT-proBNP is significantly elevated in children with acute rheumatic carditis in the acute stage compared to children with quiescent RHD and healthy subjects, in the presence of comparable echocardiographic indices of LV systolic and diastolic function.
CXCR4, but not CXCR7, Discriminates Metastatic Behavior in Non–Small Cell Lung Cancer Cells
Authors: Choi Young H. , Burdick Marie D. , Strieter Brett A. , Mehrad Borna , Strieter Robert M.
Published: September 2013

Chemokines have been implicated as key contributors of non–small cell lung cancer (NSCLC) metastasis. However, the role of CXCR7, a recently discovered receptor for CXCL12 ligand, in the pathogenesis of NSCLC is unknown. To define the relative contribution of chemokine receptors to migration and metastasis, we generated human lung A549 and H157 cell lines with stable knockdown of CXCR4, CXCR7, or both. Cancer cells exhibited chemotaxis to CXCL12 that was enhanced under hypoxic conditions, associated with a parallel induction of CXCR4, but not CXCR7. Interestingly, neither knockdown cell line differed in the rate of proliferation, apoptosis, or cell adherence; however, in both cell lines, CXCL12-induced migration was abolished when CXCR4 signaling was abrogated. In contrast, inhibition of CXCR7 signaling did not alter cellular migration to CXCL12. In an in vivo heterotropic xenograft model using A549 cells, expression of CXCR4, but not CXCR7, on cancer cells was necessary for the development of metastases. In addition, cancer cells knocked down for CXCR4 (or both CXCR4 and CXCR7) produced larger and more vascular tumors as compared with wild-type or CXCR7 knockdown tumors, an effect that was attributable to cancer cell–derived CXCR4 out competing endothelial cells for available CXCL12 in the tumor microenvironment. These results indicate that CXCR4, not CXCR7, expression engages CXCL12 to mediate NSCLC metastatic behavior.

Implications: Targeting CXCR4-mediated migration and metastasis may be a viable therapeutic option in NSCLC. Mol Cancer Res; 12(1); 38–47. ©2013 AACR.
Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers
Authors: Polkinghorn William R. , Parker Joel S. , Lee Man X. , Kass Elizabeth M. , Spratt Daniel E. , Iaquinta Phillip J. , Arora Vivek K. , Yen Wei-Feng , Cai Ling , Zheng Deyou , Carver Brett S. , Chen Yu , Watson Philip A. , Shah Neel P. , Fujisawa Sho , Goglia Alexander G. , Gopalan Anuradha , Hieronymus Haley , Wongvipat John , Scardino Peter T. , Zelefsky Michael J. , Jasin Maria , Chaudhuri Jayanta , Powell Simon N. , Sawyers Charles L.
Published: September 2013

We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.

Significance: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer. Cancer Discov; 3(11); 1245–53. ©2013 AACR.

See related commentary by Bartek et al., p. 1222

This article is highlighted in the In This Issue feature, p. 1207
Ischemia-Reperfusion Injury in Stroke
Authors: Nour May , Scalzo Fabien , Liebeskind David S.
Published: September 2013

Despite ongoing advances in stroke imaging and treatment, ischemic and hemorrhagic stroke continue to debilitate patients with devastating outcomes at both the personal and societal levels. While the ultimate goal of therapy in ischemic stroke is geared towards restoration of blood flow, even when mitigation of initial tissue hypoxia is successful, exacerbation of tissue injury may occur in the form of cell death, or alternatively, hemorrhagic transformation of reperfused tissue. Animal models have extensively demonstrated the concept of reperfusion injury at the molecular and cellular levels, yet no study has quantified this effect in stroke patients. These preclinical models have also demonstrated the success of a wide array of neuroprotective strategies at lessening the deleterious effects of reperfusion injury. Serial multimodal imaging may provide a framework for developing therapies for reperfusion injury.
Changes of Ticagrelor Formulary Tiers in the USA: Targeting Private Insurance Providers away from Government-Funded Plans
Authors: Serebruany Victor L. , DiNicolantonio James J
Published: September 2013

Context: Ticagrelor (Brilinta®) is a new oral reversible antiplatelet agent approved by the FDA in July 2011 based on the results of the PLATO (Platelet Inhibition and Patient Outcomes) trial. However, despite very favorable and broad indications, the current clinical utilization of ticagrelor is woefully small. Objective: We aimed to compare ticagrelor formulary tiers for major private (n = 8) and government-funded (n = 4) insurance providers for 2012-2013. Results: Over the last year, ticagrelor placement improved, becoming a preferred drug (from Tier 3 in 2012 to Tier 2 in 2013) for Medco, moving from Tier 4 (with a prior approval requirement) to Tier 3 (no prior approval) for the United Health Care Private Plan and achieving Tier 3 status for Apex in 2013. In contrast, ticagrelor placement did not improve for New York Medicaid, retaining Tier 3 status. In addition, many Medicare Part D formularies have significantly worse coverage than most private plans. For example, Humana Medicare Part D has Tier 3 status requiring step therapy and quantity limits, SilverScript (CVS Caremark) Part D is Tier 3 and the American Association of Retired Persons (United Health Care) Medicare Part D is Tier 4 requiring prior approval. Conclusions: Ticagrelor formulary placement is significantly better for most private providers than for government-funded plans, which may possibly be due to the selective targeting of private insurance providers and the simultaneous avoidance of government-funded plans.
Red cell-derived microparticles (RMP) as haemostatic agent
Authors: Johansen Max E. , Bidot Carlos , Horstman Lawrence L. , Ahn Yeon S. , Jy Wenche
Published: September 2013

Among circulating cell-derived microparticles, those derived from red cells (RMP) have been least well investigated. To exploit potential haemostatic benefit of RMP, we developed a method of producing them in quantity, and here report on their haemostatic properties. High-pressure extrusion of washed RBC was employed to generate RMP. RMP were identified and enumerated by flow cytometry. Their size distribution was assessed by Doppler electrophoretic light scattering analysis (DELSA). Interaction with platelets was studied by platelet aggregometry, and shear-dependent adhesion by Diamed IMPACT-R. Thrombin generation and tissue factor (TF) expression was also measured. The effect of RMP on blood samples of patients with bleeding disorders was investigated ex vivo by thromboelastography (TEG). Haemostatic efficacy in vivo was assessed by measuring reduction of blood loss and bleeding time in rats and rabbits. RMP have mean diameter of 0.45 μm and 50% of them exhibit annexin V binding, a proxy for procoagulant phospholipids (PL). No TF could be detected by flow cytometry. At saturating concentrations of MPs, RMP generated thrombin robustly but after longer delay compared to PMP and EMP. RMP enhanced platelet adhesion and aggregation induced by low-dose ADP or AA. In TEG study, RMP corrected or improved haemostatic defects in blood of patients with platelet and coagulation disorders. RMP reduced bleeding time and blood loss in thrombocytopenic rabbits (busulfan-treated) and in Plavix-treated rats. In conclusion, RMP has broad haemostatic activity, enhancing both primary (platelet) and secondary (coagulation) haemostasis, suggesting potential use as haemostatic agent for treatment of bleeding.
C1q/Tumor Necrosis Factor–Related Protein-9, a Novel Adipocyte-Derived Cytokine, Attenuates Adverse Remodeling in the Ischemic Mouse Heart via Protein Kinase A Activation
Authors: Sun Yang , Yi Wei , Yuan Yuexing , Lau Wayne Bond , Yi Dinghua , Wang Xiaoliang , Wang Yajing , Su Hui , Wang Xiaoming , Gao Erhe , Koch Walter J. , Ma Xin-Liang
Published: September 2013

Background—

C1q/tumor necrosis factor–related protein-9 (CTRP9) is a newly identified adiponectin paralog with established metabolic regulatory properties. However, the role of CTRP9 in postmyocardial infarction remodeling remains completely unknown. This study determined whether CTRP9 may regulate cardiac remodeling after acute myocardial infarction (AMI) and elucidated the underlying mechanisms.

Methods and Results—

Male adult mice were subject to AMI by left anterior descending coronary artery ligation or sham surgery and treated with saline (vehicle) or globular CTRP9 via peritoneal implant osmotic pumps for 6 weeks. H9C2 cardiac cell lines were used in vitro for determining underlying mechanisms. Adipocyte CTRP9 expression and plasma CTRP9 levels were both significantly reduced after AMI. Compared with vehicle, CTRP9 treatment improved animal survival rate (
P
<0.05), restored cardiac function (
P
<0.05), attenuated adverse remodeling (
P
<0.01), and ameliorated cardiomyocyte apoptosis and fibrosis after AMI (
P
<0.01). Among the multiple antiremodeling molecules determined, AMP-activated protein kinase, protein kinase A (PKA), and Akt were significantly activated in CTRP9-treated heart. Surprisingly, CTRP9 remains cardioprotective in mice with cardiomyocyte-specific overexpression of a mutant AMP-activated protein kinase α2 subunit (AMPK-DN). Additional in vitro experiments demonstrated that administration of either PKA inhibitor or PKA-specific small interfering RNA virtually abolished the antiapoptotic effect of CTRP9 (
P
<0.05), whereas inhibition of Akt is less effective in blocking CTRP9 cardioprotection. Finally, CTRP9 phosphorylates BCL-2-associated agonist of cell death at its multiple antiapoptotic sites, an effect blocked by PKA inhibitor.

Conclusions—

We demonstrate that adipokine CTRP9 attenuates adverse cardiac remodeling after AMI, largely via a PKA-dependent pathway.
Toll-Like Receptor 4–Dependent Microglial Activation Mediates Spinal Cord Ischemia–Reperfusion Injury
Authors: Bell Marshall T. , Puskas Ferenc , Agoston Viktor A. , Cleveland Joseph C. , Freeman Kirsten A. , Gamboni Fabia , Herson Paco S. , Meng Xianzhong , Smith Phillip D. , Weyant Michael J. , Fullerton David A. , Reece T. Brett
Published: September 2013

Background—

Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia–reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia–reperfusion injury after aortic occlusion results from TLR-4–mediated microglial activation in mice.

Methods and Results—

TLR-4 mutant and wild-type mice underwent aortic occlusion for 5 minutes, followed by 60 hours of reperfusion when spinal cords were removed for analysis. Spinal cord cytokine production and microglial activation were assessed at 6 and 36 hours after surgery. Isolated microglia from mutant and wild-type mice were subjected to oxygen and glucose deprivation for 24 hours, after which the expression of TLR-4 and proinflammatory cytokines was analyzed. Mice without functional TLR-4 demonstrated decreased microglial activation and cytokine production and had preserved functional outcomes and neuronal viability after thoracic aortic occlusion. After oxygen and glucose deprivation, wild-type microglia had increased TLR-4 expression and production of proinflammatory cytokines.

Conclusions—

The absence of functional TLR-4 attenuated neuronal injury and microglial activation after thoracic aortic occlusion in mice. Furthermore, microglial upregulation of TLR-4 occurred after oxygen and glucose deprivation, and the absence of functional TLR-4 significantly attenuated the production of proinflammatory cytokines. In conclusion, TLR-4–mediated microglia activation in the spinal cord after aortic occlusion is critical in the mechanism of paraplegia after aortic cross-clamping and may provide targets for pharmacological intervention.
Relationship Between Mitochondrial Matrix Volume and Cellular Volume in Response to Stress and the Role of ATP-Sensitive Potassium Channel
Authors: Anastacio Melissa M. , Kanter Evelyn M. , Makepeace Carol M. , Keith Angela D. , Zhang Haixia , Schuessler Richard B. , Nichols Colin G. , Lawton Jennifer S.
Published: September 2013

Background—

Cardiac myocytes demonstrate significant swelling and associated reduced contractility in response to stress that is prevented by the ATP-sensitive potassium channel opener, diazoxide (DZX) via an unknown mechanism. One proposed mechanism of cardioprotection is mitochondrial matrix swelling. To establish the relationship between mitochondrial and cellular volume during stress, this study examined the effect of DZX on mitochondrial volume.

Methods and Results—

Isolated mouse mitochondria were exposed to the following solutions: Tyrode, isolation buffer, cardioplegia (CPG)±DZX±ATP-sensitive potassium channel inhibitor, 5-hydroxydecanoate, and metabolic inhibition (MI)±DZX±5-hydroxydecanoate. Mitochondrial volume was measured. DZX resulted in significant mitochondrial swelling (
P
<0.0001 versus Tyrode). MI and CPG resulted in significant mitochondrial swelling compared with baseline volume. The addition of DZX did not alter the response of mitochondrial volume to CPG (
P
=0.912) but increased swelling in response to MI (
P
=0.036). The addition of 5-hydroxydecanoate to MI+DZX or CPG+DZX significantly reduced mitochondrial swelling (
P
<0.003 MI+DZX versus MI+DZX+5HD;
P
<0.001 CPG+DZX versus CPG+DZX+5HD).

Conclusions—

Both cellular and mitochondrial volume increased during exposure to MI and CPG. DZX did not alter mitochondrial volume during CPG; however, it was associated with an increase in mitochondrial volume during MI. 5-Hydroxydecanoate reduced mitochondrial volume during exposure to both stresses with DZX, supporting a role for a mitochondrial ATP-sensitive potassium channel in the mechanism of cardioprotection by DZX.
Preserving Prostaglandin E2 Level Prevents Rejection of Implanted Allogeneic Mesenchymal Stem Cells and Restores Postinfarction Ventricular Function
Authors: Dhingra Sanjiv , Li Peng , Huang Xi-Ping , Guo Jian , Wu Jun , Mihic Anton , Li Shu-Hong , Zang Wang-Fu , Shen Daniel , Weisel Richard D. , Singal Pawan K. , Li Ren-Ke
Published: September 2013

Background—

Allogeneic mesenchymal stem cells (MSCs) were immunoprivileged early after cardiac implantation and improved heart function in preclinical and clinical studies. However, long-term preclinical studies demonstrated that allogeneic MSCs lost their immunoprivilege and were rejected in the injured myocardium, resulting in recurrent ventricular dysfunction. This study identifies some of the mechanisms responsible for the immune switch in MSCs and suggests a new treatment to maintain immunoprivilege and preserve heart function.

Methods and Results—

Rat MSC immunoprivilege was mediated by prostaglandin E2 (PGE2)–induced secretion of 2 critical chemokines, CCL12 and CCL5. These chemokines stimulated the chemoattraction of T cells toward MSCs, suppressed cytotoxic T-cell proliferation, and induced the production of T regulatory cells. MSCs treated with 5-azacytidine for 24 hours differentiated into myogenic cells after 2 weeks, which was associated with decreased PGE2 and chemokine production and the loss of immunoprivilege. Treatment of differentiated MSCs with PGE2 restored chemokine levels and preserved MSC immunoprivilege. In a rat myocardial infarction model, allogeneic MSCs (3×10
6
cells/rat) were injected into the infarct region with or without a biodegradable hydrogel that slowly released PGE2. Five weeks later, the transplanted MSCs expressed myogenic lineage markers and were rejected in the control group, but in the PGE2-treated group, the transplanted cells survived and heart function improved.

Conclusions—

Allogeneic MSCs maintained immunoprivilege by PGE2-induced secretion of chemokines CCL12 and CCL5. Differentiation of MSCs decreased PGE2 levels, and immunoprivilege was lost. Maintaining PGE2 levels preserved immunoprivilege after differentiation, prevented rejection of implanted MSCs, and restored cardiac function.
Altered Apoptosis-Related Signaling After Cardioplegic Arrest in Patients With Uncontrolled Type 2 Diabetes Mellitus
Authors: Feng Jun , Liu Yuhong , Dobrilovic Nikola , Chu Louis M. , Bianchi Cesario , Singh Arun K. , Sellke Frank W.
Published: September 2013

Background—

We investigated the effects of cardioplegic arrest and reperfusion (CP/Rep) on myocardial apoptosis and key apoptotic mediators, such as apoptosis-inducing factor, caspase 3, caspase 8, caspase 9, poly(adenosine diphosphate-ribose) polymerase, B-cell lymphoma 2 (Bcl-2) family proteins, and protein kinase C (PKC), in uncontrolled type 2 diabetic, controlled type 2 diabetic, and nondiabetic patients.

Methods and Results—

Right atrial tissue was harvested pre- and post-CP/Rep from uncontrolled type 2 diabetic patients (hemoglobin A1c=9.6±0.25), controlled type 2 diabetic patients (hemoglobin A1c=6.5±0.15), and nondiabetic patients (hemoglobin A1c=5.4±0.12) undergoing coronary artery bypass grafting (n=8/group). Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was used for the identification of apoptotic cells. Total and modified apoptosis-inducing factor, Bcl-2 family proteins, phospho-PKC-α, phospho-PKC-β1, and poly(adenosine diphosphate-ribose) polymerase were quantified by immunoblotting or immunohistochemistry. At baseline, the number of apoptotic cells and expression of total apoptosis-inducing factor, Bcl-2, Bak, and Bax in the pre-CP/Rep atrial tissue from uncontrolled type 2 diabetic patients were significantly increased compared with those of nondiabetic or controlled type 2 diabetic patients (
P
<0.05). After CP/Rep, the amount of apoptotic cells, apoptosis-inducing factor, phospho-Bad, phospho-PKC-α, phospho-PKC-β1, and cleaved poly(adenosine diphosphate-ribose) polymerase in post-CP/Rep atrial tissue were increased in all 3 groups compared with pre-CP/Rep. These increases after CP/Rep were more pronounced in the uncontrolled type 2 diabetic group. In addition, there were significant increases in the expression of cleaved caspase 8 and caspase 9 in the basal and post-CP/Rep atrium of uncontrolled type 2 diabetic group compared with nondiabetic or controlled type 2 diabetic group.

Conclusions—

Uncontrolled diabetes mellitus is associated with increases in myocardial apoptosis and expression of key apoptosis mediators at baseline and in the setting of CP/Rep.