bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug efficacy in treating stable angina pectoris: a protocol for network meta-analysis of randomised controlled trials
Authors: Jia Yongliang , Leung Siu-wai
Published: June 2014

Introduction

There were 11 pairwise meta-analysis on the efficacy of β-blockers (including atenolol, propranolol, bisoprolol, metoprolol and nadolol), calcium channel blockers (including amlodipine, diltiazem, felodipine, nifedipine and verapamil), and nitrates (including isosorbide dinitrate, isosorbide mononitrate and nitroglycerin) in treating stable angina pectoris. No network meta-analytic study has been published to evaluate the efficacies of these antianginal drugs. Current clinical guidelines (eg, National Institute of Health and Care Excellence (NICE) clinical guideline 126) are only based on the findings of limited clinical trials and pairwise meta-analysis. This study aims to fill this gap of research by conducting a Bayesian network meta-analysis to compare all these antianginal drugs.

Methods and analyses

Randomised controlled trials (RCT) on the drug therapy of stable angina pectoris with multiple outcome measures, selected from symptomatic relief, ECG tests, exercise tests, heart rates and blood pressures, etc, will be included. Overall effect sizes will be represented as mean differences with 95% credible intervals (CrI) for continuous outcome data and as ORs with 95% CrI for dichotomous outcome data. Bayesian network meta-analysis by WinBUGS will be conducted to compare the efficacies of these drugs. Sensitivity analysis on the quality of RCTs and subgroup analysis on the category of included drugs will be performed.

Ethics and dissemination

Ethical approval is not required because this study includes no confidential personal data and interventions on the patients. Network meta-analysis is based on the RCT reports of eligible drugs in treating stable angina pectoris. The results of this study will be disseminated by an open access and peer-reviewed publication.

Trial registration number

PROSPERO CRD42014007113.
Developing Web Applications Based on Model Driven Architecture
Authors: Huang Yen-Chieh , Chu Chih-Ping
Published: June 2014

Model Driven Architecture (MDA) is a new software development framework. This paper presents a model-driven approach to the development of Web applications by combining Conallen's web applications design concept and Kleppe's MDA process. We use the UML extension mechanism, i.e. stereotypes, to define the various web elements, and use the Robustness diagram to represent MVC 2 structure for Web application. After required analysis, we start by using a use case diagram as CIM, and then transform CIM to PIM, and PIM to PSM. We propose mapping rules for model-to-model transformation. Finally, we develop a tool named WebPSM2Code, which can automatically transform PSM diagram to Web application code, such as Java, JSP, HTML, Servlet, Javascript, as well as deployment descriptor file. All the files can automatically address to the correct directory structure for JSP Web application, and the transformation rate is about 39% of the whole system. Using this methodology, systems can be analyzed, designed, and generated more easily and systematically. Thereby, the time that Web programmers spend on coding can be reduced.
Learning Bayesian Network Structure Using a MultiExpert Approach
Authors: Colace Francesco , De Santo Massimo , Greco Luca
Published: June 2014

The learning of a Bayesian network structure, especially in the case of wide domains, can be a complex, time-consuming and imprecise process. Therefore, the interest of the scientific community in learning Bayesian network structure from data is increasing: many techniques or disciplines such as data mining, text categorization, and ontology building, can take advantage from this process. In the literature, there are many structural learning algorithms but none of them provides good results for each dataset. This paper introduces a method for structural learning of Bayesian networks based on a MultiExpert approach. The proposed method combines five structural learning algorithms according to a majority vote combining rule for maximizing their effectiveness and, more generally, the results obtained by using of a single algorithm. This paper shows an experimental validation of the proposed algorithm on standard datasets.
Magnetized anisotropic dark energy cosmological models in scale covariant theory of gravitation
Authors: Katore S. D. , Sancheti M. M. , Hatkar S. P.
Published: June 2014

In the present paper, we have investigated Bianchi type II, VIII and IX spacetime in the presence of magnetized anisotropic dark energy in the Scale covariant theory of gravitation. Exact solution of the field equations are obtained by assuming the expansion anisotropy (the ratio of shear scalar to expansion scalar) to be a function of average scale factor. The isotropy of the fluid, space and expansion are examined.
A Perspective of Evolution After Five Years: A Large-Scale Study of Web Spam Evolution
Authors: Wang De , Irani Danesh , Pu Calton
Published: June 2014

Identifying and detecting web spam is an ongoing battle between spam-researchers and spammers which has been going on since search engines allowed searching of web pages to the modern sharing of web links via social networks. A common challenge faced by spam-researchers is the fact that new techniques depend on requiring a corpus of legitimate and spam web pages. Although large corpora of legitimate web pages are available to researchers, the same cannot be said about web spam or spam web pages. In this paper, we introduce the Webb Spam Corpus 2011 — a corpus of approximately 330,000 spam web pages — which we make available to researchers in the fight against spam. By having a standard corpus available, researchers can collaborate better on developing and reporting results of spam filtering techniques. The corpus contains web pages crawled from links found in over 6.3 million spam emails. We analyze multiple aspects of this corpus including redirection, HTTP headers, web page content, and classification evaluation. We also provide insights into changes in web spam since the last Webb Spam Corpus was released in 2006. These insights include: (1) spammers manipulate social media in spreading spam; (2) HTTP headers and content also change over time; (3) spammers have evolved and adopted new techniques to avoid the detection based on HTTP header information.
On the optimal wealth process in a log-normal market: Applications to risk management
Authors: Monin Phillip , Zariphopoulou Thaleia
Published: June 2014

Using a stochastic representation of the optimal wealth process in the classical Merton problem, we calculate its cumulative distribution and density functions and provide bounds and monotonicity results for these quantities under general risk preferences. We also show that the optimal wealth and portfolio processes for different utility functions are related through a deterministic transformation and appropriately modified initial conditions. We analyze the value at risk (VaR) and expected shortfall (ES) of the optimal wealth process and show how each can be used to infer a constant relative risk aversion (CRRA) investor's risk aversion coefficient. Drawing analogies to the option greeks, we study the sensitivities of the optimal wealth process with respect to the cumulative excess stock return, time, and market parameters. We conclude with a study of how sensitivities of the excess return on the optimal wealth process relate to the portfolio's beta.
Relationships between basin architecture, basin closure, and occurrence of sulphide-bearing schists: an example from Tampere Schist Belt, Finland
Authors: Kalliomäki H. , Torvela T. , Moreau J. , Kähkönen Y.
Published: June 2014

We present field observations from the Palaeoproterozoic volcano-sedimentary Tampere palaeobasin, where the primary structures have been exceptionally well preserved. We use the observations to construct a new tectonic model for the southeastern margin of the Tampere basin during its inversion and subsequent closure. The observed volcano-sedimentary and structural features suggest a change in the local structural style from thick-skinned inversion to thin-skinned thrusting, to accommodate the crustal shortening during basin closure. Furthermore, it is suggested that there is a genetic relationship between the interpreted palaeothrust and the sulphide-bearing schist horizons in the study area. On a more general note, the results imply that currently subvertical mineralized shear zones may have originally been gently dipping, further suggesting that the mineralized fluids may not necessarily have been sourced from great depths (i.e. from deep within the basement).
Gold-transporting hydrothermal fluids in the Earth's crust: an introduction
Authors: Garofalo Paolo S. , Ridley John R.
Published: June 2014

Hydrothermal ore deposits that are exploited for gold include both gold-only deposits, such as orogenic deposits, and gold-bearing examples of the common hydrothermal deposit types that are formed around upper-crustal magmatic centres, in particular porphyry and epithermal deposits. Fluid inclusion data have shown that ore fluids of gold-only deposits are compositionally distinct compared to fluids of other deposit types: Fluids of the latter deposit types are, in contrast, not distinctive, and recent research has been focussed on relating gold content to geochemical and petrological aspects of related magmatic systems and to fluid evolution on migration through the crust. This Special Publication includes an up-to-date summary of thermodynamic parameters of aqueous Au species at high temperatures and pressures, a dataset of fluid inclusion properties and compositions from orogenic deposits of different parts of the world, several comprehensive case studies of different types of gold deposits and their fluids from the USA, Brazil, Egypt, Slovakia and Bulgaria and numerical modelling aimed to define key parameters that affect fluid flow and gold deposition at a range of scales.
It's deeper than rap, toward culturally responsive CS
Authors: Miller Omoju
Published: June 2014

Using hip-hop lyrics and artificial intelligence to engage more students in computer science based on their cultural background.
Making tech more inclusive
Authors: Carson Erin
Published: June 2014

Exposing the driving causes behind the lack of diversity in our communities, and how to use your privilege for good.
Interacting with the Andrea Palladio Works
Authors: Baldissini S. , Gaiani M.
Published: June 2014

This article describes the evolution of an information system (IS) of Centro Internazionale di Studi di Architettura Andrea Palladio di Vicenza and the related interfaces from the first standalone on a CD-ROM system to the current web-based and georeferenced solution. The goal of these ISs was manifold: the dissemination, study, and analysis of architectural history. The IS was designed for many types of users. Mainly, we present the interface and the interaction techniques that were conceived and developed for large audiences during expositions, in the museum, or at home. This article presents a special focus on communicative language changes and on the level of information provided, which are determined by the different interfaces adopted over time.
Capture, Modeling, and Recognition of Expert Technical Gestures in Wheel-Throwing Art of Pottery
Authors: Manitsaris S. , Glushkova A. , Bevilacqua F. , Moutarde F.
Published: June 2014

This research has been conducted in the context of the ArtiMuse project that aims at the modeling and renewal of rare gestural knowledge and skills involved in the traditional craftsmanship and more precisely in the art of wheel-throwing pottery. These knowledge and skills constitute intangible cultural heritage and refer to the fruit of diverse expertise founded and propagated over the centuries thanks to the ingeniousness of the gesture and the creativity of the human spirit. Nowadays, this expertise is very often threatened with disappearance because of the difficulty to resist globalization and the fact that most of those “expertise holders” are not easily accessible due to geographical or other constraints. In this article, a methodological framework for capturing and modeling gestural knowledge and skills in wheel-throwing pottery is proposed. It is based on capturing gestures using wireless inertial sensors and statistical modeling. In particular, we used a system that allows for online alignment of gestures using a modified Hidden Markov Model. This methodology is implemented into a human--computer interface, which permits both the modeling and recognition of expert technical gestures. This system could be used to assist in the learning of these gestures by giving continuous feedback in real time by measuring the difference between expert and learner gestures. The system has been tested and evaluated on different potters with rare expertise, which is strongly related to their local identity.
Effects of airway tree asymmetry on the emergence and spatial persistence of ventilation defects
Authors: Leary D. , Winkler T. , Braune A. , Maksym G. N.
Published: June 2014

Asymmetry and heterogeneity in the branching of the human bronchial tree are well documented, but their effects on bronchoconstriction and ventilation distribution in asthma are unclear. In a series of seminal studies, Venegas et al. have shown that bronchoconstriction may lead to self-organized patterns of patchy ventilation in a computational model that could explain areas of poor ventilation [ventilation defects (VDefs)] observed in positron emission tomography images during induced bronchoconstriction. To investigate effects of anatomic asymmetry on the emergence of VDefs we used the symmetric tree computational model that Venegas and Winkler developed using different trees, including an anatomic human airway tree provided by M. Tawhai (University of Auckland), a symmetric tree, and three trees with intermediate asymmetry (Venegas JG, Winkler T, Musch G, Vidal Melo MF, Layfield D, Tgavalekos N, Fischman AJ, Callahan RJ, Bellani G, Harris RS. Nature 434: 777–782, 2005 and Winkler T, Venegas JG. J Appl Physiol 103: 655–663, 2007). Ventilation patterns, lung resistance (RL), lung elastance (EL), and the entropy of the ventilation distribution were compared at different levels of airway smooth muscle activation. We found VDefs emerging in both symmetric and asymmetric trees, but VDef locations were largely persistent in asymmetric trees, and bronchoconstriction reached steady state sooner than in a symmetric tree. Interestingly, bronchoconstriction in the asymmetric tree resulted in lower RL (∼%50) and greater EL (∼%25). We found that VDefs were universally caused by airway instability, but asymmetry in airway branching led to local triggers for the self-organized patchiness in ventilation and resulted in persistent locations of VDefs. These findings help to explain the emergence and the persistence in location of VDefs found in imaging studies.
IL4 Receptor ILR4α Regulates Metastatic Colonization by Mammary Tumors through Multiple Signaling Pathways
Authors: Venmar Katherine T. , Carter Kathy J. , Hwang Daniel G. , Dozier E. Ashley , Fingleton Barbara
Published: June 2014

IL4, a cytokine produced mainly by immune cells, may promote the growth of epithelial tumors by mediating increased proliferation and survival. Here, we show that the type II IL4 receptor (IL4R) is expressed and activated in human breast cancer and mouse models of breast cancer. In metastatic mouse breast cancer cells, RNAi-mediated silencing of IL4Rα, a component of the IL4R, was sufficient to attenuate growth at metastatic sites. Similar results were obtained with control tumor cells in IL4-deficient mice. Decreased metastatic capacity of IL4Rα “knockdown” cells was attributed, in part, to reductions in proliferation and survival of breast cancer cells. In addition, we observed an overall increase in immune infiltrates within IL4Rα knockdown tumors, indicating that enhanced clearance of knockdown tumor cells could also contribute to the reduction in knockdown tumor size. Pharmacologic investigations suggested that IL4-induced cancer cell colonization was mediated, in part, by activation of Erk1/2, Akt, and mTOR. Reduced levels of pAkt and pErk1/2 in IL4Rα knockdown tumor metastases were associated with limited outgrowth, supporting roles for Akt and Erk activation in mediating the tumor-promoting effects of IL4Rα. Collectively, our results offer a preclinical proof-of-concept for targeting IL4/IL4Rα signaling as a therapeutic strategy to limit breast cancer metastasis. Cancer Res; 74(16); 4329–40. ©2014 AACR.
Noninvasive Detection of Glutamate Predicts Survival in Pediatric Medulloblastoma
Authors: Wilson Martin , Gill Simrandip K. , MacPherson Lesley , English Martin , Arvanitis Theodoros N. , Peet Andrew C.
Published: June 2014

Purpose: Medulloblastoma is the most common malignant brain tumor occurring in childhood and is a significant cause of morbidity and mortality in pediatric oncology. More intense treatment strategies are recommended for patients displaying high-risk factors; however, considerable variation in outcome remains, indicating a need for improved predictive markers. In this study, 1H magnetic resonance spectroscopy (MRS) was used to investigate noninvasive molecular biomarkers of survival in medulloblastoma.

Experimental Design: MRS was performed on a series of 35 biopsy-confirmed medulloblastoma cases. One case was excluded because of poor quality MRS. The prognostic value of MRS detectable biomarkers was investigated using Cox regression, retrospectively (N = 15). A subsequent validation analysis (N = 19) was also performed to reduce the chance of type I errors. Where available, high-resolution ex vivo MRS of biopsy tissue was used to confirm biomarker assignments.

Results: The retrospective analysis revealed that creatine, glutamate, and glycine were markers of survival (P < 0.01). The validation analysis showed that glutamate was a robust marker, with a hazard ration (HR) of 8.0 for the full dataset (P = 0.0003, N = 34). A good correlation between in vivo and ex vivo MRS glutamate/total-choline was found (P = 0.001), validating the in vivo assignment. Ex vivo glutamate/total-choline was also associated with survival (P < 0.01).

Conclusion: The identification of glutamate as a predictive biomarker of survival in pediatric medulloblastoma provides a clinically viable risk factor and highlights the importance of more detailed studies into the metabolism of this disease. Noninvasive biomarker detection using MRS may offer improved disease monitoring and potential for widespread use following multicenter validation. Clin Cancer Res; 20(17); 4532–9. ©2014 AACR.
The Combination of Circulating Ang1 and Tie2 Levels Predicts Progression-Free Survival Advantage in Bevacizumab-Treated Patients with Ovarian Cancer
Authors: Backen Alison , Renehan Andrew G. , Clamp Andrew R. , Berzuini Carlo , Zhou Cong , Oza Amit , Bannoo Selina , Scherer Stefan J. , Banks Rosamonde E. , Dive Caroline , Jayson Gordon C.
Published: June 2014

Purpose: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab.

Experimental Design: Pretreatment training (n = 91) and validation (n = 114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset.

Results: The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica internal endothelial cell kinase 2) concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cutoffs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients in both datasets (median, 23.0 months vs. 16.2; P = 0.003) for the interaction of Ang1–Tie2 treatment in Cox regression analysis. The prognostic indices derived from the training set also distinguished high and low probability for progression in the validation set (P = 0.008), generating similar values for HR (0.21 vs. 0.27) between treatment and control arms for patients with high Ang1 and low Tie2 values.

Conclusions: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer. These findings need to be validated in larger trials due to the limitation of sample size in this study. Clin Cancer Res; 20(17); 4549–58. ©2014 AACR.
Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations
Authors: Zimmer Lisa , Barlesi Fabrice , Martinez-Garcia Maria , Dieras Veronique , Schellens Jan H.M. , Spano Jean-Philippe , Middleton Mark R. , Calvo Emiliano , Paz-Ares Luiz , Larkin James , Pacey Simon , Venturi Miro , Kraeber-Bodéré Françoise , Tessier Jean J.L. , Eberhardt Wilfried Ernst Erich , Paques Michel , Guarin Ernesto , Meresse Valerie , Soria Jean-Charles
Published: June 2014

Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor.

Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non–small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added.

Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications.

Conclusions: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251–61. ©2014 AACR.
Human Pancreas Endocrine Cell Populations and Activating ABCC8 Mutations
Authors: Busiah Kanetee , Verkarre Virginie , Cavé Hélène , Scharfmann Raphael , Polak Michel
Published: June 2014

Background/Aims: Activating mutations in the ABCC8 gene encoding the KATP channel subunit SUR1 cause β-cell dysfunction with non-autoimmune diabetes mellitus in neonates or infants. We investigated whether activating ABCC8 mutations affect endocrine pancreas development. Methods: We studied a male infant with compound heterozygous ABCC8 mutations (p.Arg826Trp/p.Ile93Thr) causing neonatal diabetes mellitus. He died of ketoacidosis. Postmortem pancreas specimens were evaluated by fluorescent microscopy after immunostaining for insulin, glucagon, somatostatin, and PCNA, and Hoechst 33342 nuclear staining. We compared the findings to those in 5 age-matched controls. Results: The number of islets was decreased and the number of single or small clusters of insulin cells increased in the patient compared to the age-matched controls. The islets in the patient had an insulin-cell core surrounded by intermingled glucagon and somatostatin cells. The insulin/Hoechst surface ratio was decreased and the glucagon/Hoechst surface ratio increased in the patient (4.3 and 8.8%, respectively) versus the controls (8.2 and 3.1%, respectively). Somatostatin surface staining was similar in the patient and controls (4 vs. 4.7%). PCNA staining was increased 3- to 3.5-fold, indicating increased insulin-cell proliferation compared to controls. Conclusion: Activating ABCC8 mutations impaired the balance between β and α cells in the patient, suggesting an effect on β-cell mass development.
Peripheral Arterial Function and Coronary Microvascular Function in Patients with Variant Angina
Authors: Parrinello Rossella , Sestito Alfonso , Di Franco Antonino , Russo Giulio , Villano Angelo , Figliozzi Stefano , Nerla Roberto , Tarzia Pierpaolo , Stazi Alessandra , Lanza Gaetano A. , Crea Filippo
Published: June 2014

Objectives: In this study, we assessed whether any abnormalities in coronary microvascular and peripheral vasodilator functions are present in patients with variant angina (VA) caused by epicardial coronary artery spasm (CAS). Methods: We studied 23 patients with VA (i.e. angina at rest, ST-segment elevation during angina attacks and documented occlusive CAS at angiography) and 18 matched healthy controls. Endothelium-dependent and -independent coronary microvascular function was assessed by measuring coronary blood flow (CBF) response to adenosine and the cold pressor test (CPT) in the left anterior descending artery by transthoracic Doppler echocardiography. Systemic endothelium-dependent and -independent arterial dilator function was assessed by measuring brachial flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD), respectively. Results: In VA patients, CBF responses to both adenosine (1.71 ± 0.25 vs. 2.97 ± 0.80, p < 0.01) and CPT (1.68 ± 0.23 vs. 2.58 ± 0.60, p < 0.01) were reduced compared to controls. Brachial FMD was also lower (3.87 ± 2.06 vs. 8.51 ± 2.95%, p < 0.01), but NMD was higher (16.7 ± 1.8 vs. 11.9 ± 1.4%, p < 0.01) in patients compared to controls. Differences were independent of the presence of coronary atherosclerotic lesions at angiography. Conclusions: Our data show that patients with VA have a generalized vascular dysfunction that involves both peripheral artery vessels and coronary microcirculation.
Placental Sprouty 2 (SPRY2): Relation to Placental Growth and Maternal Metabolic Status
Authors: Bassols Judit , Moreno-Navarrete Jose , Carreras-Badosa Gemma , Diaz Marta , Prats-Puig Anna , Palomer Anna-Maria , de Zegher Francis , Ibáñez Lourdes , Fernandez-Real Jose-Manuel , Lopez-Bermejo Abel
Published: June 2014

Background:SPROUTY2 (SPRY2) is a membrane-associated protein expressed by placental macrophages with regulatory roles in tissue growth and development. The SPRY2 locus was shown to be associated with body fat distribution and susceptibility to type 2 diabetes. Objectives: We assessed whether SPRY2 mRNA levels are related with maternal metabolic status and with placental weight. We also studied the association of placental mRNA of SPRY2 with macrophage-derived inflammatory genes. Methods: A maternal metabolic profile [C-peptide, post-load glucose and high-molecular-weight (HMW) adiponectin] was assessed between 24 and 28 weeks of gestation in 200 control women delivering adequate-for-gestational-age (AGA) infants. Placentas and newborns were weighed at delivery. Placental mRNA levels of SPRY2 and of macrophage-derived inflammatory genes MMP2, TNFα and CD163 were quantified by real-time PCR. Women delivering small-for-gestational-age infants (SGA, n = 25) and women with gestational diabetes (GDM, n = 25) were also studied as validation groups for placental growth. Results: In control women delivering AGA infants, placental SPRY2 mRNA levels showed positive associations with a more adverse maternal metabolic status (higher maternal C-peptide and post-load glucose and lower HMW adiponectin), with more placental weight and with a more placental inflammatory phenotype (higher placental mRNA levels of MMP2,TNFα and CD163) (all p < 0.05 to p = 0.001). Compared to AGA infants, placental weight and placental SPRY2 mRNA levels were lower in placentas from SGA infants and higher in placentas from women with GDM (all p < 0.0001). Conclusions: Our results suggest a link between placental SPRY2 mRNA levels and placental growth, which may be modulated by maternal metabolic status and placental inflammation.
Laparoendoscopic Single-Site Surgery for Extremely Large Ovarian Cysts: A Feasibility, Safety, and Patient Satisfaction Study
Authors: Song Taejong , Kim Mi Kyoung , Kim Mi-La , Yoon Bo Sung , Seong Seok Ju
Published: June 2014

Background/Aims: To assess the feasibility, safety and patient satisfaction of laparoendoscopic single-site (LESS) surgery for extremely large ovarian cysts. Methods: We conducted a prospective study of LESS surgery among women with ovarian cysts with a minimum diameter ≥15 cm and with radiological and laboratory features suggestive of benign disease. The primary outcomes were perioperative complication rate, conversion rate and patient satisfaction. Results: A total of 21 consecutive patients underwent the following LESS surgery over a period of 17 months: ovarian cystectomy (76%), adnexectomy (10%) and staging procedure (14%). Histological findings included benign (85%), borderline (10%) and malignant tumors (5%). Spillage occurred for 2 patients (10%). LESS surgery was successful without conversion in 20 patients (95%). There was 1 perioperative complication with subcutaneous hematoma (5%). The median operative time and estimated blood loss were 79.8 min (39-155) and 60 ml (10-180), respectively. Patients were highly satisfied with the results of LESS surgery, with a mean surgery satisfaction score of 9.4 ± 0.8 on a scale of 1-10. More than 71% of patients reported that the scar was invisible, and 95% said that they would recommend LESS surgery to others. Conclusion: Based on our results, with proper patient selection, the size of an ovarian cyst does not necessarily constitute a contraindication for LESS surgery.
Bone Remodeling in Choroidal Osteoma Monitored by Fundus Photography and Spectral-Domain Optical Coherence Tomography
Authors: Kamalden Tengku Ain , Lingam Gopal , Sundar Gangadhara
Published: June 2014

Choroidal osteoma is a benign ossifying tumor of the choroid, consisting of mature bone tissue. It has been described to enlarge and evolve at varying rates over time. Here, we report and quantify the progression of a unilateral choroidal osteoma in a 7-year-old boy by fundus photography, and document tumor remodeling by spectral domain optical coherence tomography images.
Development of Hemipenes in the Ball Python Snake Python regius
Authors: Leal Francisca , Cohn Martin J.
Published: June 2014

Within amniotes, external copulatory organs have undergone extensive morphological diversification. One of the most extreme examples is squamate (lizards and snakes) hemipenes, which are paired copulatory organs that extend from the lateral margins of the cloaca. Here, we describe the development of hemipenes in a basal snake, the ball python (Python regius). Snake hemipenes arise as a pair of lateral swellings on either side of the caudal part of the cloaca, and these paired outgrowths persist to form the left and right hemipenes. In non-squamate amniotes, external genitalia form from paired swellings that arise on the anterior side of the cloaca, which then fuse medially to form a single genital tubercle, the anlagen of the penis or clitoris. Whereas in non-squamate amniotes, Sonic hedgehog (Shh)-expressing cells of the cloacal endoderm form the urethral or sulcus epithelium and are required for phallus outgrowth, the hemipenes of squamates lack an endodermal contribution, and the sulcus does not express Shh. Thus, snake hemipenes differ from the genital tubercles of non-squamate amniotes both in their embryonic origins and in at least part of patterning mechanisms, which raises the possibility that hemipenes may not be direct homologs of the unpaired amniote penis. Nonetheless, we find that some developmental genes show similar expression patterns in snake hemipenes buds and non-squamate genital tubercles, suggesting that homologous developmental mechanisms are involved in aspects of external genital development across amniotes, even when these structures may have different developmental origins and may have arisen independently during evolution.
Endothelial Deletion of Phospholipase D2 Reduces Hypoxic Response and Pathological Angiogenesis
Authors: Ghim Jaewang , Moon Jin-Sook , Lee Chang Sup , Lee Junyeop , Song Parkyong , Lee Areum , Jang Jin-Hyeok , Kim Dayea , Yoon Jong Hyuk , Koh Young Jun , Chelakkot Chaithanya , Kang Byung Jun , Kim Jung-Min , Kim Kyung Lock , Yang Yong Ryoul , Kim Youngmi , Kim Sun-Hee , Hwang Daehee , Suh Pann-Ghill , Koh Gou Young , Kong Young-Yun , Ryu Sung Ho
Published: June 2014

Objective—

Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis that occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α and target genes are important for the angiogenic functions of ECs. Phospholipase D2 (PLD2) is a crucial signaling mediator that stimulates the production of the second messenger phosphatidic acid. PLD2 is involved in various cellular functions; however, its specific roles in ECs under hypoxia and in vivo angiogenesis remain unclear. In the present study, we investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo.

Approach and Results—

Pld2
knockout ECs exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of hypoxia-inducible factor-1α target genes, including
VEGF
,
PFKFB3
,
HMOX-1
, and
NTRK2
. Consistent with this, PLD2 contributed to hypoxia-induced hypoxia-inducible factor-1α expression at the translational level. The roles of PLD2 in hypoxia-induced in vivo pathological angiogenesis were assessed using oxygen-induced retinopathy and tumor implantation models in endothelial-specific
Pld2
knockout mice.
Pld2
endothelial-specific knockout retinae showed decreased neovascular tuft formation, despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in
Pld2
endothelial-specific knockout mice.

Conclusions—

Our findings demonstrate a novel role for endothelial PLD2 in the survival and migration of ECs under hypoxia via the expression of hypoxia-inducible factor-1α and in pathological retinal angiogenesis and tumor angiogenesis in vivo.
Pulmonary Arterial Hypertension
Authors: Lai Yen-Chun , Potoka Karin C. , Champion Hunter C. , Mora Ana L. , Gladwin Mark T.
Published: June 2014

Pulmonary arterial hypertension is a progressive disorder in which endothelial dysfunction and vascular remodeling obstruct small pulmonary arteries, resulting in increased pulmonary vascular resistance and pulmonary pressures. This leads to reduced cardiac output, right heart failure, and ultimately death. In this review, we attempt to answer some important questions commonly asked by patients diagnosed with pulmonary arterial hypertension pertaining to the disease, and aim to provide an explanation in terms of classification, diagnosis, pathophysiology, genetic causes, demographics, and prognostic factors. Furthermore, important molecular pathways that are central to the pathogenesis of pulmonary arterial hypertension are reviewed, including nitric oxide, prostacyclin, endothelin-1, reactive oxygen species, and endothelial and smooth muscle proliferation.
The Genetics of Pulmonary Arterial Hypertension
Authors: Austin Eric D. , Loyd James E.
Published: June 2014

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (
BMPR2
) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH (
CAV1
,
KCNK3
,
EIF2AK4
). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease.
Cerebrovascular Events in 21 105 Patients With Atrial Fibrillation Randomized to Edoxaban Versus Warfarin
Authors: Giugliano Robert P. , Ruff Christian T. , Rost Natalia S. , Silverman Scott , Wiviott Stephen D. , Lowe Cheryl , Deenadayalu Naveen , Murphy Sabina A. , Grip Laura T. , Betcher Joshua M. , Duggal Anil , Dave Jay , Shi Minggao , Mercuri Michele , Antman Elliott M. , Braunwald Eugene
Published: June 2014

Background and Purpose—

The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate–high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously.

Methods—

We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events.

Results—

Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65–0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91–1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year;
P
=0.81), but more frequent with low-dose edoxaban (2.48% per year;
P
<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds.

Conclusions—

In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00781391.
What Did John Hear?
Authors: Witetschek Stephan
Published: June 2014

The passage of John the Baptist’s question (Matt 11:2-19 par. Luke 7:18-35) is a key text in the double tradition (and, therefore, in “Q”). When it comes to the narrative introduction (Matt 11:2-3 par. Luke 7:18-19), however, reconstructing a common Q text behind the two versions proves difficult, since both Matthew and Luke have reworked the introduction in their respective ways. Recent reconstructions prefer a “minimalist” solution that leaves the setting relatively open, with some narrative gaps. This article attempts to integrate these gaps into a meaningful reading of Q as a narrative. After giving an account of previous work on the reconstruction of this Q passage and discussing its central issues, a narratological approach to Q allows understanding the gaps in this Q passage as indicators of overarching narrative cohesion in Q.
Jesus “Coming” in the Flesh
Authors: Jensen Matthew David
Published: June 2014

This article argues that the present tense-form (ἐρχόµενον) used in the confession of 2 John 7 should be understood as parallel to the perfect tense-form (ἐληλυθότα) used in the confession of 1 John 4:2. After critically reviewing the five current ways the present tense-form is interpreted, the article outlines how recent research into verbal aspect indicates that the present and perfect tense-forms are closely related. Evidence of this relationship is then provided from 1 John allowing some conclusions to be drawn about the five current interpretive options.
The North Caucasus in Contemporary U.S.-Russia Relations: Key Problems and Implications for the Future
Authors: Suchkov Maxim A.
Published: June 2014

The North Caucasus is a most significant but a least understood problem in contemporary U.S.-Russia relations. The United States as one of the prime pace-setters in the region shaped its own attitude towards Russia’s most volatile region. Over more than twenty years, Washington experienced at least three major stages in its “Caucasus strategy”, and each stage had its impact on the North Caucasus. Since the beginning, the two states stuck to conflicting narratives of developments in the region. With time, some of the assessments were re-evaluated, but some continue to impede cooperation on key security issues. The present article explores these phenomena and examines what implications major events like the 9/11 attacks, the Caucasus Emirate enlistment among top terrorist organisations, the Boston marathon bombings, etc. had for the U.S.-Russia joint efforts in fighting terrorism. It also assesses areas of potential disagreement in the North Caucasus between the two countries.
The “Babak Khorramdin Organisation”: A Mysterious Opposition Group in the Islamic Republic of Iran
Authors: Cohen Ronen A.
Published: June 2014

A clandestine group, symbolically called after the 9th century Iranian historical figure, “Babak Khorramdin Organisation”, appeared after the Islamic Revolution with the aim of overthrowing the Islamic government and restoring the Iranian nationalism at the expense of what they consider to be an overcultivation of the Muslim and Shi‘a identity. The article describes the organisation’s structure, character and methods, its political and national agenda, its vision and its struggle against the Islamic regime.
Notes on Early Land Plants Today. 58. Historical circumscription of Schistochilaceae (Marchantiophyta) and a new combination in Schistochila
Authors: He Xiaolan , Glenny David , Söderström Lars , Hagborg Anders , Von Konrat Matt
Published: June 2014

The family Schistochilaceae Buch (1928: 9) consists of approximately 80 extant species. More than two-thirds of its diversity occurs in temperate to subantarctic South America and Australasia, and nearly one third in the tropical mountain forests of Southeast Asia and the western Pacific Islands. The plants of Schistochilaceae are usually robust and form a prominent component of the ground layer of cool temperate forests or upper montane tropical forests, commonly forests in which Nothofagus is a dominant genus.  The first species of the family, published as Jungermannia appendiculata Hooker (1818: tab. 15), Jungermannia glaucescens Hooker (1818: tab. 39), Jungermannia lamellata Hooker (1818: tab. 49), Jungermannia nobilis Hooker (1818: tab. 11), Jungermannia sphagnoides Schwägrichen (1814: 23) and Jungermannia thouarsii Hooker (1818: tab. 48), were described during 1814–1818. Dumortier established the genus Schistochila Dumortier (1835: 15) to accommodate the above mentioned species except Jungermannia glaucescens and Jungermannia sphagnoides, but he also added one new species, Schistochila pinnatifolia Dumortier (1835: 15) nom. inval. (ICN Art. 38.1(a); no description; McNeill et al. 2012). The definition of Schistochilaceae has remained largely unchanged since it was separated from Scapaniaceae Migula (1904: 479) by Buch (1928) and then later Balantiopsaceae Buch (1955: 23). The presence of magenta rhizoids, winged and complicate-bilobed leaves with smaller dorsal lobes, a shoot calyptra elaborated into a well-developed coelocaule, and a cylindrical sporophyte capsule with straight valves generally defines the family. These features, to a great extent, isolate Schistochilaceae from the rest of the leafy liverworts. Therefore, taxonomic rearrangements or revisions, based on morphological investigations, have mostly been at generic level or below (Grolle 1966, 1968, Hässel 1973, Schuster 1971a, Schuster & Engel 1977, 1985). So far, taxonomic revisions have only been done at regional scales, a study at global scale is under way (Glenny et al., unpublished).
Notes on Early Land Plants Today. 59. Leptolejeunea himalayensis and Leptocolea mirpurensis (Marchantiophyta, Lejeuneaceae) synonymous with Lejeunea cocoes and Cololejeunea raduliloba, respectively
Authors: SHU Lei , Zhu Rui-Liang
Published: June 2014

Lejeuneaceae is the largest family of the liverworts with about 1700 currently accepted species (He & Zhu 2011, He et al. 2012), but some of them are poorly known and their status is still unclear. Leptolejeunea himalayensis Pandé & Misra (1943: 168) is known only from India and previously suspected of belonging to one member of Lejeunea Libert (1820: 372) (Awasthi 1986). Leptocolea mirpurensis Khan (1957: 23) from Bangladesh has never been studied since its first description in 1957. Although the types of the two taxa were not available for our study, the original description and illustrations (Pandé & Misra 1943, Khan 1957) undoubtedly indicate that Leptolejeunea himalayensis and Leptocolea mirpurensis are conspecific with Lejeunea cocoes Mitten (1861: 114) and Cololejeunea raduliloba Stephani (1895: 251), respectively. Lejeunea cocoes has been reported for India (Singh & Nath 2007, Manju et al. 2012), and is also known in China, Indonesia, Malaysia, Papua New Guinea, and Sri Lanka (So & Zhu 1998, Zhu & So 2001, Lee 2013), furthermore from Chagos, Diego Garcia (Seaward et al. 2006) and from the Fiji Islands (Pócs et al. 2013). Cololejeunea raduliloba, a paleotropical species (Zhu & So 2001), is newly reported for Bangladesh.
Chaenothecopsis neocaledonica sp. nov.: The first resinicolous mycocalicioid fungus from an araucarian conifer
Authors: Rikkinen Jouko , Tuovila Hanna , Beimforde Christina , Seyfullah Leyla , Perrichot Vincent , Schmidt Alexander R
Published: June 2014

A new resinicolous species of the genus Chaenothecopsis (Ascomycota, Mycocaliciales) is described from resin of Agathis ovata in New Caledonia. Chaenothecopsis neocaledonica sp. nov. is the first mycocalicioid fungus to be described from the exudates of Southern Hemisphere conifers of the family Araucariaceae. It is easily distinguished from related Northern Hemisphere species by its larger ascospores and unique capitulum structure.