bluuebunny/crossref_metadata_2025 huggingface dataset:
Usefulness of the Pain Tracking Technique in Acute Mechanical Low Back Pain
Authors: Bravo Acosta Tania , Martín Cordero Jorge E. , Hernández Tápanes Solangel , Pedroso Morales Isis , Fernández Cuesta José Ignacio , Leyva Serrano Maritza
Published: July 2015

Objective. To evaluate the usefulness of the pain tracking technique in acute mechanical low back pain. Method. We performed an experimental prospective (longitudinal) explanatory study between January 2011 and September 2012. The sample was randomly divided into two groups. Patients were assessed at the start and end of the treatment using the visual analogue scale and the Waddell test. Treatment consisted in applying the pain tracking technique to the study group and interferential current therapy to the control group. At the end of treatment, cryotherapy was applied for 10 minutes. The Wilcoxon signed-rank test and the Mann Whitney test were used. They were performed with a predetermined significance level of p≤0.05. Results. Pain was triggered by prolonged static posture and intense physical labor and intensified through trunk movements and when sitting and standing. The greatest relief was reported in lateral decubitus position and in William’s position. The majority of the patients had contracture. Pain and disability were modified with the rehabilitation treatment in both groups. Conclusions. Both the pain tracking and interferential current techniques combined with cryotherapy are useful treatments for acute mechanical low back pain. The onset of analgesia is faster when using the pain tracking technique.
Sound Propagation in a Duct with Wall Corrugations Having Square-Wave Profiles
Authors: Hawwa Muhammad A.
Published: July 2015

Acoustic wave propagation in ducts with rigid walls having square-wave wall corrugations is considered in the context of a perturbation formulation. Using the ratio of wall corrugation amplitude to the mean duct half width, a small parameter is defined and a two levels of approximations are obtained. The first-order solution produces an analytical description of the pressure field inside the duct. The second-order solution yields an analytical estimate of the phase speed of waves transmitting through the duct. The effect of wall corrugation density on acoustic impedance and wave speeds is highlighted. The analysis reveals that waves propagating in a duct with square-wave wall corrugation are slower than waves propagating in a duct with sinusoidal wave corrugation having the same corrugation wavelength.
The Pricing of Vulnerable Options in a Fractional Brownian Motion Environment
Authors: Wang Chao , Zhou Shengwu , Yang Jingyuan
Published: July 2015

Under the assumption of the stock price, interest rate, and default intensity obeying the stochastic differential equation driven by fractional Brownian motion, the jump-diffusion model is established for the financial market in fractional Brownian motion setting. With the changes of measures, the traditional pricing method is simplified and the general pricing formula is obtained for the European vulnerable option with stochastic interest rate. At the same time, the explicit expression for it comes into being.
Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence
Authors: Perdisa Francesco , Gostyńska Natalia , Roffi Alice , Filardo Giuseppe , Marcacci Maurilio , Kon Elizaveta
Published: July 2015

Among the current therapeutic approaches for the regeneration of damaged articular cartilage, none has yet proven to offer results comparable to those of native hyaline cartilage. Recently, it has been claimed that the use of mesenchymal stem cells (MSCs) provides greater regenerative potential than differentiated cells, such as chondrocytes. Among the different kinds of MSCs available, adipose-derived mesenchymal stem cells (ADSCs) are emerging due to their abundancy and easiness to harvest. However, their mechanism of action and potential for cartilage regeneration are still under investigation, and many other aspects still need to be clarified. The aim of this systematic review is to give an overview ofin vivostudies dealing with ADSCs, by summarizing the main evidence for the treatment of cartilage disease of the knee.
Noninvasive Optical Imaging andIn VivoCell Tracking of Indocyanine Green Labeled Human Stem Cells Transplanted at Superficial or In-Depth Tissue of SCID Mice
Authors: Sabapathy Vikram , Mentam Jyothsna , Jacob Paul Mazhuvanchary , Kumar Sanjay
Published: July 2015

Stem cell based therapies hold great promise for the treatment of human diseases; however results from several recent clinical studies have not shown a level of efficacy required for their use as a first-line therapy, because more often in these studies fate of the transplanted cells is unknown. Thus monitoring the real-time fate ofin vivotransplanted cells is essential to validate the full potential of stem cells based therapy. Recent studies have shown how real-timein vivomolecular imaging has helped in identifying hurdles towards clinical translation and designing potential strategies that may contribute to successful transplantation of stem cells and improved outcomes. At present, there are no cost effective and efficient labeling techniques for tracking the cells underin vivoconditions. Indocyanine green (ICG) is a safer, economical, and superior labelling technique forin vivooptical imaging. ICG is a FDA-approved agent and decades of usage have clearly established the effectiveness of ICG for human clinical applications. In this study, we have optimized the ICG labelling conditions that is optimal for noninvasive optical imaging and demonstrated that ICG labelled cells can be successfully used forin vivocell tracking applications in SCID mice injury models.
Trajectory Optimization for a Cruising Unmanned Aerial Vehicle Attacking a Target at Back Slope While Subjected to a Wind Gradient
Authors: Jiang Tieying , Li Jie , Li Bing , Huang Kewei , Yang Chengwei , Jiang Yimeng
Published: July 2015

The trajectory of a tubular launched cruising unmanned aerial vehicle is optimized using the modified direct collocation method for attacking a target at back slope under a wind gradient. A mathematical model of the cruising unmanned aerial vehicle is established based on its operational and motion features under a wind gradient to optimize the trajectory. The motion characteristics of  “altitude adjustment” and “suicide attack” are taken into full account under the combat circumstance of back slope time key targets. By introducing a discrete time function, the trajectory optimization is converted into a nonlinear programming problem and the SNPOT software is applied to solve for the optimal trajectory of the missile under different wind loads. The simulation results show that, for optimized trajectories, the average attack time decreased by up to 29.1% and the energy consumption is reduced by up to 25.9% under specified wind gradient conditions.A,ωdire, andWmaxhave an influence on the flight trajectories of cruising unmanned aerial vehicle. This verifies that the application of modified direct collocation method is reasonable and feasible in an effort to achieve more efficient missile trajectories.
Novel Chaos Secure Communication System Based on Walsh Code
Authors: Zhang Gang , Cui Niting , Zhang Tianqi
Published: July 2015

A multiuser communication scheme which is a hybrid of Walsh code with DCSK and CDSK is proposed to improve low data transmission rate of Differential Chaos Shift Keying (DCSK), poor bit error ratio (BER) performance of Correlation Delay Shift Keying (CDSK), and disadvantage of orthogonality in traditional multiuser DCSK. It not only overcomes the disadvantages of DCSK and CDSK, but also has better performance than CDSK and higher transmission data rate than DCSK. It has been proved that the novel multiuser CDSK-DCSK has better properties than traditional Multiple Input Multiple Output-Differential Chaos Shift Keying (MIMO-DCSK) and Modified-Differential Chaos Shift Keying (M-DCSK). Also the multiuser interference is greatly suppressed due to the orthogonality of Walsh code.
Numerical Algorithm for Delta of Asian Option
Authors: Zhang Boxiang , Yu Yang , Wang Weiguo
Published: July 2015

We study the numerical solution of the Greeks of Asian options. In particular, we derive a close form solution of Δ of Asian geometric option and use this analytical form as a control to numerically calculate Δ of Asian arithmetic option, which is known to have no explicit close form solution. We implement our proposed numerical method and compare the standard error with other classical variance reduction methods. Our method provides an efficient solution to the hedging strategy with Asian options.
Design and Experimentation of Piezoelectric Crystal Sensor Array for Grain Cleaning Loss
Authors: Ni Jun , Mao Hanping , Pang Fangrong , Zhu Yan , Yao Xia , Tian Yongchao
Published: July 2015

In order to improve the accuracy and reliability for detection of grains cleaning loss, a piezoelectric crystal sensor array was proposed in full width of distribution to realize the online multipoints detection. The dynamic model for grain collision sensor array was evaluated by the method of experimental model analysis. The distribution of low-level vibration and deformation was tested for the sensitive elements of detection array using dynamic signal tester. The location and quantity of the piezoelectric crystal units were determined. The simulation was done based on the software ANSYS for the impacts of grains on the sensitive elements. A quantitative analysis was developed to correct the positions of the piezoelectric crystal units and the construction was adjusted according to the deformation contours. The exact positions were quantitatively analyzed and corrected based on the numerical results for the deformation placement, which was used for optimizing the array construction. Then, the grain impact experiment was established on the test bench. The results showed that the performance was stable for the piezoelectric sensor array, and output signal amplitude was about 2.5 V, with uniform sensitivity in the whole range. The present array sensor helps to provide a technical foundation for detection of grain cleaning loss.
Papillary Thyroid Microcarcinoma with a Large Cystic Dilated Lymph Node Metastasis to the Neck Mimicking a Branchial Cleft Cyst: A Potential Pitfall
Authors: Ozdamar Osman Ilkay , Acar Gul Ozbilen , Kafkasli Cigdem , Kalcioglu M. Tayyar , Zenginkinet Tulay , Tamer H. Gonca
Published: July 2015

Lateral cervical cystic mass in a young adult very rarely could be a first sign of an occult thyroid papillary microcarcinoma metastasis. In this paper, we presented a 37-year-old male patient whose preoperative 6 cm left lateral cervical cystic mass was initially diagnosed as branchial cleft cyst, but then the postoperative histopathological examination of the mass was revealed as papillary thyroid carcinoma metastasis. Preoperative fine needle aspiration biopsy was relevant with a branchial cleft cyst. In the left thyroid lobe there were 3 solid nodules with 4, 6, and 12 mm dimensions, respectively. One of the nodules had malignant well-differentiated cells diagnosed after fine needle aspiration biopsy. After total thyroidectomy, histopathologic evaluation of biopsy material’s showed papillary thyroid microcarcinomas. This case indicates that especially in a young adult lateral cervical cystic mass should be carefully considered preoperatively for the possibility of metastatic occult thyroid carcinoma, especially for papillary carcinoma in differential diagnosis, and evaluation of the thyroid gland should be taken into account.
Pruritus in Systemic Diseases: A Review of Etiological Factors and New Treatment Modalities
Authors: Tarikci Nagihan , Kocatürk Emek , Güngör Şule , Oğuz Topal Ilteriş , Ülkümen Can Pelin , Singer Ralfi
Published: July 2015

Pruritus is the most frequently described symptom in dermatology and can significantly impair the patient’s quality of life. In 10–50% of adults with persistent pruritus, it can be an important dermatologic clue for the presence of a significant underlying systemic disease such as renal insufficiency, cholestasis, hematologic disorder, or malignancy (Etter and Myers, 2002; Zirwas and Seraly, 2001). This review describes the presence of pruritus in different systemic diseases. It is quite important to discover the cause of pruritus for providing relief for the patients experiencing substantial morbidity caused by this condition.
Linoleic Acid Induced Acute Hepatitis: A Case Report and Review of the Literature
Authors: Bilal Mohammad , Patel Yogesh , Burkitt Micheal , Babich Michael
Published: July 2015

Several dietary supplements used for weight loss have been reported to cause hepatotoxicity. Conjugated Linoleic Acid (CLA) is a dietary supplement that has been shown to cause reduction in body fat mass. Here, we present the first case of CLA induced acute hepatitis in the United States and only the third case in the worldwide literature along with a brief review of the literature.
Abnormal Expression of Prostaglandins E2 and F2αReceptors and Transporters in Patients with Endometriosis
Authors: Rakhila Halima , Bourcier Nathalie , Akoum Ali , Pouliot Marc
Published: July 2015

Objective.To investigate the level of expression of prostaglandin receptivity and uptake factors in eutopic and ectopic endometrium of women with endometriosis.Design.Prospective study.Setting.Human reproduction research laboratory.Patients.Seventy-eight patients with endometriosis and thirty healthy control subjects.Intervention(s).Endometrial and endometriotic tissue samples were obtained during laparoscopic surgery.Main Outcome Measure(s).Real-time polymerase chain reaction assay of mRNA encoding prostaglandin E2 receptors (EP1, EP2, EP3, and EP4), prostaglandin F2αreceptor (FP), prostaglandin transporter (PGT), and multidrug resistance-associated protein 4 (MRP4); immunohistochemical localization of expressed proteins.Results.Marked increases in receptors EP3, EP4, and FP and transporters PGT and MRP4 in ectopic endometrial tissue were noted, without noticeable change associated with disease stage. An increase in EP3 expression and decreases in FP and PGT were observed in the eutopic endometrium of endometriosis patients in conjunction with the phases of the menstrual cycle.Conclusion(s).This study is the first to demonstrate a possible relationship between endometriosis and enhanced prostaglandin activity. In view of the wide range of prostaglandin functions, increasing cell receptivity and facilitating uptake in endometrial tissue could contribute to the initial steps of overgrowth and have an important role to play in the pathogenesis and symptoms of this disease.
In VitroEffects of Strontium on Proliferation and Osteoinduction of Human Preadipocytes
Authors: Nardone V. , Zonefrati R. , Mavilia C. , Romagnoli C. , Ciuffi S. , Fabbri S. , Palmini G. , Galli G. , Tanini A. , Brandi M. L.
Published: July 2015

Development of tools to be used forin vivobone tissue regeneration focuses on cellular models and differentiation processes. In searching for all the optimal sources, adipose tissue-derived mesenchymal stem cells (hADSCs or preadipocytes) are able to differentiate into osteoblasts with analogous characteristics to bone marrow mesenchymal stem cells, producing alkaline phosphatase (ALP), collagen, osteocalcin, and calcified nodules, mainly composed of hydroxyapatite (HA). The possibility to influence bone differentiation of stem cells encompasses local and systemic methods, including the use of drugs administered systemically. Among the latter, strontium ranelate (SR) represents an interesting compound, acting as an uncoupling factor that stimulates bone formation and inhibits bone resorption. The aim of our study was to evaluate thein vitroeffects of a wide range of strontium (Sr2+) concentrations on proliferation, ALP activity, and mineralization of a novel finite clonal hADSCs cell line, named PA20-h5. Sr2+promoted PA20-h5 cell proliferation while inducing the increase of ALP activity and gene expression as well as HA production duringin vitroosteoinduction. These findings indicate a role for Sr2+in supporting bone regeneration during the process of skeletal repair in general, and, more specifically, when cell therapies are applied.
Weakly Bound States of Elementary Excitations in Graphene Superlattice in Quantizing Magnetic Field
Authors: Kryuchkov Sergei V. , Kukhar’ Egor I.
Published: July 2015

The spectrum of allowed energy of electron in graphene superlattice in the quantizing magnetic field is investigated. Such spectrum consists of number of so-called magnetic minibands. The width of these minibands depends on the superlattice barriers power and on the magnetic field intensity. The explicit form of electron spectrum is derived in the case of weak magnetic field. The possibility of electron-electron and electron-phonon bound states is shown. The binding energies of these states are calculated. The binding energy is shown to be the function of magnetic field intensity.
Performance Analysis of Heterogeneous Data Centers in Cloud Computing Using a Complex Queuing Model
Authors: Bai Wei-Hua , Xi Jian-Qing , Zhu Jia-Xian , Huang Shao-Wei
Published: July 2015

Performance evaluation of modern cloud data centers has attracted considerable research attention among both cloud providers and cloud customers. In this paper, we investigate the heterogeneity of modern data centers and the service process used in these heterogeneous data centers. Using queuing theory, we construct a complex queuing model composed of two concatenated queuing systems and present this as an analytical model for evaluating the performance of heterogeneous data centers. Based on this complex queuing model, we analyze the mean response time, the mean waiting time, and other important performance indicators. We also conduct simulation experiments to confirm the validity of the complex queuing model. We further conduct numerical experiments to demonstrate that the traffic intensity (or utilization) of each execution server, as well as the configuration of server clusters, in a heterogeneous data center will impact the performance of the system. Our results indicate that our analytical model is effective in accurately estimating the performance of the heterogeneous data center.
Where Can Colorectal Cancer Screening Interventions Have the Most Impact?
Authors: Siegel Rebecca L. , Sahar Liora , Robbins Anthony , Jemal Ahmedin
Published: July 2015

Background: Although colorectal cancer death rates in the United States have declined by half since 1970, large geographic disparities persist. Spatial identification of high-risk areas can facilitate targeted screening interventions to close this gap.

Methods: We used the Getis-Ord Gi* statistic within ArcGIS to identify contemporary colorectal cancer “hotspots” (spatial clusters of counties with high rates) based on county-level mortality data from the national vital statistics system. Hotspots were compared with the remaining aggregated counties (non-hotspot United States) by plotting trends from 1970 to 2011 and calculating rate ratios (RR). Trends were quantified using joinpoint regression.

Results: Spatial mapping identified three distinct hotspots in the contemporary United States where colorectal cancer death rates were elevated. The highest rates were in the largest hotspot, which encompassed 94 counties in the Lower Mississippi Delta [Arkansas (17), Illinois (16), Kentucky (3), Louisiana (6), Mississippi (27), Missouri (15), and Tennessee (10)]. During 2009 to 2011, rates here were 40% higher than the non-hotspot United States [RR, 1.40; 95% confidence interval (CI), 1.34–1.46], despite being 18% lower during 1970 to 1972 (RR, 0.82; 95% CI, 0.78–0.86). The elevated risk was similar in blacks and whites. Notably, rates among black men in the Delta increased steadily by 3.5% per year from 1970 to 1990, and have since remained unchanged. Rates in hotspots in west central Appalachia and eastern Virginia/North Carolina were 18% and 9% higher, respectively, than the non-hotspot United States during 2009 to 2011.

Conclusions: Advanced spatial analysis revealed large pockets of the United States with excessive colorectal cancer death rates.

Impact: These well-defined areas warrant prioritized screening intervention. Cancer Epidemiol Biomarkers Prev; 24(8); 1151–6. ©2015 AACR.
Preclinical Development of an Anti-NaPi2b (SLC34A2) Antibody–Drug Conjugate as a Therapeutic for Non–Small Cell Lung and Ovarian Cancers
Authors: Lin Kedan , Rubinfeld Bonnee , Zhang Crystal , Firestein Ron , Harstad Eric , Roth Leslie , Tsai Siao Ping , Schutten Melissa , Xu Keyang , Hristopoulos Maria , Polakis Paul
Published: July 2015

Purpose: Antibody–drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium–phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies.

Experimental Design: The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non–small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys.

Results: We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression.

Conclusions: Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments. Clin Cancer Res; 21(22); 5139–50. ©2015 AACR.
NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma
Authors: Huang Junwei , Zhou Yi , Thomas Gregory S. , Gu Zhimin , Yang Ye , Xu Hongwei , Tricot Guido , Zhan Fenghuang
Published: July 2015

Purpose: CKS1B is significantly upregulated in multiple myeloma and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCFSkp2 activation and offers a more specific approach to protein degradation inhibition than total proteasomal inhibition. The goal of this study was to evaluate whether MLN4924 is effective in high CKS1B conditions and identify mechanisms regulating drug potency.

Experimental Design: Bortezomib and MLN4924 sensitivity was assessed through proliferation, viability, clonogenic potential, and senescence induction in cells overexpressing CKS1B. The mechanism for MLN4924 sensitivity was elucidated by immunoblot analysis of SCFskp substrates and confirmed by shRNA knockdown. The clinical relevance of the NEDD8 pathway was examined in gene expression profiles (GEP) derived from healthy people, patients with monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.

Results: Cells overexpressing CKS1B were resistant to bortezomib but sensitive to MLN4924. Treatment of CKS1B-overexpressing cells with MLN4924 decreased proliferation, clonogenicity, and induced senescence. MLN4924, but not bortezomib, induced stabilization of p21 and knockdown of p21 resulted in loss of MLN4924 sensitivity. Patients with MGUS and multiple myeloma exhibited increased expression of NEDD8 pathway genes relative to normal plasma cells. Multiple myeloma patients with high NEDD8 expression were linked to bortezomib resistance in clinical trials, and had inferior outcomes.

Conclusions: Our data demonstrate that cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offer a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in multiple myeloma patients exhibiting elevated expression of CKS1B. Clin Cancer Res; 21(24); 5532–42. ©2015 AACR.
The Protective Effect of Peanut, Walnut, and Almond Consumption on the Development of Breast Cancer
Authors: Soriano-Hernandez Alejandro D. , Madrigal-Perez Daniela G. , Galvan-Salazar Hector R. , Arreola-Cruz Alejandro , Briseño-Gomez Lorena , Guzmán-Esquivel José , Dobrovinskaya Oxana , Lara-Esqueda Agustin , Rodríguez-Sanchez Iram P. , Baltazar-Rodriguez Luz M. , Espinoza-Gomez Francisco , Martinez-Fierro Margarita L. , de-Leon-Zaragoza Luis , Olmedo-Buenrostro Bertha A. , Delgado-Enciso Ivan
Published: July 2015

Background/Aims: Breast cancer is the most common gynecologic malignancy known worldwide. The consumption of certain foods may modify the risk for its development. Peanuts and other seeds have shown anticarcinogenic effects in vitro, but there are a few studies that evaluate the effect of their consumption on the development of breast cancer. The aim of the present study was to determine whether there is an association between the consumption of peanuts, walnuts, and almonds and the development of breast cancer. Methods: We analyzed 97 patients presenting with breast cancer and 104 control subjects that did not have the pathology (BIRADS 1-2). An analysis of the main clinical characteristics and lifelong seed consumption was carried out. The association between the consumption of these foods and the risk for breast cancer was estimated by odds ratios and 95% confidence intervals, controlling other risk factors, using the Mantel-Haenszel analysis. Results: The high consumption of peanuts, walnuts, or almonds significantly reduced the risk for breast cancer by 2-3 times. This protective effect was not found with low or moderate seed consumption when compared with null consumption. Conclusions: High consumption of peanuts, walnuts, and almonds appears to be a protective factor for the development of breast cancer.
Bezoar in a Pediatric Oncology Patient Treated with Coca-Cola
Authors: Naramore Sara , Virojanapa Amy , Bell Moshe , Jhaveri Punit N.
Published: July 2015

A bezoar is a mass of indigestible material. Bezoars can present with a gradual onset of non-specific gastrointestinal symptoms including abdominal pain, nausea and vomiting. However, bezoars can result in more serious conditions such as intestinal bleeding or obstruction. Without quick recognition, particularly in susceptible individuals, the diagnosis and treatment can be delayed. Currently resolution is achieved with enzymatic dissolution, endoscopic fragmentation or surgery. We describe, to our knowledge, the first pediatric patient with lymphoma to have had a bezoar treated with Coca-Cola.
Randomized, Double-Blind, Placebo-Controlled, Withdrawal Study of Colestilan after Dose Titration in Chronic Kidney Disease Dialysis Patients with Hyperphosphatemia
Authors: Hertel Joachim , Locatelli Francesco , Spasovski Goce , Dimkovic Nada , Wanner Christoph
Published: July 2015

Background/Aims: Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c). Methods: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period. Results: A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal. Conclusion: In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels.
Prenatal Diagnosis of DNA Copy Number Variations by Genomic Single-Nucleotide Polymorphism Array in Fetuses with Congenital Heart Defects
Authors: Tang Shaohua , Lv Jiaojiao , Chen Xiangnan , Bai Lili , Li Huanzheng , Chen Chong , Wang Ping , Xu Xueqin , Lu Jianxin
Published: July 2015

Objectives: To evaluate the usefulness of single-nucleotide polymorphism (SNP) array for prenatal genetic diagnosis of congenital heart defect (CHD), we used this approach to detect clinically significant copy number variants (CNVs) in fetuses with CHDs. Methods: A HumanCytoSNP-12 array was used to detect genomic samples obtained from 39 fetuses that exhibited cardiovascular abnormalities on ultrasound and had a normal karyotype. The relationship between CNVs and CHDs was identified by using genotype-phenotype comparisons and searching of chromosomal databases. All clinically significant CNVs were confirmed by real-time PCR. Results: CNVs were detected in 38/39 (97.4%) fetuses: variants of unknown significance were detected in 2/39 (5.1%), and clinically significant CNVs were identified in 7/39 (17.9%). In 3 of the 7 fetuses with clinically significant CNVs, 3 rare and previously undescribed CNVs were detected, and these CNVs encompassed the CHD candidate genes FLNA (Xq28 dup), BCOR (Xp11.4 dup), and RBL2 (16q12.2 del). Conclusion: Compared with conventional cytogenetic genomics, SNP array analysis provides significantly improved detection of submicroscopic genomic aberrations in pregnancies with CHDs. Based on these results, we propose that genomic SNP array is an effective method which could be used in the prenatal diagnostic test to assist genetic counseling for pregnancies with CHDs.
Oxidation and Cognitive Impairment in the Aging Zebrafish
Authors: Ruhl Tim , Jonas Annika , Seidel Nathan Ian , Prinz Nicole , Albayram Onder , Bilkei-Gorzo Andras , von der Emde Gerhard
Published: July 2015

Background: The zebrafish has become an established model organism in aging research giving insight into general aging processes in vertebrates. Oxidative stress in aging may damage proteins and lipids in brain cells. Enhanced levels of oxidized macromolecules exert neurotoxic effects that could lead to disturbances in neuronal functioning and cognitive skills. Objective: This study aims to investigate a possible relation between oxidative stress and learning deficits during aging in zebrafish. Methods: We tested zebrafish of different ages in a color discrimination paradigm for associative learning and in a hole board task for spatial learning abilities. Afterwards, we determined the levels of oxidized lipids and proteins as well as the amount of lipofuscin in the learning-relevant brain regions of animals of the same age. Results: While young zebrafish at the age of 1 year successfully completed both learning tasks, cognitive abilities were significantly impaired in older animals. Learning deficits occurred at the age of 2 years, where we also detected significantly increased levels of lipofuscin and oxidized proteins in the zebrafish medial and lateral pallial areas of the dorsal telencephalon. Conclusion: These data suggest that enhanced oxidative stress may contribute to behavioral and cognitive impairments in the aging zebrafish.
Emerging Role of Hypofractionated Radiotherapy with Simultaneous Integrated Boost in Modern Radiotherapy of Breast Cancer
Authors: Nitsche Mirko , Dunst Juergen , Carl Ulrich M. , Hermann Robert M.
Published: July 2015

Hypofractionated radiotherapy for breast cancer is becoming increasingly important. The scientific background of this development as well as the introduction of the simultaneous integrated boost to the primary tumor region in this context are discussed here.
Effect of P2Y12 inhibitors on inflammation and immunity
Authors: Storey Robert , Thomas Mark
Published: July 2015

Platelet P2Y12 inhibitors form a major part of the treatment strategy for patients with acute coronary syndromes (ACS) due to the importance of the platelet P2Y12 receptor in mediating the pathophysiology of arterial thrombosis. It has been increasingly recognised that platelets also have a critical role in inflammation and immune responses. P2Y12 inhibitors reduce platelet release of pro-inflammatory α-granule contents and the formation of pro-inflammatory platelet-leukocyte aggregates. These are important mediators of inflammation in a variety of different contexts. Clinical evidence shows that P2Y12 inhibition by clopidogrel is associated with a reduction in platelet-related mediators of inflammation, such as soluble P-selectin and CD40L, following atherothrombosis. Clopidogrel in addition to aspirin, compared to aspirin alone, also reduces markers of systemic inflammation such as tumour necrosis factor (TNF) α and C-reactive protein (CRP) following ACS. The more potent thienopyridine P2Y12 inhibitor, prasugrel, has been shown to decrease platelet P-selectin expression and platelet-leukocyte aggregate formation compared to clopidogrel. The PLATO study suggested that the novel P2Y12 inhibitor ticagrelor might improve clinical outcomes from pulmonary infections and sepsis compared to clopidogrel in patients with ACS. Ticagrelor is a more potent P2Y12 inhibitor than clopidogrel and also inhibits cellular adenosine uptake via equilibrative nucleoside transporter (ENT) 1, whereas clopidogrel does not. Further examination of the involvement of these mechanisms in inflammation and immunity is therefore warranted.
T- wave axis deviation is associated with biomarkers of low-grade inflammation
Authors: Bonaccio Marialaura , Di Castelnuovo Augusto , Rago Livia , De Curtis Amalia , Assanelli Deodato , Badilini Fabio , Vaglio Martino , Costanzo Simona , Persichillo Mariarosaria , Cerletti Chiara , Donati Maria Benedetta , de Gaetano Giovanni , Iacoviello Licia ,   the MOLI-SANI study Investigators
Published: July 2015

T-wave axis deviation (TDev) may help identifying subjects at risk for major cardiac events and mortality, but the pathogenesis of TDev is not well established; in particular, the possible association between TDev and inflammation is unexplored and unknown. We aimed at investigating the association between low-grade inflammation and TDev abnormalities by conducting a cross-sectional analysis on 17,507 subjects apparently free from coronary heart and haematological diseases enrolled in the MOLI-SANI study. TDev was measured from a standard 12-lead resting electrocardiogram. High sensitivity (Hs) C-reactive protein (CRP), leukocyte (WBC) and platelet counts, neutrophil or granulocyte to lymphocyte ratios were used as markers of inflammation. In multivariable model subjects reporting high CRP levels had higher odds of having borderline and abnormal TDev (OR=1.70; 95 %CI: 1.53–1.90 and OR=1.72; 95 %CI: 1.23–2.41, respectively); the association was still significant, although reduced, after controlling for body mass index (OR=1.17; 95 %CI: 1.05–1.32, for borderline and OR=1.46; 95 %CI: 1.03–2.08, for abnormal). Similarly, higher neutrophil or granulocyte to lymphocyte ratios were associated with increased odds of having abnormal TDev. Neither platelet nor leukocyte counts were associated with abnormal TDev. The relationship between CRP with TDev abnormalities was significantly stronger in men, in non- obese or normotensive individuals, and in those without metabolic syndrome. In conclusion, C-reactive protein and some cellular biomarkers of inflammation such as granulocyte or neutrophil to lymphocyte ratios were independently associated with abnormal TDev, especially in subjects at low CVD risk. These results suggest that a low-grade inflammation likely contributes to the pathogenesis of T- wave axis deviation.
Practical management of bleeding in patients receiving non-vitamin K antagonist oral anticoagulants
Authors: Pollack Charles V. , Weitz Jeffrey I.
Published: July 2015

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in the prevention and treatment of venous thromboembolism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, including consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence supports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in life-threatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anticoagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers.
Ethnic diversity in the genetics of venous thromboembolism
Authors: Tang Liang , Hu Yu
Published: July 2015

Genetic susceptibility is considered as a crucial factor for the development of venous thromboembolism (VTE). Epidemiologic and genetic studies have revealed clear disparities in the incidence of VTE and the distribution of genetic factors for VTE in populations stratified by ethnicity worldwide. While gain-of-function polymorphisms in the procoagulant genes are common inherited factors in European-origin populations, the most prevalent molecular basis for venous thrombosis in Asians is confirmed to be dysfunctional variants in the anticoagulant genes. With the breakthrough of genomic technologies, a set of novel common alleles and rare mutations associated with VTE have also been identified, in different ethnic groups. Several putative pathways contributing to the pathogenesis of thrombophilia in populations of African-ancestry are largely unknown, as current knowledge of hereditary and acquired risk factors do not fully explain the highest risk of VTE in Black groups. In-depth studies across diverse ethnic populations are needed to unravel the whole genetics of VTE, which will help developing individual risk prediction models and strategies to minimise VTE in all populations.
Intramural Ventricular Recording and Pacing in Patients With Refractory Ventricular Tachycardia
Authors: AbdelWahab Amir , Stevenson William , Thompson Kara , Parkash Ratika , Gray Christopher , Gardner Martin , Sapp John
Published: July 2015

Background—

Ablation of ventricular arrhythmias (VA) can be limited by intramural substrate not amenable to endocardial or epicardial ablation. Feasibility of irrigated needle ablation has been shown, but optimal means of identifying targets is not clear. We analyzed intramural needle electrograms in relation to endocardial electrograms.

Methods and Results—

Eight sequential patients (mean age, 56 years) who had failed 1 to 4 prior ablations underwent irrigated needle ablation were included. At selected sites, the needle was advanced into the myocardium. Bipolar and unipolar electrograms from the needle and catheter tip were analyzed. The needle was deployed at 75 sites with suspected intramural substrate among 2309 mapping sites. Intramural bipolar electrogram amplitude and duration correlated closely with endocardial electrograms, but were greater in amplitude and duration (1.5±1.4 versus 0.6±0.5 mV and 131±66 versus 112±51 ms;
P
=0.001 for both). During sinus rhythm intramural late potentials tended to be more common than endocardial late potentials (53.6% versus 35.7%;
P
=0.12). Intramural electrograms during VA preceded endocardial electrograms (−29±34 versus −15±21 ms;
P
=0.001). Irrigated needle ablation terminated VA at 12 of 28 sites with ablation during VA. Termination site needle electrograms tended to be earlier than nontermination sites (−54±37 versus −36±33 ms pre-QRS;
P
=0.15). Pacemapping from the needle at 19 sites matched the VA at 18 and showed stimulus to QRS of 60±51 ms.

Conclusions—

Recordings from intramural needle may be useful for selecting ablation targets during ventricular tachycardia and for substrate mapping. Further study is needed to develop methods to guide selection of optimal sites for needle deployment and ablation.
Everolimus Eluting Stents Versus Coronary Artery Bypass Graft Surgery for Patients With Diabetes Mellitus and Multivessel Disease
Authors: Bangalore Sripal , Guo Yu , Samadashvili Zaza , Blecker Saul , Xu Jinfeng , Hannan Edward L.
Published: July 2015

Background—

In patients with diabetes mellitus and multivessel disease, coronary artery bypass graft surgery and percutaneous coronary intervention are treatment options. However, there is paucity of data comparing coronary artery bypass graft surgery against newer generation stents.

Methods and Results—

Patients included in the New York State registries who had diabetes mellitus and underwent isolated coronary artery bypass graft surgery or percutaneous coronary intervention with everolimus eluting stent (EES) for multivessel disease were included. Propensity score matching was used to assemble a cohort with similar baseline characteristics. The primary outcome was all-cause mortality. Secondary outcomes were myocardial infarction (MI), stroke, and repeat revascularization. Short-term (within 30 days) and long-term outcomes were evaluated. Among 16 089 patients with diabetes mellitus and multivessel disease, 8096 patients with similar propensity scores were included. At short-term, EES was associated with a lower risk of death (hazard ratio [HR] =0.58; 95% confidence interval [CI], 0.34–0.98;
P
=0.04) and stroke (HR=0.14; 95% CI, 0.06–0.30;
P
<0.0001) but higher risk of MI (HR=2.44; 95% CI, 1.13–5.31;
P
=0.02). At long-term, EES was associated with a similar risk of death (425 [10.50%] versus 414 [10.23%] events; HR=1.12; 95% CI, 0.96–1.30;
P
=0.16), a lower risk of stroke (118 [2.92%] versus 157 [3.88%] events; HR=0.76; 95% CI, 0.58–0.99;
P
=0.04) but a higher risk of MI (260 [6.42%] versus 166 [4.10%] events; HR=1.64; 95% CI, 1.32–2.04;
P
<0.0001) and repeat revascularization (889 [21.96%] versus 421 [10.40%] events; HR=2.42; 95% CI, 2.12–2.76;
P
<0.0001). The higher risk of MI was not seen in the subgroup of EES patients who underwent complete revascularization (HR=1.37; 95% CI, 0.76–2.47;
P
=0.30).

Conclusions—

In patients with diabetes mellitus and multivessel disease, EES was associated with lower upfront risk of death and stroke when compared with coronary artery bypass graft surgery. However, at long-term, EES was associated with similar risk of death, a higher risk of MI (in those with incomplete revascularization), and repeat revascularization but a lower risk of stroke.
Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II–Induced Hypertension
Authors: Xiao Liang , Kirabo Annet , Wu Jing , Saleh Mohamed A. , Zhu Linjue , Wang Feng , Takahashi Takamune , Loperena Roxana , Foss Jason D. , Mernaugh Raymond L. , Chen Wei , Roberts Jackson , Osborn John W. , Itani Hana A. , Harrison David G.
Published: July 2015

Rationale:

Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues.

Objective:

To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension.

Methods and Results:

Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II–induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4
+
and CD8
+
T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1β, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II–treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation.

Conclusions:

Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.
Learnable vs. Unlearnable Harmony Patterns
Authors: Lai Regine
Published: July 2015

The present study provides empirical evidence for Heinz’s (2010) Subregular Hypothesis, which predicts that some gaps found in the typology of phonotactic patterns are due to learnability—more specifically, that only phonotactic patterns with specific computational properties are humanly learnable. The study compares the learnability of two long-distance harmony patterns that differ typologically (attested vs. unattested) and computationally (Strictly Piecewise vs. Locally Testable) using the artificial-language-learning paradigm. The results reveal a general bias toward learning the attested, Strictly Piecewise pattern, exactly as the Subregular Hypothesis predicts.
A Minimalist Condition on Semantic Reconstruction
Authors: Ruys E. G.
Published: July 2015

This article explains three known constraints on scope reconstruction—reconstruction is blocked into wh-islands, after remnant movement, and after countercyclic merger—by postulating an underlying condition on semantic reconstruction, which follows naturally from Minimalist assumptions on chain interpretation in combination with the principle of compositionality. The result is a unifying alternative analysis of the data discussed in Cresti 1995 , Fox 1999 , and Sauerland and Elbourne 2002 , among others.