bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous Spleen Rupture in a Teenager: An Uncommon Cause of Acute Abdomen
Authors: Maria Verroiotou , Saad Al Mogrampi , Fardellas Ioannis
Published: April 2013

Spontaneous spleen rupture is a rare complication of infectious diseases and it can become a potentially life-threatening condition if not diagnosed in time. A 17-year-old Greek female presented to the ER due to acute abdominal pain, mainly of the left upper quadrant. She had no recent report of trauma. The patient was pale, her blood pressure was 90/70 mmHg, and her pulse was 120 b/min. Clinical examination of the abdomen revealed muscle contraction and resistance. The patient was submitted to an ultrasound of the upper abdomen and to a CT scanning of the abdomen that revealed an extended intraperitoneal hemorrhage due to spleen rupture. Due to the patient’s hemodynamic instability, she was taken to the operation room and splenectomy was performed. Following a series of laboratory examinations, the patient was diagnosed to be positive for current cytomegalovirus infection. The postoperative course was uneventful, and in a two year follow-up the patient is symptom-free. Spontaneous spleen rupture due to Cytomegalovirus infection is a rare clinical entity, described in few case reports in the world literature and should always be taken into consideration in differential diagnosis of acute abdomen, especially in adolescents with no recent report of trauma.
Synthesis of Hydroxyapatite Nanoparticles in Presence of a Linear Polysaccharide
Authors: Monreal Romero Humberto A. , Mora Ruacho José , Martínez Pérez Carlos A. , García Casillas Perla E.
Published: April 2013

Hydroxyapatite nanoparticles compounds were synthesized. Natural hydroxyapatite and a linear polysaccharide (1–3 linked   β-D galactopyranose and 1,4 linked 3,6 anhydro-α-L-galactopyranose) were used as a precursor in its formation. Our purpose was to produce nanoparticles in the presence of a linear polysaccharide with the use of a gelification method. The powder sample was evaluated by scanning tunneling microscope (STM), Brunauer-Emmett-Teller (BET) analysis, X-ray diffraction pattern (XRD), differential thermal analysis (DTA), infrared (IR) analysis, and thermal gravimetric analysis (TGA). According to the results, it was found that these nanoparticles can successfully be synthesized using a polysaccharide in a solution. On the other hand, the XRD peak intensity corresponds to hydroxyapatite structure in the range of temperature of 810°C. The influence of the polysaccharide on the evolution of the nanoparticles has been demonstrated. This observation opens up new routes for the fabrication of nanoparticles using polysaccharides network. The synthesized nanoparticles have diameters ranging from 10 nm to 11 nm approximately. The elaboration conditions such as pH and concentration were optimized in this solution.
Declassifying Myrmecophily in the Coleoptera to Promote the Study of Ant-Beetle Symbioses
Authors: Mynhardt Glené
Published: April 2013

The symbiotic associations between beetles and ants have been observed in at least 35 beetle families. Among myrmecophiles, beetles exhibit the most diverse behavioral and morphological adaptations to a life with ants. These various associations have historically been grouped into discrete but overlapping behavioral categories, many of which are still used in the modern literature. While these behavioral classifications provide a rich foundation for the study of ant-beetle symbioses, the application of these systems in future studies may be less than effective. Since morphological characteristics often provide the only information of myrmecophilous beetles, they should be studied in a species-by-species fashion, as behavioral data are often limited or unavailable. Similarly, behavioral studies should focus on the target species at hand, avoiding discrete classification schemes. I formally propose the rejection of any classification scheme, in order to promote future studies of myrmecophily in both taxonomic and evolutionary studies.
Traveling Wavefronts of Competing Pioneer and Climax Model with Nonlocal Diffusion
Authors: Yu Xiaojing , Weng Peixuan , Huang Yehui
Published: April 2013

We study a competing pioneer-climax species model with nonlocal diffusion. By constructing a pair of upper-lower solutions and using the iterative technique, we establish the existence of traveling wavefronts connecting the pioneer-existence equilibrium and the coexistence equilibrium. We also discuss the asymptotic behavior of the wave tail for the traveling wavefronts ass=x+ct→−∞.
On Uncertainty Principle for Quaternionic Linear Canonical Transform
Authors: Kou Kit Ian , Ou Jian-Yu , Morais Joao
Published: April 2013

We generalize the linear canonical transform (LCT) to quaternion-valued signals, known as the quaternionic linear canonical transform (QLCT). Using the properties of the LCT we establish an uncertainty principle for the QLCT. This uncertainty principle prescribes a lower bound on the product of the effective widths of quaternion-valued signals in the spatial and frequency domains. It is shown that only a 2D Gaussian signal minimizes the uncertainty.
Risk Prison and Hepatitis B Virus Infection among Inmates with History of Drug Injection in Isfahan, Iran
Authors: Dana Daneshmand , Zary Nokhodian , Peyman Adibi , Behrooz Ataei
Published: April 2013

Objectives. Hepatitis B virus (HBV) is a health problem among injection drug users (IDUs) in prison. The aim of this study is to evaluate the association of factors of incarceration with HBV infection in prisoners with history of drug injection in Isfahan, Iran. Methods. In a cross‐sectional study, all IDUs inmates were enrolled. Sociodemographic characteristics and associated risk factors were obtained. Blood samples were collected and serological markers for HBV were analyzed. For data analysis, odds ratio and logistic regression were used. Results. Of the IDUs inmates, 970 subjects participated in the study. History of imprisonment (OR: 1.82, 95% CI: 1.28–2.57), multiple incarceration (OR: 1.43, 95% CI: 1.01–2.02), and total duration of imprisonment (OR: 2.70, 95% CI: 1.94–3.74) were significantly associated with prevalence of HBV among IDUs inmates. Multivariate analysis of associated factors showed that only total duration of incarceration is significantly associated with HBV infection. Conclusion. In conclusion, according to our results, multiple and duration of incarcerations will be considered as important risk factors of HBV infection in IDUs inmates. This fact makes it important to set some screening and prevention programs in prisons to decrease the risk of being infected and prevent the transmission of these diseases.
Trait Hostility, Perceived Stress, and Sleep Quality in a Sample of Normal Sleepers
Authors: Taylor Nicholas D. , Fireman Gary D. , Levin Ross
Published: April 2013

Objective. To date, no studies have directly examined the effects of cognitive trait hostility on prospectively assessed sleep quality. This is important as individuals with heightened trait hostility demonstrate similar patterns of reactivity to perceived stressors as is often reported by poor sleepers. The present study hypothesized that increased trait hostility is associated with poorer subjective sleep quality and that perceived stress mediates this relationship.Methods. A sample of 66 normal sleepers completed daily sleep and stress logs for two weeks. Trait hostility was measured retrospectively.Results. The cognitive dimension of trait hostility was significantly correlated with subjectively rated sleep quality indicators, and these relationships were significantly mediated by perceived daily stress. Individuals with higher levels of trait cognitive hostility reported increased levels of perceived stress which accounted for their poorer sleep ratings as measured by both retrospective and prospective measures.Conclusions. Overall, the findings indicate that high levels of cognitive hostility are a significant risk factor for disturbed sleep and suggest that this might be a fruitful target for clinical intervention.
Complete Convergence of the Maximum Partial Sums for Arrays of Rowwise of AANA Random Variables
Authors: Shen Aiting , Wu Ranchao , Chen Yan , Zhou Yu
Published: April 2013

The limiting behavior of the maximum partial sums(1/an)max1≤j≤n|∑i=1j‍Xni|is investigated, and some new results are obtained, where{Xni,i≥1,n≥1}is an array of rowwise AANA random variables and{an,n≥1}is a sequence of positive real numbers. As an application, the Chung-type strong law of large numbers for arrays of rowwise AANA random variables is obtained. The results extend and improve the corresponding ones of Hu and Taylor (1997) for arrays of rowwise independent random variables.
Optimizing TCP Performance in Multi-AP Residential Broadband Connections via Minislot Access
Authors: Giustiniano Domenico , Goma Eduard , Lopez Toledo Alberto , Athanasiou George
Published: April 2013

The high bandwidth demand of Internet applications has recently driven the need of increasing the residential download speed. A practical solution to the problem is to aggregate the bandwidth of 802.11 access points (APs) backhauls in range. Since 802.11 devices are usually single radio, the communication to APs on different radio channels requires a time-division multiple access (TDMA) policy at the client station. With an in-depth experimental analysis and a customized 802.11 driver, in this paper, we show that the usage of multi-AP TDMA policy may cause degradation of the TCP throughput and an underutilization of the AP backhauls. We then introduce a simple analytical model that accurately predicts the TCP round-trip time (RTT) with a multi-AP TDMA policy and propose a resource allocation algorithm to reduce the observed TCP RTT with a very low computational cost. Our proposed scheme runs locally at the client station and improves the aggregate throughput up to 1.5 times compared to state-of-the-art allocations. We finally show that the throughput achieved by our algorithm is very close to the theoretical upper bound in key simulation scenarios.
On the Security of a Certificateless Proxy Signature Scheme with Message Recovery
Authors: Shi Wenbo , He Debiao , Gong Peng
Published: April 2013

A proxy signature scheme allows a proxy signer to sign messages on behalf of an original signer within a given context. It has lots of practical applications in distributed systems, grid computing, mobile agent applications, distributed shared object systems, global distribution networks, and mobile communications. Recently, Padhye et al. proposed a certificateless proxy signature scheme with message recovery and claimed the scheme is secure against both of the two types of adversaries. However, in this paper, we will show that Padhye et al.’s scheme is not secure against the Type I adversary. The analysis shows their scheme is not secure for practical applications.
Management of a Severely Submerged Primary Molar: A Case Report
Authors: Parisay Iman , Kebriaei Fatemeh , Varkesh Bentolhoda , Soruri Milad , Ghafourifard Roya
Published: April 2013

Ankylosis is a condition frequently associated with primary molars, wherein the ankylosed primary teeth remain in a fixed position, while the adjacent teeth continue to erupt, moving occlusally. In this case report, a five-year-old boy, who had a retained and submerged left lower second primary molar, was presented. Luxation of ankylosed primary molar was considered as a treatment approach. After four months, the tooth erupted to the occlusal level, and there was evidence of further development of a permanent successor in radiographic evaluation. After one year, tooth mobility, bone formation, and development of a permanent successor were in good condition.
A 75-Year-Old Female with Hemoptysis and Recurrent Respiratory Infections
Authors: Baker Mary S. , Diab Khalil
Published: April 2013

This paper describes the case of a 75-year-old female who presented with significant hemoptysis over a 7–10 day period. She had a history of a left lower lobectomy 10 years prior for a “lung abscess.” She subsequently had multiple episodes of cough, fevers, and possible pneumonia treated with multiple courses of Amoxicillin and Amoxicillin/Clavulanate. Review of her chest CT upon presentation to the hospital showed a large necrotic lingular infiltrate, which had been progressively increasing in size over at least one year. Bronchoscopy showed a yellowish, soft round body in the superior lingular subsegment. Endobronchial and transbronchial biopsies showedactinomycesspecies. This is a very interesting case of indolent actinomycosis which we suspect had a very slow progressive course secondary to the multiple courses of antibiotics that the patient was treated with.
New Insights in Recurrent HCV Infection after Liver Transplantation
Authors: Hsu Shih-Hsien , Yeh Ming-Lun , Wang Shen-Nien
Published: April 2013

Hepatitis C virus (HCV) is a small-enveloped RNA virus belonging to the Flaviviridae family. Since first identified in 1989, HCV has been estimated to infect 170 million people worldwide. Mostly chronic hepatitis C virus has a uniform natural history, from liver cirrhosis to the development of hepatocellular carcinoma. The current therapy for HCV infection consists of a combination of Pegylated interferon and ribavirin. On the other hand, HCV-related liver disease is also the leading indication for liver transplantation. However, posttransplant HCV re-infection of the graft has been reported to be universal. Furthermore, the graft after HCV re-infection often results in accelerated progression to liver failure. In addition, treatment of recurrent HCV infection after liver transplantation is often compromised by enhanced adverse effects and limited efficacy of interferon-based therapies. Taken together, poor outcome after HCV re-infection, regardless of grafts or recipients, poses a major issue for the hepatologists and transplant surgeons. The aim of this paper is to review several specific aspects regarding HCV re-infection after transplant: risk factors, current therapeutics for HCV in different stages of liver transplantation, cellular function of HCV proteins, and molecular mechanisms of HCV entry. Hopefully, this paper will inspire new strategies and novel inhibitors against recurrent HCV infection after liver transplantation and greatly improve its overall outcome.
Evaluations of the Antimicrobial Activities and Chemical Compositions of Body Fat from the AmphibiansLeptodactylus macrosternumMiranda-Ribeiro (1926) andLeptodactylus vastusAdolf Lutz (1930) in Northeastern Brazil
Authors: Cabral Mario Eduardo Santos , Dias Diógenes de Queiroz , Sales Débora Lima , Oliveira Olga Paiva , Teles Diego Alves , Filho João Antonio de Araujo , Sousa José Guilherme Gonçalves de , Coutinho Henrique Douglas Melo , Costa José Galberto Martins da , Kerntopf Marta Regina , Alves Rômulo Romeu da Nóbrega , Almeida Waltécio de Oliveira
Published: April 2013

Leptodactylus macrosternumandL. vastus(family: Leptodactylidae) are commonly encountered in the “Caatinga” biome in northern Brazil. The body fat ofL. vastusis used as a zootherapeutic for treating a number of human maladies. The aim of this work was to determine the chemical composition of the body fats ofL. macrosternumandL. vastusand to evaluate their antimicrobial activities as well as the ecological implications of their use in traditional folk medicine. Oils were extracted from body fat located in the ventral region ofL. macrosternum(OLM) andL. vastus(OLV) using hexane as a solvent. The fatty acids were identified by GC-MS. The antimicrobial activities of the oils, either alone or in combination with antibiotics and antifungal drugs, were tested on standard strains of microorganisms as well as on multiresistant strains ofEscherichia coliandStaphylococcus. OLM contained 40% saturated and 60% unsaturated fatty acids, while OLV contained 58.33% saturated and 41.67% unsaturated fatty acids. Our results indicated that both OLM and OLV demonstrated relevant antimicrobial activities (with MIC 256 μg/mL for both) againstPseudomonas aeruginosaandCandida krusei. However, no antimicrobial effects were observed when these oils were combined with antibiotics or antifungal drugs.
Evaluating Green Performance of Suppliers via Analytic Network Process and TOPSIS
Authors: Akman Gülşen , Pışkın Hamit
Published: April 2013

Developments in environmental issues in the last few years have been forcing manufacturing companies to improve their environmental performances. Many firms developed integrated relationships with their suppliers to increase their environmental performance and to decrease their hazardous effects on the environment. Then, selecting suitable and green suppliers in the supply chain has become a key strategic consideration. A performance evaluation system for green suppliers is necessary to determine the suitability of suppliers to cooperate with the firm. Therefore, in this study, a model for evaluating green performance of suppliers is proposed, and a hybrid multicriteria decision making model is developed in order to evaluate green performance of the suppliers. The analytical network process technique is applied to handle the relationships and dependence of selection criteria and subcriteria and determine weights of the criteria. The technique for order preference by similarity to ideal solution is used to sequence the suppliers for ideal solution of the suppliers’ green performance evaluation problem. After a comprehensive literature survey, evaluation criteria of green performance for suppliers are determined. Finally, green performance of 18 suppliers of an automobile company was evaluated by this model. These 18 suppliers manufacture chassis and its components.
A Novel Method for the Accurate Evaluation of Poisson’s Ratio of Soft Polymer Materials
Authors: Lee Jae-Hoon , Lee Sang-Soo , Chang Jun-Dong , Thompson Mark S. , Kang Dong-Joong , Park Sungchan , Park Seonghun
Published: April 2013

A new method with a simple algorithm was developed to accurately measure Poisson’s ratio of soft materials such as polyvinyl alcohol hydrogel (PVA‐H) with a custom experimental apparatus consisting of a tension device, a micro X‐Y stage, an optical microscope, and a charge‐coupled device camera. In the proposed method, the initial positions of the four vertices of an arbitrarily selected quadrilateral from the sample surface were first measured to generate a 2D 1st‐order 4‐node quadrilateral element for finite element numerical analysis. Next, minimum and maximum principal strains were calculated from differences between the initial and deformed shapes of the quadrilateral under tension. Finally, Poisson’s ratio of PVA‐H was determined by the ratio of minimum principal strain to maximum principal strain. This novel method has an advantage in the accurate evaluation of Poisson’s ratio despite misalignment between specimens and experimental devices. In this study, Poisson’s ratio of PVA‐H was 0.44 ± 0.025 (n = 6) for 2.6–47.0% elongations with a tendency to decrease with increasing elongation. The current evaluation method of Poisson’s ratio with a simple measurement system can be employed to a real‐time automated vision‐tracking system which is used to accurately evaluate the material properties of various soft materials.
Celecoxib Improves Host Defense through Prostaglandin Inhibition duringHistoplasma capsulatumInfection
Authors: Pereira Priscilla Aparecida Tartari , Trindade Bruno Caetano , Secatto Adriana , Nicolete Roberto , Peres-Buzalaf Camila , Ramos Simone Gusmão , Sadikot Ruxana , Bitencourt Claudia da Silva , Faccioli Lúcia Helena
Published: April 2013

Prostaglandins act as mediators of inflammation and, similar to cytokines, function as immune modulators during innate and adaptive immune responses. Therefore, using a pharmacological inhibitor, celecoxib, we investigated the role of prostaglandins in host defense againstHistoplasma capsulatuminfection in C57BL/6 mice. Our results showed that treatment with celecoxib inhibited cyclooxygenase 2, reduced the total fungal burden, and reduced the concentration of PGE2, cytokines, lymphocytes, neutrophils, and mononuclear cells in the bronchoalveolar space and lung parenchyma. In addition, celecoxib treatment increased the synthesis of nitric oxide, IFN-γ, LTB4, and the phagocytic capacity of alveolar macrophages. Moreover, celecoxib treatment increased the survival of mice after infection with a lethal inoculum ofH. capsulatum. These results suggest that prostaglandins alter the host immune response and play an important role in the pathogenesis of histoplasmosis. Thus, the inhibition of prostaglandins could be a valuable immunomodulatory strategy and antifungal therapy for histoplasmosis treatment.
Information Leakage of VGF2 Structure
Authors: Cui Ting , Jin Chen-hui , Huang Ke-feng
Published: April 2013

The block cipher VGF2 was designed at Inscrypt 2009. It was based on a new variant of generalized Feistel structure. By checking the property of the linear permutation, we find a full round differential in VGF2 with probability 1. Since this differential cannot distinguish the correct unknown key from the wrong keys, we fail in launching a key-recovery attack on this structure. However, we may guess half part of the plaintext without calculating the key. And we notice that this weakness may cause insecurity in some special environments.
CUZD1 and Anti-CUZD1 Antibodies as Markers of Cancer and Inflammatory Bowel Diseases
Authors: Liaskos Christos , Rigopoulou Eirini I. , Orfanidou Timoklia , Bogdanos Dimitrios P. , Papandreou Christos N.
Published: April 2013

CUZD1, the CUB, and zona pellucida-like domains-containing protein 1, is a newly identified antigen of pancreatic autoantibodies (PAB) giving a reticulogranular pattern in patients with inflammatory bowel diseases, and in particular Crohn’s disease. The exact mechanisms by which this pancreatic antigen becomes the target of IBD-specific pancreatic autoantibodies are unclear. At the same time, evolving data strongly support a role for CUZD1 in carcinogenesis. HumanCUZD1is mapped at chromosome 10q26.13 and the loss of this region is a frequent event in various malignant tumours. mRNA overexpression of CUZD1 has been noted in ovarian cancer and serum levels of CUZD1 are elevated in women with ovarian cancer and patients suffering from pancreatic cancer. CUZD1 appears to be one of the relatively few biomarkers that serve as both cancer biomarker and autoantigen of autoantibodies in an autoimmune disease unrelated to cancerous organs. This review discusses the role of CUZD1 in cancer and autoimmunity. We anticipate that a better understanding of the function of CUZD1 will help us to understand how it becomes the focus of an autoimmune attack specifically targeting the intestine and its enigmatic role in carcinogenesis.
Wireless Virtual Multiple Antenna Networks for Critical Process Control: Protocol Design and Experiments
Authors: Savazzi Stefano
Published: April 2013

Wireless telemetry systems for remote monitoring and control of industrial processes are now becoming a relevant topic in the field of networked control. Wireless closed-loop control systems have stricter delay and link reliability requirements compared to conventional sensor networks for open-loop monitoring and call for the development of advanced network architectures. By following the guidelines introduced by recent standardization, this paper focuses on the most recent technological advances to enable wireless networked control for tight closed-loop applications with cycle times below 100 ms. The cooperative network paradigm is indicated as the key technology to enable cable replacing even in critical control applications. A cooperative communication system enables wireless devices placed at geographically separated locations to act as a virtual ensemble of antennas that creates a virtual multiple-antenna-distributed system. A proprietary link-layer protocol/based on the IEEE 802.15.4 physical layer has been developed and tested in an indoor environment characterized by non-line-of-sight (NLOS) propagation and dense obstacles. The measurements obtained from the testbed evaluate experimentally the benefits (and the limitations) of cable replacing in critical process control.
Particle Swarm Optimization for Multiband Metamaterial Fractal Antenna
Authors: Choudhury Balamati , Manickam Sangeetha , Jha R. M.
Published: April 2013

The property of self-similarity, recursive irregularity, and space filling capability of fractal antennas makes it useful for various applications in wireless communication, including multiband miniaturized antenna designs. In this paper, an effort has been made to use the metamaterial structures in conjunction with the fractal patch antenna, which resonates at six different frequencies covering both C and X band. Two different types of square SRR are loaded on the fractal antenna for this purpose. Particle swarm optimization (PSO) is used for optimization of these metamaterial structures. The optimized metamaterial structures, after loading upon, show significant increase in performance parameters such as bandwidth, gain, and directivity.
Stalling the Engine of Resistance: Targeting Cancer Metabolism to Overcome Therapeutic Resistance
Authors: Butler Ethan B. , Zhao Yuhua , Muñoz-Pinedo Cristina , Lu Jianrong , Tan Ming
Published: April 2013

Cancer cells are markedly different from normal cells with regards to how their metabolic pathways are used to fuel cellular growth and survival. Two basic metabolites that exemplify these differences through increased uptake and altered metabolic usage are glucose and glutamine. These molecules can be catabolized to manufacture many of the building blocks required for active cell growth and proliferation. The alterations in the metabolic pathways necessary to sustain this growth have been linked to therapeutic resistance, a trait that is correlated with poor patient outcomes. By targeting the metabolic pathways that import, catabolize, and synthesize essential cellular components, drug-resistant cancer cells can often be resensitized to anticancer treatments. The specificity and efficacy of agents directed at the unique aspects of cancer metabolism are expected to be high; and may, when in used in combination with more traditional therapeutics, present a pathway to surmount resistance within tumors that no longer respond to current forms of treatment. Cancer Res; 73(9); 2709–17. ©2013 AACR.
DDB2 Suppresses Epithelial-to-Mesenchymal Transition in Colon Cancer
Authors: Roy Nilotpal , Bommi Prashant V. , Bhat Uppoor G. , Bhattacharjee Shaumick , Elangovan Indira , Li Jing , Patra Krushna C. , Kopanja Dragana , Blunier Adam , Benya Richard , Bagchi Srilata , Raychaudhuri Pradip
Published: April 2013

Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial-to-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here, we show that the xeroderma pigmentosum group E (XPE) gene product, damaged DNA-binding protein (DDB)-2, is downregulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer. Cancer Res; 73(12); 3771–82. ©2013 AACR.
A Model of Postsurgical Advanced Metastatic Breast Cancer More Accurately Replicates the Clinical Efficacy of Antiangiogenic Drugs
Authors: Guerin Eric , Man Shan , Xu Ping , Kerbel Robert S.
Published: April 2013

The failure rate of randomized phase III oncology clinical trials is extremely high, even when preceded by encouraging preclinical studies and phase II trial results of the same therapy. Thus, there is considerable effort being made to improve the predictive clinical potential of preclinical models, in addition to improving phase II trial design. With respect to the former, preclinical models have historically relied heavily on treatment of primary spontaneous or transplanted tumors rather than the more common and therapeutically challenging clinical trial circumstance of advanced metastatic disease. Here, we show that the oral antiangiogenic tyrosine kinase inhibitor (TKI), sunitinib, which failed to meet primary or secondary survival endpoints in 4 separate phase III metastatic breast cancer (MBC) trials, either alone or with chemotherapy, similarly failed to show monotherapy or combination chemotherapy efficacy in a model of postsurgical advanced MBC using a metastatic variant of the MDA-MB-231 triple-negative human breast cancer. In contrast, the drug was effective when used to treat established orthotopic primary tumors. Similar results were obtained with pazopanib monotherapy, another antiangiogenic oral TKI. However, when an antibody targeting the VEGF pathway (DC101) was tested, it showed a trend in modestly improving the efficacy of paclitaxel therapy, thus resembling to a degree prior phase III clinical results of bevacizumab plus paclitaxel in MBC. Our results suggest the potential value of treating postsurgical advanced metastatic disease as a possible strategy to improve preclinical models for predicting outcomes in patients with metastatic disease. Cancer Res; 73(9); 2743–8. ©2013 AACR.
Animal Models of Human Prostate Cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee
Authors: Ittmann Michael , Huang Jiaoti , Radaelli Enrico , Martin Philip , Signoretti Sabina , Sullivan Ruth , Simons Brian W. , Ward Jerrold M. , Robinson Brian D. , Chu Gerald C. , Loda Massimo , Thomas George , Borowsky Alexander , Cardiff Robert D.
Published: April 2013

Animal models, particularly mouse models, play a central role in the study of the etiology, prevention, and treatment of human prostate cancer. While tissue culture models are extremely useful in understanding the biology of prostate cancer, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The National Cancer Institute (NCI) Mouse Models of Human Cancers Consortium convened a group of human and veterinary pathologists to review the current animal models of prostate cancer and make recommendations about the pathologic analysis of these models. More than 40 different models with 439 samples were reviewed, including genetically engineered mouse models, xenograft, rat, and canine models. Numerous relevant models have been developed over the past 15 years, and each approach has strengths and weaknesses. Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas. In addition, numerous models with multiple genetic alterations display aggressive phenotypes characterized by sarcomatoid carcinomas and metastases, which is presumably a histologic manifestation of epithelial–mesenchymal transition. The significant progress in development of improved models of prostate cancer has already accelerated our understanding of the complex biology of prostate cancer and promises to enhance development of new approaches to prevention, detection, and treatment of this common malignancy. Cancer Res; 73(9); 2718–36. ©2013 AACR.
White Coat Hypertension Is More Risky Than Prehypertension
Authors: Sung Shih-Hsien , Cheng Hao-Min , Wang Kang-Ling , Yu Wen-Chung , Chuang Shao-Yuan , Ting Chih-Tai , Lakatta Edward G. , Yin Frank C.P. , Chou Pesus , Chen Chen-Huan
Published: April 2013

Arterial aging may link cardiovascular risk to white coat hypertension (WCH). The aims of the present study were to investigate the role of arterial aging in the white coat effect, defined as the difference between office and 24-hour ambulatory systolic blood pressures, and to compare WCH with prehypertension (PH) with respect to target organ damage and long-term cardiovascular mortality. A total of 1257 never-been-treated volunteer subjects from a community-based survey were studied. WCH and PH were defined by office and 24-hour ambulatory blood pressures. Left ventricular mass index, carotid intima-media thickness, estimated glomerular filtration rate, carotid-femoral pulse wave velocity, carotid augmentation index, amplitude of the reflection pressure wave, and 15-year cardiovascular mortality were determined. Subjects with WCH were significantly older and had greater body mass index, blood pressure values, intima-media thickness, carotid-femoral pulse wave velocity, augmentation index, amplitude of the backward pressure wave, and a lower estimated glomerular filtration rate than PH. Amplitude of the backward pressure wave was the most important independent correlate of the white coat effect in multivariate analysis (model
r
2
=0.451; partial
r
2
/model
r
2
=90.5%). WCH had significantly greater cardiovascular mortality than PH (hazard ratio, 2.94; 95% confidence interval, 1.09–7.91), after accounting for age, sex, body mass index, smoking, fasting plasma glucose, and total cholesterol/high-density lipoprotein-cholesterol ratio. Further adjustment of the model for amplitude of the backward pressure wave eliminated the statistical significance of the WCH effect. In conclusion, the white coat effect is mainly caused by arterial aging. WCH carries higher risk for cardiovascular mortality than PH, probably via enhanced wave reflections that accompany arterial aging.
Association of Smoking With Phenotype at Diagnosis and Vascular Interventions in Patients With Renal Artery Fibromuscular Dysplasia
Authors: Savard Sébastien , Azarine Arshid , Jeunemaitre Xavier , Azizi Michel , Plouin Pierre-François , Steichen Olivier
Published: April 2013

The pathogenesis of fibromuscular dysplasia (FMD) remains unclear, but tobacco use is thought to be involved. This retrospective cross-sectional study aimed to evaluate smoking first as a risk factor for renal artery FMD diagnosis and second as a modifier of the clinical and radiological phenotype of this disease. We retrieved 337 adult patients diagnosed with FMD in a referral center for hypertension management, who were first individually matched to controls with essential hypertension for sex, age, systolic blood pressure, number of antihypertensive drugs, and year of visit. Smoking status and other relevant data were collected at first visit. The proportion of current smokers was higher for patients with FMD than for the controls (30% and 18%, respectively,
P
<0.001; odds ratio, 2.5 [95% confidence interval, 1.6–3.9]). Second, characteristics of FMD were compared between current smokers and other patients. Among patients with multifocal FMD, current smokers experienced an earlier diagnosis of hypertension (36 versus 42 years, respectively;
P
<0.001) and FMD (43 versus 51 years;
P
<0.001) than other patients, and a greater likelihood of renal artery interventions (57% versus 31%;
P
<0.001) and of kidney asymmetry (21% versus 4%;
P
=0.001). In conclusion, current smoking is associated with a higher likelihood of renal artery FMD diagnosis. Rather than a higher incidence of FMD, this may reflect a more aggressive course in smokers, who have earlier hypertension leading to increased and earlier recognition of the disease. Smoking cessation should be strongly encouraged in patients with FMD.
Blood Pressure in Treated Hypertensive Individuals With the
MTHFR
677TT Genotype Is Responsive to Intervention With Riboflavin
Authors: Wilson Carol P. , McNulty Helene , Ward Mary , Strain J.J. , Trouton Tom G. , Hoeft Birgit A. , Weber Peter , Roos Franz F. , Horigan Geraldine , McAnena Liadhan , Scott John M.
Published: April 2013

Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the
MTHFR
677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (≤140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (
P
<0.001). Correspondingly, an overall treatment effect of 5.6±2.6 mm Hg (
P
=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8±2.9 and 137.1±3.0 mm Hg (treatment group) and 143.5±3.0 and 144.3±3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (
P
=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the
MTHFR
677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: ISRCTN23620802.
Body Fat Is Associated With Reduced Aortic Stiffness Until Middle Age
Authors: Corden Ben , Keenan Niall G. , de Marvao Antonio S.M. , Dawes Timothy J.W. , DeCesare Alain , Diamond Tamara , Durighel Giuliana , Hughes Alun D. , Cook Stuart A. , O’Regan Declan P.
Published: April 2013

Obesity is a major risk factor for cardiometabolic disease, but the effect of body composition on vascular aging and arterial stiffness remains uncertain. We investigated relationships among body composition, blood pressure, age, and aortic pulse wave velocity in healthy individuals. Pulse wave velocity in the thoracic aorta, an indicator of central arterial stiffness, was measured in 221 volunteers (range, 18–72 years; mean, 40.3±13 years) who had no history of cardiovascular disease using cardiovascular MRI. In univariate analyses, age (
r
=0.78;
P
<0.001) and blood pressure (
r
=0.41;
P
<0.001) showed a strong positive association with pulse wave velocity. In multivariate analysis, after adjustment for age, sex, and mean arterial blood pressure, elevated body fat% was associated with reduced aortic stiffness until the age of 50 years, thereafter adiposity had an increasingly positive association with aortic stiffness (β=0.16;
P
<0.001). Body fat% was positively associated with cardiac output when age, sex, height, and absolute lean mass were adjusted for (β=0.23;
P
=0.002). These findings suggest that the cardiovascular system of young adults may be capable of adapting to the state of obesity and that an adverse association between body fat and aortic stiffness is only apparent in later life.
Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers
Authors: Azizi Michel , Blanchard Anne , Charbit Beny , Wuerzner Grégoire , Peyrard Séverine , Ezan Eric , Funck-Brentano Christian , Ménard Joël
Published: April 2013

Dietary sodium, the main determinant of the pharmacodynamic response to renin–angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin–angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC
0–∞
: 0.74; [90% CI, 0.66–0.82] and 0.69 [90% CI, 0.54–0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin–angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC
0–24
of plasma drug concentration explained <1% and 21% of the variance of the AUC
0–24
of delta plasma renin concentration for candesartan (
P
=0.8882/
P
=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.
Urinary Magnesium Excretion and Risk of Hypertension
Authors: Joosten Michel M. , Gansevoort Ron T. , Mukamal Kenneth J. , Kootstra-Ros Jenny E. , Feskens Edith J.M. , Geleijnse Johanna M. , Navis Gerjan , Bakker Stephan J.L. ,   the PREVEND Study Group
Published: April 2013

Observational studies on dietary or circulating magnesium and risk of hypertension have reported weak-to-modest inverse associations, but have lacked measures of actual dietary uptake. Urinary magnesium excretion, an indicator of intestinal magnesium absorption, may provide a better insight in this association. We examined 5511 participants aged 28 to 75 years free of hypertension in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective population–based cohort study. Circulating magnesium was measured in plasma and urinary magnesium in two 24-hour urine collections, both at baseline. Incident hypertension was defined as blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic, or initiation of antihypertensive medication. During a median follow-up of 7.6 years (interquartile range, 5.0–9.3 years), 1172 participants developed hypertension. The median urinary magnesium excretion was 3.8 mmol/24 hour (interquartile range, 2.9–4.8 mmol/24 hour). Urinary magnesium excretion was associated with risk of hypertension in an inverse log-linear fashion, and this association remained after adjustment for age, sex, body mass index, smoking status, alcohol intake, parental history of hypertension, and urinary excretion of sodium, potassium, and calcium. Each 1-unit increment in ln-transformed urinary magnesium excretion was associated with a 21% lower risk of hypertension after multivariable adjustment (adjusted hazard ratio, 0.79; 95% confidence interval, 0.71–0.88). No associations were observed between circulating magnesium and risk of hypertension. In conclusion, in this cohort of men and women, urinary magnesium excretion was inversely associated with risk of hypertension across the entire range of habitual dietary intake.
Neutral Stability, Rate Propagation, and Critical Branching in Feedforward Networks
Authors: Cayco-Gajic N. Alex , Shea-Brown Eric
Published: April 2013

Recent experimental and computational evidence suggests that several dynamical properties may characterize the operating point of functioning neural networks: critical branching, neutral stability, and production of a wide range of firing patterns. We seek the simplest setting in which these properties emerge, clarifying their origin and relationship in random, feedforward networks of McCullochs-Pitts neurons. Two key parameters are the thresholds at which neurons fire spikes and the overall level of feedforward connectivity. When neurons have low thresholds, we show that there is always a connectivity for which the properties in question all occur, that is, these networks preserve overall firing rates from layer to layer and produce broad distributions of activity in each layer. This fails to occur, however, when neurons have high thresholds. A key tool in explaining this difference is the eigenstructure of the resulting mean-field Markov chain, as this reveals which activity modes will be preserved from layer to layer. We extend our analysis from purely excitatory networks to more complex models that include inhibition and local noise, and find that both of these features extend the parameter ranges over which networks produce the properties of interest.
A Calcium-Based Simple Model of Multiple Spike Interactions in Spike-Timing-Dependent Plasticity
Authors: Uramoto Takumi , Torikai Hiroyuki
Published: April 2013

Spike-timing-dependent plasticity (STDP) is a form of synaptic modification that depends on the relative timings of presynaptic and postsynaptic spikes. In this letter, we proposed a calcium-based simple STDP model, described by an ordinary differential equation having only three state variables: one represents the density of intracellular calcium, one represents a fraction of open state NMDARs, and one represents the synaptic weight. We shown that in spite of its simplicity, the model can reproduce the properties of the plasticity that have been experimentally measured in various brain areas (e.g., layer 2/3 and 5 visual cortical slices, hippocampal cultures, and layer 2/3 somatosensory cortical slices) with respect to various patterns of presynaptic and postsynaptic spikes. In addition, comparisons with other STDP models are made, and the significance and advantages of the proposed model are discussed.
Identifying Functional Bases for Multidimensional Neural Computations
Authors: Kaardal Joel , Fitzgerald Jeffrey D. , Berry Michael J. , Sharpee Tatyana O.
Published: April 2013

Current dimensionality-reduction methods can identify relevant subspaces for neural computations but do not favor one basis over the other within the relevant subspace. Finding the appropriate basis can simplify the description of the nonlinear computation with respect to the relevant variables, making it easier to elucidate the underlying neural computation and make hypotheses about the neural circuitry, giving rise to the observed responses. Part of the problem is that although some of the dimensionality reduction methods can identify many of the relevant dimensions, it is usually difficult to map out or interpret the nonlinear transformation with respect to more than a few relevant dimensions simultaneously without some simplifying assumptions. While recent approaches make it possible to create predictive models based on many relevant dimensions simultaneously, there still remains the need to relate such predictive models to the mechanistic descriptions of the operation of underlying neural circuitry. Here we demonstrate that transforming to a basis within the relevant subspace where the neural computation is best described by a given nonlinear function often makes it easier to interpret the computation and describe it with a small number of parameters. We refer to the corresponding basis as the functional basis, and illustrate the utility of such transformation in the context of logical OR and logical AND functions. We show that although dimensionality-reduction methods such as spike-triggered covariance are able to find a relevant subspace, they often produce dimensions that are difficult to interpret and do not correspond to a functional basis. The functional features can be found using a maximum likelihood approach. The results are illustrated using simulated neurons and recordings from retinal ganglion cells. The resulting features are uniquely defined and nonorthogonal, and they make it easier to relate computational and mechanistic models to each other.