bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic alcohol feeding inhibits physiological and molecular parameters of intestinal and renal riboflavin transport
Authors: Subramanian Veedamali S. , Subramanya Sandeep B. , Ghosal Abhisek , Said Hamid M.
Published: June 2013

Vitamin B2 (riboflavin, RF) is essential for normal human health. Mammals obtain RF from exogenous sources via intestinal absorption and prevent its urinary loss by reabsorption in the kidneys. Both of these absorptive events are carrier-mediated and involve specific RF transporters (RFVTs). Chronic alcohol consumption in humans is associated with a high prevalence of RF deficiency and suboptimal levels, but little is known about the effect of chronic alcohol exposure on physiological and molecular parameters of the intestinal and renal RF transport events. We addressed these issues using rats chronically fed an alcohol liquid diet and pair-fed controls as a model. The results showed that chronic alcohol feeding significantly inhibits carrier-mediated RF transport across the intestinal brush-border and basolateral membrane domains of the polarized enterocytes. This inhibition was associated with a parallel reduction in the expression of the rat RFVT-1 and -3 at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Chronic alcohol feeding also caused a significant inhibition in RF uptake in the colon. Similarly, a significant inhibition in carrier-mediated RF transport across the renal brush-border and basolateral membrane domains was observed, which again was associated with a significant reduction in the level of expression of RFVT-1 and -3 at the protein, mRNA, and hnRNA levels. These findings demonstrate that chronic alcohol exposure impairs both intestinal absorption and renal reabsorption processes of RF and that these effects are, at least in part, mediated via transcriptional mechanism(s) involving the slc52a1 and slc52a3 genes.
Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain
Authors: Seabrooke Sara , O'Donnell Michael J.
Published: June 2013

The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain.
Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin
Authors: Bao Jialing , Yura Renee E. , Matters Gail L. , Bradley S. Gaylen , Shi Pan , Tian Fang , Bond Judith S.
Published: June 2013

Meprin metalloproteases are highly expressed at the luminal interface of the intestine and kidney and in certain leukocytes. Meprins cleave a variety of substrates in vitro, including extracellular matrix proteins, adherens junction proteins, and cytokines, and have been implicated in a number of inflammatory diseases. The linkage between results in vitro and pathogenesis, however, has not been elucidated. The present study aimed to determine whether meprins are determinative factors in disrupting the barrier function of the epithelium. Active meprin A or meprin B applied to Madin-Darby canine kidney (MDCK) cell monolayers increased permeability to fluorescein isothiocyanate-dextran and disrupted immunostaining of the tight junction protein occludin but not claudin-4. Meprin A, but not meprin B, cleaved occludin in MDCK monolayers. Experiments with recombinant occludin demonstrated that meprin A cleaves the protein between Gly100and Ser101on the first extracellular loop. In vivo experiments demonstrated that meprin A infused into the mouse bladder increased the epithelium permeability to sodium fluorescein. Furthermore, monocytes from meprin knockout mice on a C57BL/6 background were less able to migrate through an MDCK monolayer than monocytes from their wild-type counterparts. These results demonstrate the capability of meprin A to disrupt epithelial barriers and implicate occludin as one of the important targets of meprin A that may modulate inflammation.
Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction
Authors: Li Shenyang , Mariappan Nithya , Megyesi Judit , Shank Brian , Kannan Krishnaswamy , Theus Sue , Price Peter M. , Duffield Jeremy S. , Portilla Didier
Published: June 2013

We examined the effects of increased expression of proximal tubule peroxisome proliferator-activated receptor (PPAR)α in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction (UUO), PPARα expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARα transgenic (Tg) mice. When compared with wild-type mice subjected to UUO, PPARα Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-β1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, α-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARα Tg mice. Overexpression of PPARα in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid-mediated increased production of TGF-β, demonstrating PPARα signaling reduces epithelial TGF-β production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARα Tg mice after UUO. Increased expression of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in wild-type mice was also significantly reduced in kidney tissue of PPARα Tg mice. In contrast, the expression of anti-inflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARα Tg mice when compared with wild-type mice subjected to UUO. Our studies demonstrate several mechanisms by which preserved expression of proximal tubule PPARα reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy.
How attention extracts objects from noise
Authors: Pratte Michael S. , Ling Sam , Swisher Jascha D. , Tong Frank
Published: June 2013

The visual system is remarkably proficient at extracting relevant object information from noisy, cluttered environments. Although attention is known to enhance sensory processing, the mechanisms by which attention extracts relevant information from noise are not well understood. According to the perceptual template model, attention may act to amplify responses to all visual input, or it may act as a noise filter, dampening responses to irrelevant visual noise. Amplification allows for improved performance in the absence of visual noise, whereas a noise-filtering mechanism can only improve performance if the target stimulus appears in noise. Here, we used fMRI to investigate how attention modulates cortical responses to objects at multiple levels of the visual pathway. Participants viewed images of faces, houses, chairs, and shoes, presented in various levels of visual noise. We used multivoxel pattern analysis to predict the viewed object category, for attended and unattended stimuli, from cortical activity patterns in individual visual areas. Early visual areas, V1 and V2, exhibited a benefit of attention only at high levels of visual noise, suggesting that attention operates via a noise-filtering mechanism at these early sites. By contrast, attention led to enhanced processing of noise-free images (i.e., amplification) only in higher visual areas, including area V4, fusiform face area, mid-Fusiform area, and the lateral occipital cortex. Together, these results suggest that attention improves people's ability to discriminate objects by de-noising visual input in early visual areas and amplifying this noise-reduced signal at higher stages of visual processing.
Glycine transporter 1 modulates GABA release from amacrine cells by controlling occupancy of coagonist binding site of NMDA receptors
Authors: Rozsa Eva , Vigh Jozsef
Published: June 2013

The occupancy of coagonist binding sites of NMDA receptors (NMDARs) by glycine or d-serine has been thought to mediate NMDAR-dependent excitatory signaling, as simultaneous binding of glutamate and a coagonist is obligatory for NMDAR activation. Amacrine cells (ACs) mediating GABAergic feedback inhibition of mixed bipolar cells (Mbs) in the goldfish retina have been shown to express NMDARs. Here we studied whether NMDAR-mediated GABAergic inhibitory currents ( IGABA) recorded from the axon terminals of Mbs are influenced by experimental manipulations altering retinal glycine and d-serine levels. Feedback IGABA in Mb axon terminals was triggered by focal NMDA application or by synaptically released glutamate from depolarized Mb terminals. In both cases, blocking the coagonist binding sites of NMDARs eliminated the NMDAR-dependent IGABA, demonstrating that coagonist binding is critical in mediating NMDAR activity-triggered GABA release. Glycine transporter 1 (GLYT1) inhibition increased IGABA, indicating that coagonist binding sites of NMDARs on ACs providing GABAergic feedback inhibition to Mbs were not saturated. Focal glycine application, in the presence of the ionotropic glycine receptor blocker strychnine, triggered a GLYT1-dependent current in ACs, suggesting that GLYT1 expressed by putative glycinergic ACs controls the saturation level of NMDARs' coagonist sites. External d-serine also increased NMDAR activation-triggered IGABA in Mbs, further substantiating that the coagonist sites were unsaturated. Together, our findings demonstrate that coagonist modulation of glutamatergic input to GABAergic ACs via NMDARs is strongly reflected in the AC neuronal output (i.e., transmitter release) and thus is critical in GABAergic signal transfer function in the inner retina.
Arabin Cerclage Pessary as a Treatment of an Acute Urinary Retention in a Pregnant Woman with Uterine Prolapse
Authors: Martínez-Varea Alicia , Nohales-Alfonso Francisco , Diago Almela Vicente José , Perales-Marín Alfredo
Published: June 2013

A 35-year-old gravida 7, para 1, and abortus 5 female with hypogastric pain and inability to void urine after 14 + 3 weeks of amenorrhea was examined in the emergency department. One year before, a uterine prolapse had been diagnosed in another hospital. Examination showed a uterine prolapse grade 2 with palpable bladder. The patient was unable to void urine. After a manual reduction of the uterine prolapse, the patient underwent an emergency catheterization for bladder drainage. A Hodge pessary (size 70) was placed, which led to spontaneous micturitions. Due to the persistence of the symptoms the following day, Hodge pessary was replaced by an Arabin cerclage pessary. Although the pessary could be removed from the beginning of the second trimester, due to the uterine prolapse as a predisposing factor in the patient and the uncomplicated progression of pregnancy, it was decided to maintain it in our patient. Therefore, Arabin cerclage pessary allowed a successful pregnancy outcome and was not associated with threatened preterm delivery or vaginal infection.
Synergistic Effect of Iodide Ion and 4-Hydroxy Coumarin on the Corrosion Inhibition of Mild Steel in Hydrochloric Acid
Authors: Krishnamurthy Shyamala R. , Parameswaran Meenakshi H. N.
Published: June 2013

No discussion of the use of inhibitors in acid solution is complete without mentioning the phenomenon of synergism. Synergism also operates in corrosion protection where an enhanced inhibition may be related to interaction between inhibitor compounds. This effect has been observed since the earlier days of inhibitor technology and continues to be a potent tool in the development of acid inhibitors for specialized uses. Hence, in this paper, the corrosion inhibition behavior of mild steel (MS) in 1 M hydrochloric acid in the presence of 4-hydroxy coumarin (4HC) and potassium iodide (KI) has been investigated using the mass loss method and electrochemical techniques. The inhibitive performance of 4HC is considerably enhanced by the addition of KI. The addition of KI to different concentrations of 4HC has intensified its efficiency through considerable reduction in the mass loss, corrosion current density , double layer capacitance , and increase in charge transfer resistance . The calculated synergism parameter “” is greater than unity, thereby proving the fact that the improvement in inhibition efficiency of 4HC, generated by the addition of KI, is due to synergism.
Assessment of Pollen Viability, Germination, and Tube Growth in Eight Tunisian Caprifig (Ficus caricaL.) Cultivars
Authors: Gaaliche Badii , Majdoub Afifa , Trad Mehdi , Mars Messaoud
Published: June 2013

The evaluation of pollen viability and its germination capacity are two essential criteria for pollinator’s characterization. This study was carried out to evaluate pollen quality of eight caprifigs grown in the center-east and north-west of Tunisia. Two colorimetric tests 2,3,5-triphenyl tetrazolium chloride (TTC) and acetocarmine were used to estimate pollen viability. Germination rate and pollen tube growth in a culture medium containing 5% sucrose, 5 ppm boric acid (H3BO3) and 1% agar were registered after 24, 48, and 72 hours (H) of incubation. Results showed that the highest pollen viability rate (84%) was obtained by TTC test in caprifig Assafri, followed by Jrani (80.2%), Djebba 2 (77.8%), and Djebba 1 (73.6%). That of other caprifigs did not exceed 50% for the two tests. In all caprifig types, germination rate and pollen tube growth varied according to the incubation period. The highest percentage of germination (72%) and maximum pollen tube length (960 μm) were recorded after 72 H of incubation in caprifigs Assafri and Jrani, respectively. Among the caprifigs studied, four types (Assafri, Jrani, Djebba 1, and Djebba 2) appeared to be suitable pollinators with respect to the criteria investigated.
Stress-Softening and Residual Strain Effects in Suture Materials
Authors: Elías-Zúñiga Alex , Montoya Beatriz , Ortega-Lara Wendy , Flores-Villalba Eduardo , Rodríguez Ciro A. , Siller Hector R. , Díaz-Elizondo José A. , Martínez-Romero Oscar
Published: June 2013

This work focuses on the experimental characterization of suture material samples of MonoPlus, Monosyn, polyglycolic acid, polydioxanone 2–0, polydioxanone 4–0, poly(glycolide-co-epsilon-caprolactone), nylon, and polypropylene when subjected to cyclic loading and unloading conditions. It is found that all tested suture materials exhibit stress-softening and residual strain effects related to the microstructural material damage upon deformation from the natural, undistorted state of the virgin suture material. To predict experimental observations, a new constitutive material model that takes into account stress-softening and residual strain effects is developed. The basis of this model is the inclusion of a phenomenological nonmonotonous softening function that depends on the strain intensity between loading and unloading cycles. The theory is illustrated by modifying the non-Gaussian average-stretch, full-network model to capture stress-softening and residual strains by using pseudoelasticity concepts. It is shown that results obtained from theoretical simulations compare well with suture material experimental data.
MIMO Antenna Array Design with Polynomial Factorization
Authors: Wang Wen-Qin , Shao Huaizong , Cai Jingye
Published: June 2013

One of the main advantages of multiple-input multiple-output (MIMO) antenna is that the degrees-of-freedom can be significantly increased by the concept of virtual antenna array, and thus the MIMO antenna array should be carefully designed to fully utilize the virtual antenna array. In this paper, we design the MIMO antenna array with the polynomial factorization method. For a desired virtual antenna array, the polynomial factorization method can optimally design the specified MIMO transmitter and receiver. The array performance is examined by analyzing the degrees-of-freedom and statistical output signal-to-interference-plus-noise ratio (SINR) performance. Design examples and simulation results are provided.
Pathophysiologic Mechanisms of Cardiovascular Disease in Obstructive Sleep Apnea Syndrome
Authors: Zamarrón Carlos , Valdés Cuadrado Luis , Álvarez-Sala Rodolfo
Published: June 2013

Obstructive sleep apnea syndrome (OSAS) is a highly prevalent sleep disorder, characterized by repeated disruptions of breathing during sleep. This disease has many potential consequences including excessive daytime sleepiness, neurocognitive deterioration, endocrinologic and metabolic effects, and decreased quality of life. Patients with OSAS experience repetitive episodes of hypoxia and reoxygenation during transient cessation of breathing that provoke systemic effects. Furthermore, there may be increased levels of biomarkers linked to endocrine-metabolic and cardiovascular alterations. Epidemiological studies have identified OSAS as an independent comorbid factor in cardiovascular and cerebrovascular diseases, and physiopathological links may exist with onset and progression of heart failure. In addition, OSAS is associated with other disorders and comorbidities which worsen cardiovascular consequences, such as obesity, diabetes, and metabolic syndrome. Metabolic syndrome is an emerging public health problem that represents a constellation of cardiovascular risk factors. Both OSAS and metabolic syndrome may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (e.g., hypoxemia, sleep disruption, activation of the sympathetic nervous system, and inflammatory activation). It has been found that CPAP therapy for OSAS provides an objective improvement in symptoms and cardiac function, decreases cardiovascular risk, improves insulin sensitivity, and normalises biomarkers. OSAS contributes to the pathogenesis of cardiovascular disease independently and by interaction with comorbidities. The present review focuses on indirect and direct evidence regarding mechanisms implicated in cardiovascular disease among OSAS patients.
A Model Reduction Method for Parallel Software Testing
Authors: Sun Tao , Ye Xinming
Published: June 2013

Modeling and testing for parallel software systems are very difficult, because the number of states and execution sequences expands significantly caused by parallel behaviors. In this paper, a model reduction method based on Coloured Petri Net (CPN) is shown, which could generate a functionality-equivalent and trace-equivalent model with smaller scale. Model-based testing for parallel software systems becomes much easier after the model is reduced by the reduction method. Specifically, a formal model for software system specification is constructed based on CPN. Then the places in the model are divided into input places, output places, and internal places; the transitions in the model are divided into input transitions, output transitions, and internal transitions. Internal places and internal transitions could be reduced if preconditions are matching, and some other operations should be done for functionality equivalence and trace equivalence. If the place and the transition are in a parallel structure, then many execution sequences will be removed from the state space. We have proved the equivalence and have analyzed the reduction effort, so that we could get the same testing result with much lower testing workload. Finally, some practices and a performance analysis show that the method is effective.
Z‐Contrast STEM Imaging of Long‐Range Ordered Structures in Epitaxially Grown CoPt Nanoparticles
Authors: Sato Kazuhisa , Yanajima Keigo , Konno Toyohiko J.
Published: June 2013

We report on atomic structure imaging of epitaxial L10 CoPt nanoparticles using chemically sensitive high‐angle annular dark‐field scanning transmission electron microscopy (HAADF‐STEM). Highly ordered nanoparticles formed by annealing at 973 K show single‐variant structure with perpendicular c‐axis orientation, while multivariant ordered domains are frequently observed for specimens annealed at 873 K. It was found that the (001) facets of the multivariant particles are terminated by Co atoms rather than by Pt, presumably due to the intermediate stage of atomic ordering. Coexistence of single‐variant particles and multivariant particles in the same specimen film suggests that the interfacial energy between variant domains be small enough to form such structural domains in a nanoparticle as small as 4 nm in diameter.
Interior Point Method for Solving Fuzzy Number Linear Programming Problems Using Linear Ranking Function
Authors: Zhong Yi-hua , Jia Yan-lin , Chen Dandan , Yang Yan
Published: June 2013

Recently, various methods have been developed for solving linear programming problems with fuzzy number, such as simplex method and dual simplex method. But their computational complexities are exponential, which is not satisfactory for solving large-scale fuzzy linear programming problems, especially in the engineering field. A new method which can solve large-scale fuzzy number linear programming problems is presented in this paper, which is named a revised interior point method. Its idea is similar to that of interior point method used for solving linear programming problems in crisp environment before, but its feasible direction and step size are chosen by using trapezoidal fuzzy numbers, linear ranking function, fuzzy vector, and their operations, and its end condition is involved in linear ranking function. Their correctness and rationality are proved. Moreover, choice of the initial interior point and some factors influencing the results of this method are also discussed and analyzed. The result of algorithm analysis and example study that shows proper safety factor parameter, accuracy parameter, and initial interior point of this method may reduce iterations and they can be selected easily according to the actual needs. Finally, the method proposed in this paper is an alternative method for solving fuzzy number linear programming problems.
Nonlocal Integrodifferential Boundary Value Problem for Nonlinear Fractional Differential Equations on an Unbounded Domain
Authors: Zhang Lihong , Ahmad Bashir , Wang Guotao , Agarwal Ravi P. , Al-Yami Maryem , Shammakh Wafa
Published: June 2013

This paper investigates the existence of nonnegative solutions for nonlinear fractional differential equations with nonlocal fractional integrodifferential boundary conditions on an unbounded domain by means of Leray-Schauder nonlinear alternative theorem. An example is discussed for the illustration of the main work.
Preparation and Structural Properties of Free Films from Rapeseed Oil-Based Rigid Polyurethane-Montmorillonite Nanocomposites
Authors: Gaidukov Sergey , Cabulis Ugis , Gromilova Karina , Tupureina Velta , Grigalovica Agnese
Published: June 2013

The preparation of free standing films of biobased rigid polyurethanes (PU) from rapeseed oil (RO) and diethanolamine (DEA) polyol and its modification with organomontmorillonite (OMMT) nanoparticles are described. Heat enthalpy of the interaction duringin situmixing of RO/DEA polyol and OMMT is measured in isothermal profile. The Fourier transform infrared spectral analysis (FTIR-ATR) is used to determine the urethane group concentration and hydrogen bonds formation in PU and PU/OMMT nanocomposites. X-ray diffraction shows the formation of intercalated and exfoliated structures of OMMT. The glass-transition temperature is used to demonstrate the formation for the intercalated and exfoliated nanocomposites of an interphase with a possible compact structure and the altered polymer chain mobility. The prepared PU/OMMT nanocomposites are also characterized by the enhanced thermal degradation characteristics upon heating in air atmosphere.
Dried Ginger (Zingiber officinalis) Inhibits Inflammation in a Lipopolysaccharide-Induced Mouse Model
Authors: Choi You Yeon , Kim Mi Hye , Hong Jongki , Kim Sung-Hoon , Yang Woong Mo
Published: June 2013

Objectives. Ginger rhizomes have a long history of human use, especially with regards to their anti-inflammatory properties. However, the mechanisms by which ginger acts on lipopolysaccharide-(LPS-)induced inflammation have not yet been identified. We investigated the anti-inflammatory effects of driedZingiber officinalis(DZO) on LPS-induced hepatic injury.Methods. ICR mice were given a DZO water extract (100, 1000 mg/kg) orally for three consecutive days. On the third day, they were administered by LPS intraperitoneally. To investigate the anti-inflammatory effects of DZO, histological, cytokine expression, and protein factor analyses were performed.Results. Oral administration of DZO significantly reduced pathological changes in the liver and proinflammatory cytokines including interferon-(IFN-)γand interleukin-(IL-)6 in the serum. In addition, DZO inhibited LPS-induced NF-κB activation by preventing degradation of the IκB-α, as well as the phosphorylation of ERK1/2, SAPK/JNK, and p38 MAPKs. These were associated with a decrease in the expression of inducible nitric oxide synthase (iNOS) and cyclooxyenase-2 (COX-2).Conclusions. Our data provide evidence for the hepatoprotective mechanisms of DZO as an anti-inflammatory effect. Furthermore, use of DZO to treat could provide therapeutic benefits in clinical settings.
S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab
Authors: Burbridge Mike F. , Bossard Céline J. , Saunier Carine , Fejes Imre , Bruno Alain , Léonce Stéphane , Ferry Gilles , Da Violante Georges , Bouzom François , Cattan Valérie , Jacquet-Bescond Anne , Comoglio Paolo M. , Lockhart Brian P. , Boutin Jean A. , Cordi Alex , Ortuno Jean-Claude , Pierré Alain , Hickman John A. , Cruzalegui Francisco H. , Depil Stéphane
Published: June 2013

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.
Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients
Authors: Hernández Carmen , Orbe Josune , Roncal Carmen , Alvarez-Hernandez Maria , de Lizarrondo Sara Martinez , Alves Maria T. , Mata Jesus García , Páramo José A.
Published: June 2013

A prothrombotic state is one of the hallmarks of malignancy and a major contributor to morbidity and mortality in cancer patients. Tissue factor (TF) is often overexpressed in malignancy and is a prime candidate in predicting the hypercoagulable state. Moreover, increased number of TF-exposing microparticles (MPs) in cancer patients may contribute to venous thromboembolism (VTE). We have conducted a prospective cohort study to determine whether elevated TF antigen, TF activity and TF associated to MPs (MPs-TF) are predictive of VTE and mortality in cancer patients. The studied population consisted of 252 cancer patients and 36 healthy controls. TF antigen and activity and MPs-TF were determined by ELISA and chromogenic assays. During a median follow-up of 10 months, 40 thrombotic events were recorded in 34 patients (13.5%), and 73 patients (28.9%) died. TF antigen and activity were significantly higher in patients than in controls (p<0.01) mainly in patients with advanced stages, whereas no differences were observed for TF activity of isolated MPs. We did not find a statistically significant association of TF variables with the risk of VTE. Multivariate analysis adjusting for age, sex, type of cancer and other confounding variables showed that TF activity (p<0.01) and MPs-TF activity (p<0.05) were independently associated with mortality. In conclusion, while TF variables were not associated with future VTE in cancer patients, we found a strong association of TF and MPs-TF activity with mortality, thus suggesting they might be good prognostic markers in cancer patients.
Fibroblast Growth Factor Homologous Factors Modulate Cardiac Calcium Channels
Authors: Hennessey Jessica A. , Wei Eric Q. , Pitt Geoffrey S.
Published: June 2013

Rationale
:

Fibroblast growth factor (FGF) homologous factors (FHFs; FGF11–14) are intracellular modulators of voltage-gated Na
+
channels, but their cellular distribution in cardiomyocytes indicated that they performed other functions.

Objective
:

We aimed to uncover novel roles for FHFs in cardiomyocytes, starting with a proteomic approach to identify novel interacting proteins.

Methods and Results
:

Affinity purification of FGF13 from rodent ventricular lysates followed by mass spectroscopy revealed an interaction with junctophilin-2, a protein that organizes the close apposition of the L-type Ca
2+
channel Ca
V
1.2 and the ryanodine receptor 2 in the dyad. Immunocytochemical analysis revealed that overall T-tubule structure and localization of ryanodine receptor 2 were unaffected by FGF13 knockdown in adult ventricular cardiomyocytes but localization of Ca
V
1.2 was affected. FGF13 knockdown decreased Ca
V
1.2 current density and reduced the amount of Ca
V
1.2 at the surface as a result of aberrant localization of the channels. Ca
V
1.2 current density and channel localization were rescued by expression of an shRNA-insensitive FGF13, indicating a specific role for FGF13. Consistent with these newly discovered effects on Ca
V
1.2, we demonstrated that FGF13 also regulated Ca
2+
-induced Ca
2+
release, indicated by a smaller Ca
2+
transient after FGF13 knockdown. Furthermore, FGF13 knockdown caused a profound decrease in the cardiac action potential half-width.

Conclusions
:

This study demonstrates that FHFs not only are potent modulators of voltage-gated Na
+
channels but also affect Ca
2+
channels and their function. We predict that FHF loss-of-function mutations would adversely affect currents through both Na
+
and Ca
2+
channels, suggesting that FHFs may be arrhythmogenic loci, leading to arrhythmias through a novel, dual-ion channel mechanism.
Stress Cardiac Magnetic Resonance Imaging Provides Effective Cardiac Risk Reclassification in Patients With Known or Suspected Stable Coronary Artery Disease
Authors: Shah Ravi , Heydari Bobak , Coelho-Filho Otavio , Murthy Venkatesh L. , Abbasi Siddique , Feng Jiazhuo H. , Pencina Michael , Neilan Tomas G. , Meadows Judith L. , Francis Sanjeev , Blankstein Ron , Steigner Michael , di Carli Marcelo , Jerosch-Herold Michael , Kwong Raymond Y.
Published: June 2013

Background—

A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes.

Methods and Results—

In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (<1%), moderate (1% to 3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66;
P
<0.0001) with low negative event rates of major adverse cardiac events and cardiac death (0.6% and 0.4%, respectively). This prognostic robustness was maintained in patients with previous coronary artery disease (hazard ratio=8.17;
P
<0.0001; 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (adjusted for age and previous coronary artery disease) improved discrimination of major adverse cardiac events (C statistic, 0.81–0.86;
P
=0.04; adjusted hazard ratio=7.37;
P
<0.0001) and reclassified 91.5% of patients at moderate pretest risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/y and 4.9%/y for low and high risk posttest, respectively). Categorical net reclassification index was 0.229 (95% confidence interval, 0.063–0.391). Continuous net reclassification improvement was 1.11 (95% confidence interval, 0.81–1.39).

Conclusions—

Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease.

Clinical Trial Registration:—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01821924.
Nonstationary Australasian Teleconnections and Implications for Paleoclimate Reconstructions
Authors: Gallant Ailie J. E. , Phipps Steven J. , Karoly David J. , Mullan A. Brett , Lorrey Andrew M.
Published: June 2013

The stationarity of relationships between local and remote climates is a necessary, yet implicit, assumption underlying many paleoclimate reconstructions. However, the assumption is tenuous for many seasonal relationships between interannual variations in the El Niño–Southern Oscillation (ENSO) and the southern annular mode (SAM) and Australasian precipitation and mean temperatures. Nonstationary statistical relationships between local and remote climates on the 31–71-yr time scale, defined as a change in their strength and/or phase outside that expected from local climate noise, are detected on near-centennial time scales from instrumental data, climate model simulations, and paleoclimate proxies.

The relationships between ENSO and SAM and Australasian precipitation were nonstationary at 21%–37% of Australasian stations from 1900 to 2009 and strongly covaried, suggesting common modulation. Control simulations from three coupled climate models produce ENSO-like and SAM-like patterns of variability, but differ in detail to the observed patterns in Australasia. However, the model teleconnections also display nonstationarity, in some cases for over 50% of the domain. Therefore, nonstationary local–remote climatic relationships are inherent in environments regulated by internal variability. The assessments using paleoclimate reconstructions are not robust because of extraneous noise associated with the paleoclimate proxies.

Instrumental records provide the only means of calibrating and evaluating regional paleoclimate reconstructions. However, the length of Australasian instrumental observations may be too short to capture the near-centennial-scale variations in local–remote climatic relationships, potentially compromising these reconstructions. The uncertainty surrounding nonstationary teleconnections must be acknowledged and quantified. This should include interpreting nonstationarities in paleoclimate reconstructions using physically based frameworks.
Health Inequalities in Global Context
Authors: Beckfield Jason , Olafsdottir Sigrun , Bakhtiari Elyas
Published: June 2013

The existence of social inequalities in health is well established. One strand of research focuses on inequalities in health within a single country. A separate and newer strand of research focuses on the relationship between inequality and average population health across countries. Despite the theorization of (presumably variable) social conditions as “fundamental causes” of disease and health, the cross-national literature has focused on average, aggregate population health as the central outcome. Controversies currently surround macro-structural determinants of overall population health, such as income inequality. We advance and redirect these debates by conceptualizing inequalities in health as cross-national variables that are sensitive to social conditions. Using data from 48 World Values Survey countries, representing 74% of the world’s population, we examine cross-national variation in inequalities in health. The results reveal substantial variation in health inequalities according to income, education, sex, and migrant status. While higher socioeconomic position is associated with better self-rated health around the globe, the size of the association varies across institutional context and across dimensions of stratification. There is some evidence that education and income are more strongly associated with self-rated health than sex or migrant status.
Connecting the Dots
Authors: Melin Molly M. , Grigorescu Alexandru
Published: June 2013

We explore states’ decisions to escalate disputes over their territorial claims or settle them peacefully. We complement existing arguments by accounting for the fact that states are often simultaneously entangled in multiple territorial claims. We build on previous scholarship in positing that two states involved in a territorial dispute will act based on information they glean from each other’s reputation for dealing with claims with other states and their recent actions involving disputes with other states. Because states know that their actions will impact their adversaries’ calculations, the existence of multiple ongoing territorial claims will act as a deterrent from any type of action to resolve the dispute, whether militarized or peaceful. Our hypotheses therefore consider the impact of the number of states’ other territorial claims as well as the number of their adversaries’ claims. Tests using the Issue Correlates of War data support our arguments.
Patrimonial Violence
Authors: Deere Carmen Diana , Contreras Jacqueline , Twyman Jennifer
Published: June 2013

Patrimonial violence, defined minimally as the violation of women’s property rights, is increasingly recognized as a form of gender violence, along with physical, psychological, and sexual violence. Research in Ecuador on the extent to which women are aware of their property rights and the situations in which patrimonial violence is most likely to occur shows that, while most women seem to be aware of certain fundamentals, there are many misconceptions, particularly regarding the status of individual property. Women’s lack of legal knowledge often undermines their ability to obtain their rightful share of the division of property upon separation, divorce, or widowhood. Moreover, patrimonial violence is often aggravated by the presence of other forms of violence against women.

La violencia patrimonial, definida mínimamente como la violación de los derechos de propiedad de las mujeres, se reconoce cada vez más como una forma de violencia de género, a la par que la violencia física, psicológica y sexual. Investigaciones sobre el grado en que las mujeres son conscientes de sus derechos de propiedad y las situaciones en las que es más probable que se produzca violencia patrimonial en Ecuador muestran que, mientras que la mayoría de las mujeres parece estar conscientes de ciertos fundamentos, manejan muchas ideas equivocadas, particularmente con respecto al estado de la propiedad individual. Su falta de conocimiento legal a menudo socava su capacidad de obtener una parte justa de la división de bienes ocurrida a raíz de una separación, divorcio o viudez. Lo que es más, la violencia patrimonial a menudo se ve agravada por la presencia de otras formas de violencia contra la mujer.
Indigenous Women and Violence in Colombia
Authors: Tovar-Restrepo Marcela , Irazábal Clara
Published: June 2013

The violence and de/reterritorializing strategies used by armed groups in Colombia disproportionally affect indigenous peoples, especially indigenous women, whose ethno-gender roles, forms of territoriality, agency, and autonomy are being altered. Conflict and new forms of territoriality restrict the satisfaction of ethno-gender-based material needs and interests, with negative impacts on women’s own and their families’ lives. At the same time, they offer some women new roles, agency, and autonomy and empowerment through individual and collective action. Policy makers should strive to open up these windows of opportunity for indigenous women while protecting them from the depredations of war.

La violencia y las estrategias de des/reterritorialización utilizadas por grupos armados en Colombia afectan desproporcionadamente a los indígenas, especialmente a las mujeres indígenas, cuyos roles etno-géneros, formas de territorialidad, agencia, y autonomía están siendo alterados. El conflicto y las nuevas formas de territorialidad restringen la satisfacción de necesidades materiales e intereses de tipo etno-género con impactos negativos en las vidas propias de las mujeres y de las de sus familias. Al mismo tiempo, presentan nuevos roles, agencia, autonomía, y empoderamiento a algunas mujeres a través de la acción individual y colectiva. Los formuladores de políticas deberían esforzarse para abrir estos espacios de oportunidad para mujeres indígenas al mismo tiempo que las protejan de las depredaciones de guerra.
Independent-Mobility Rights and the State of Public Transport Accessibility for Disabled People
Authors: Ahmad Mahtab
Published: June 2013

A total of 245 rural men and women with physical disabilities were interviewed to assess their access to road transport. The overall level of access was poor for both the men and women with physical disabilities. Poor environmental conditions and terminal facilities, unfriendly vehicles and behavior of transport staff, and travel safety and security threats were the barriers that prevented them to access routes. The findings indicate that without having a clear understanding of the transport-accessibility challenges at transport-planning levels and adopting equities in practice, the promotion of disability rights in local transport would be impossible in developing societies like Pakistan.
Parental employment and child behaviors
Authors: Hadzic Renata , Magee Christopher A. , Robinson Laura
Published: June 2013

This study examined whether hours of parental employment were associated with child behaviors via parenting practices. The sample included 2,271 Australian children aged 4–5 years at baseline. Two-wave panel mediation models tested whether parenting practices that were warm, hostile, or characterized by inductive reasoning linked parent’s hours of paid employment with their child’s behavior at age 6–7 years. There were significant indirect effects linking mother employment to child behavior. No paid employment and full-time work hours were associated with more behavioral problems in children through less-warm parenting practices; few hours or long hours were associated with improved behavioral outcomes through less-hostile parenting practices. These findings may have implications for developing policies to enable parents to balance work and family demands.
Associations between inflammation, nocturnal back pain and fatigue in ankylosing spondylitis and improvements with etanercept therapy
Authors: Hammoudeh Mohammed , Zack Debra J , Li Wenzhi , Stewart V Michelle , Koenig Andrew S
Published: June 2013

Objectives

To investigate the relationships between inflammation, nocturnal back pain and fatigue in ankylosing spondylitis (AS) and the impact of 12 weeks' etanercept treatment versus sulfasalazine or placebo.

Methods

Data were combined from four clinical trials for patients with AS who received at least one dose of etanercept, sulfasalazine or placebo and had at least one postbaseline assessment value. Linear regression was performed (controlling for site, protocol and demographics), to explore the relationship between inflammation (C-reactive protein [CRP]), nocturnal back pain (visual analog scale [VAS] 0–100 mm) and fatigue (VAS 0–100 mm Bath AS Disease Activity Index fatigue item).

Results

Out of 1283 patients (etanercept, n = 867; sulfasalazine, n = 187; placebo, n = 229), improvement in nocturnal back pain was a significant predictor of improvement in fatigue. Significant correlations were found between nocturnal back pain and fatigue, but not CRP levels. Etanercept provided significantly greater pain/fatigue improvement than sulfasalazine or placebo. Improvements in nocturnal back pain and fatigue had weak relationships with improvement in inflammation (CRP level).

Conclusions

AS patients treated with etanercept demonstrated superior improvement in nocturnal back pain and fatigue versus sulfasalazine or placebo. Decrease in nocturnal back pain can improve fatigue. Assessing treatment response using CRP levels alone may be misleading without also examining patient-reported outcomes such as back pain and fatigue.
Two nonsynonymous polymorphisms (F31I and V57I) of the STK15 gene and breast cancer risk: A meta-analysis based on 5966 cases and 7609 controls
Authors: Qin Kai , Wu Cheng , Wu Xiaoting
Published: June 2013

Objectives

This meta-analysis examined the relationship between two nonsynonymous polymorphisms (F31I and V57I) of the aurora kinase A ( STK15) gene and breast cancer risk.

Methods

A systematic search of the PubMed® and EMBASE™ databases was undertaken to identify case–control studies that investigated the relationship between STK15 gene polymorphisms and breast cancer risk.

Results

This meta-analysis included seven case–control studies (5966 breast cancer cases; 7609 controls). Combined results, based on all seven studies, showed that breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype. In a subgroup analysis by race, breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype in Asians and Caucasians. Combined results, based on four studies, suggested that the STK15 V57I gene polymorphism was unlikely to be associated with breast cancer risk in either Asians or Caucasians.

Conclusions

The present meta-analysis suggests that the STK15 F31I polymorphism is a strong predisposing risk factor for breast cancer, but no significant association existed between the STK15 V57I polymorphism and the risk of breast cancer.