bluuebunny/crossref_metadata_2025 huggingface dataset:
Store-operated channels in the pulmonary circulation of high- and low-altitude neonatal lambs
Authors: Parrau Daniela , Ebensperger Germán , Herrera Emilio A. , Moraga Fernando , Riquelme Raquel A. , Ulloa César E. , Rojas Rodrigo T. , Silva Pablo , Hernandez Ismael , Ferrada Javiera , Diaz Marcela , Parer Julian T. , Cabello Gertrudis , Llanos Aníbal J. , Reyes Roberto V.
Published: February 2013

We determined whether store-operated channels (SOC) are involved in neonatal pulmonary artery function under conditions of acute and chronic hypoxia, using newborn sheep gestated and born either at high altitude (HA, 3,600 m) or low altitude (LA, 520 m). Cardiopulmonary variables were recorded in vivo, with and without SOC blockade by 2-aminoethyldiphenylborinate (2-APB), during basal or acute hypoxic conditions. 2-APB did not have effects on basal mean pulmonary arterial pressure (mPAP), cardiac output, systemic arterial blood pressure, or systemic vascular resistance in both groups of neonates. During acute hypoxia 2-APB reduced mPAP and pulmonary vascular resistance in LA and HA, but this reduction was greater in HA. In addition, isolated pulmonary arteries mounted in a wire myograph were assessed for vascular reactivity. HA arteries showed a greater relaxation and sensitivity to SOC blockers than LA arteries. The pulmonary expression of two SOC-forming subunits, TRPC4 and STIM1, was upregulated in HA. Taken together, our results show that SOC contribute to hypoxic pulmonary vasoconstriction in newborn sheep and that SOC are upregulated by chronic hypoxia. Therefore, SOC may contribute to the development of neonatal pulmonary hypertension. We propose SOC channels could be potential targets to treat neonatal pulmonary hypertension.
Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants
Authors: Papin James F. , Wolf Roman F. , Kosanke Stanley D. , Jenkins Justin D. , Moore Sara N. , Anderson Michael P. , Welliver Robert C.
Published: February 2013

Respiratory syncytial virus (RSV) infection of the lower respiratory tract is the leading cause of respiratory failure among infants in the United States of America and annually results in >300,000 deaths worldwide. Despite the importance of RSV, there is no licensed vaccine, and no specific form of therapy. This is largely due to the absence of an appropriate animal model for the evaluation of vaccines and therapeutic agents. We inoculated anesthetized infant (4 wk) baboons ( Papio anubis) with a human strain of RSV intranasally or intratracheally. Baboons were monitored daily for clinical changes. Anesthetized baboons were intubated at various intervals, and bronchoalveolar lavage (BAL) was performed for viral culture and determination of leukocyte counts. Sham-infected baboons served as controls. Necropsies were performed on infected baboons on days 1, 3, 5, 8, or 13 after inoculation, with pathological analysis and immunohistochemical staining of lung tissues to detect RSV antigen. Infected baboons developed tachypnea and reduced oxygenation peaking from 4 to 8 days after infection and persisting for ≥14 days. Virus was recoverable in BAL fluid up to 8 days following infection. Necropsy revealed intense interstitial pneumonia, sloughing of the bronchiolar epithelium, and obstruction of the bronchiolar lumen with inflammatory cells and sloughed epithelial cells. RSV antigen was identified in bronchiolar and alveolar epithelium. We conclude that RSV-infected infant baboons develop clinical and pathological changes that parallel those observed in human infants with RSV infection. The infant baboon represents a much-needed model for studying the pathogenesis of RSV infection and evaluating antivirals and vaccines.
Relationship between bradykinin-induced relaxation and endogenous epoxyeicosanoid synthesis in human bronchi
Authors: Tabet Yacine , Sirois Marco , Sirois Chantal , Rizcallah Edmond , Rousseau Éric
Published: February 2013

Epoxyeicosanoids (EETs) are produced by cytochrome P-450 epoxygenase; however, it is not yet known what triggers their endogenous production in epithelial cells. The relaxing effects of bradykinin are known to be related to endogenous production of epithelial-derived hyperpolarizing factors (EpDHF). Because of their effects on membrane potential, EETs have been reported to be EpDHF candidates (Benoit C, Renaudon B, Salvail D, Rousseau E. Am J Physiol Lung Cell Mol Physiol 280: L965–L973, 2001.). Thus, we hypothesized that bradykinin (BK) may stimulate endogenous EET production in human bronchi. To test this hypothesis, the relaxing and hyperpolarizing effects of BK and 14,15-EET were quantified on human bronchi, as well as the effects of various enzymatic inhibitors on these actions. One micromolar BK or 1 μM 14,15-EET induced a 45% relaxation on the tension induced by 30 nM U-46619 [a thromboxane-prostanoid (TP)-receptor agonist]. These BK-relaxing effects were reduced by 42% upon addition of 10 nM iberiotoxin [a large-conductance Ca2+-sensitive K+(BKCa) channel blocker], by 27% following addition of 3 μM 14,15-epoxyeicosa-5(Z)-enoic acid (an EET antagonist), and by 32% with 3 μM N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH, an epoxygenase inhibitor). Hence, BK and 14,15-EET display net hyperpolarizing effects on airway smooth muscle cells that are related to the activation of BKCachannels and ultimately yielding to relaxation. Data also indicate that 3 μM MS-PPOH reduced the hyperpolarizing effects of BK by 43%. Together, the present data support the current hypothesis suggesting a direct relationship between BK and the production of EET regioisomers. Because of its potent anti-inflammatory and relaxing properties, epoxyeicosanoid signaling may represent a promising target in asthma and chronic obstructive pulmonary disease.
High-intensity training induces EIB in rats through neuron transdifferentiation of adrenal medulla chromaffin cells
Authors: He Ruoxi , Feng Juntao , Xun Qiufen , Qin Qingwu , Hu Chengping
Published: February 2013

A high prevalence of exercise-induced bronchoconstriction (EIB) can be found in elite athletes, but the underlying mechanisms remain elusive. Airway responsiveness, NGF and epinephrine (EPI) levels, and chromaffin cell structure in high- (HiTr) and moderate-intensity training (MoTr) rats with or without ovalbumin (OVA) sensitization were measured in a total of 120 male Sprague-Dawley rats. The expression of NGF-associated genes in rat adrenal medulla was tested. Both HiTr and OVA intervention significantly increased airway resistance to aerosolized methacholine measured by whole body plethysmography. HiTr significantly increased inflammatory reaction in the lung with a major increase in peribronchial lymphocyte infiltration, whereas OVA significantly increased the infiltration of various inflammatory cells with an over 10-fold increase in eosinophil level in bronchoalveolar lavage. Both HiTr and OVA intervention upregulated circulating NGF level and peripherin level in adrenal medulla, but downregulated phenylethanolamine N-methyl transferase level in adrenal medulla and circulating EPI level. HiTr + OVA and HiTr + ExhEx (exhaustive exercise) interventions significantly enhanced most of the HiTr effects. The elevated NGF level was significantly associated with neuronal conversion of adrenal medulla chromaffin cells (AMCC). The levels of p-Erk1/2, JMJD3, and Mash1 were significantly increased, but the levels of p-p38 and p-JNK were significantly decreased in adrenal medulla in HiTr and OVA rats. Injection of NGF antiserum and moderate-intensity training reversed these changes observed in HiTr and/or OVA rats. Our study suggests that NGF may play a vital role in the pathogenesis of EIB by inducing neuron transdifferentiation of AMCC via MAPK pathways and subsequently decreasing circulating EPI.
The Influence of Flightless I on Toll-Like-Receptor-Mediated Inflammation in a Murine Model of Diabetic Wound Healing
Authors: Ruzehaji Nadira , Mills Stuart J. , Melville Elizabeth , Arkell Ruth , Fitridge Robert , Cowin Allison J.
Published: February 2013

Impaired wound healing and ulceration represent a serious complication of both type 1 and type 2 diabetes. Cytoskeletal protein Flightless I (Flii) is an important inhibitor of wound repair, and reduced Flii gene expression in fibroblasts increased migration, proliferation, and adhesion. As such it has the ability to influence all phases of wound healing including inflammation, remodelling and angiogenesis. Flii has the potential to modulate inflammation through its interaction with MyD88 which it an adaptor protein for TLR4. To assess the effect of Flii on the inflammatory response of diabetic wounds, we used a murine model of streptozocin-induced diabetes and Flii genetic mice. Increased levels of Flii were detected in Flii transgenic murine wounds resulting in impaired healing which was exacerbated when diabetes was induced. When Flii levels were reduced in diabetic wounds of Flii-deficient mice, healing was improved and decreased levels of TLR4 were observed. In contrast, increasing the level of Flii in diabetic mouse wounds led to increased TLR4 and NF-κB production. Treatment of murine diabetic wounds with neutralising antibodies to Flii led to an improvement in healing with decreased expression of TLR4. Decreasing the level of Flii in diabetic wounds may therefore reduce the inflammatory response and improve healing.
The Method of Fischer-Riesz Equations for Elliptic Boundary Value Problems
Authors: Alsaedy A. , Tarkhanov N.
Published: February 2013

We develop the method of Fischer-Riesz equations for general boundary value problems elliptic in the sense of Douglis-Nirenberg. To this end we reduce them to a boundary problem for a (possibly overdetermined) first-order system whose classical symbol has a left inverse. For such a problem there is a uniquely determined boundary value problem which is adjoint to the given one with respect to the Green formula. On using a well-elaborated theory of approximation by solutions of the adjoint problem, we find the Cauchy data of solutions of our problem.
Two Classifiers Based on Serum Peptide Pattern for Prediction of HBV-Induced Liver Cirrhosis Using MALDI-TOF MS
Authors: Cao Yuan , He Kun , Cheng Ming , Si Hai-Yan , Zhang He-Lin , Song Wei , Li Ai-Ling , Hu Cheng-Jin , Wang Na
Published: February 2013

Chronic infection with hepatitis B virus (HBV) is associated with the majority of cases of liver cirrhosis (LC) in China. Although liver biopsy is the reference method for evaluation of cirrhosis, it is an invasive procedure with inherent risk. The aim of this study is to discover novel noninvasive specific serum biomarkers for the diagnosis of HBV-induced LC. We performed bead fractionation/MALDI-TOF MS analysis on sera from patients with LC. Thirteen feature peaks which had optimal discriminatory performance were obtained by using support-vector-machine-(SVM-) based strategy. Based on the previous results, five supervised machine learning methods were employed to construct classifiers that discriminated proteomic spectra of patients with HBV-induced LC from those of controls. Here, we describe two novel methods for prediction of HBV-induced LC, termed LC-NB and LC-MLP, respectively. We obtained a sensitivity of 90.9%, a specificity of 94.9%, and overall accuracy of 93.8% on an independent test set. Comparisons with the existing methods showed that LC-NB and LC-MLP held better accuracy. Our study suggests that potential serum biomarkers can be determined for discriminating LC and non-LC cohorts by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. These two classifiers could be used for clinical practice in HBV-induced LC assessment.
The Impact of the Rotor Slot Number on the Behaviour of the Induction Motor
Authors: Gyftakis Konstantinos N. , Kappatou Joya
Published: February 2013

The impact of the rotor slot number selection on the induction motors is investigated. Firstly, analytical equations will reveal the spatial harmonic index of the air gap magnetic flux density, connected to the geometrical features and the saturation of the induction motor. Then, six motors with different rotor slot numbers are simulated and studied with FEM. The stator is identical in all motors. The motors are examined under time-harmonic analysis at starting and at 1440 rpm. Their electromagnetic characteristics, such as electromagnetic torque, stator current, and magnetic flux density, are extracted and compared to each other. The analysis will reveal that the proper rotor slot number selection has a strong impact on the induction motor performance.
CD44-Positive Cancer Stem Cells Expressing Cellular Prion Protein Contribute to Metastatic Capacity in Colorectal Cancer
Authors: Du Lei , Rao Guanhua , Wang Hongyi , Li Baowei , Tian Weili , Cui Jiantao , He Leya , Laffin Brian , Tian Xiuyun , Hao Chunyi , Liu Hongmin , Sun Xin , Zhu Yushan , Tang Dean G. , Mehrpour Maryam , Lu Youyong , Chen Quan
Published: February 2013

Cancer stem cells are implicated in tumor progression, metastasis, and recurrence, although the exact mechanisms remain poorly understood. Here, we show that the expression of cellular prion protein (PrPc, PRNP) is positively correlated with an increased risk of metastasis in colorectal cancer. PrPc defines a subpopulation of CD44-positive cancer stem cells that contributes to metastatic capacity. PrPc+CD44+ colorectal cancer stem cells displayed high liver metastatic capability, unlike PrPc−CD44+ stem cells, that was inhibited by RNAi-mediated attenuation of PrPc. Notably, administration of PrPc monoclonal antibodies significantly inhibited tumorigenicity and metastasis of colorectal cancer stem cells in mouse models of orthotopic metastasis. PrPc promoted epithelial to mesenchymal transition (EMT) via the ERK2 (MAPK1) pathway, thereby conferring high metastatic capacity. Our findings reveal the function of PrPc in regulating EMT in cancer stem cells, and they identify PrPc as candidate therapeutic target in metastatic colorectal cancer. Cancer Res; 73(8); 2682–94. ©2013 AACR.
CSF1R Signaling Blockade Stanches Tumor-Infiltrating Myeloid Cells and Improves the Efficacy of Radiotherapy in Prostate Cancer
Authors: Xu Jingying , Escamilla Jemima , Mok Stephen , David John , Priceman Saul , West Brian , Bollag Gideon , McBride William , Wu Lily
Published: February 2013

Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIM), including CD11b (ITGAM)+F4/80 (EMR1)+ tumor-associated macrophages (TAM), and CD11b+Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSC), respond to cancer-related stresses and play critical roles in promoting tumor angiogenesis, tissue remodeling, and immunosuppression. In this report, we used a prostate cancer model to investigate the effects of irradiation on TAMs and MDSCs in tumor-bearing animals. Unexpectedly, when primary tumor sites were irradiated, we observed a systemic increase of MDSCs in spleen, lung, lymph nodes, and peripheral blood. Cytokine analysis showed that the macrophage colony-stimulating factor CSF1 increased by two-fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy. Mechanistic investigations revealed the recruitment of the DNA damage-induced kinase ABL1 into cell nuclei where it bound the CSF1 gene promoter and enhanced CSF1 gene transcription. When added to radiotherapy, a selective inhibitor of CSF1R suppressed tumor growth more effectively than irradiation alone. Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of TIMs that can limit the efficacy of radiotherapy. Furthermore, they suggest that CSF1 inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes. Cancer Res; 73(9); 2782–94. ©2013 AACR.
Chemotherapy Acts as an Adjuvant to Convert the Tumor Microenvironment into a Highly Permissive State for Vaccination-Induced Antitumor Immunity
Authors: Kang Tae Heung , Mao Chih-Ping , Lee Sung Yong , Chen Alexander , Lee Ji-Hyun , Kim Tae Woo , Alvarez Ronald D. , Roden Richard B.S. , Pardoll Drew , Hung Chien-Fu , Wu T.-C.
Published: February 2013

Multiple classes of pharmacologic agents have the potential to induce the expression and release of proinflammatory factors from dying tumor cells. As a result, these cells can in theory elicit an immune response through various defined mechanisms to permanently eradicate disseminated cancer. However, the impact of chemotherapy on the tumor-specific immune response in the context of the tumor microenvironment is largely unknown. Within the tumor microenvironment, the immune response promoted by chemotherapy is antagonized by an immune-suppressive milieu, and the balance of these opposing forces dictates the clinical course of disease. Here, we report that high antigen exposure within the tumor microenvironment following chemotherapy is sufficient to skew this balance in favor of a productive immune response. In elevating antigen exposure, chemotherapy can achieve long-term control of tumor progression without the need of an additional adjuvant. We found that chemotherapy initiated this phenomenon in the tumor microenvironment through an accumulation of dendritic cells, which stimulated CD8+ T cells and the type I IFN pathway. From this conceptual base, we developed a simple approach to cancer therapy combining chemotherapy and vaccination that may be widely applicable. Cancer Res; 73(8); 2493–504. ©2013 AACR.
Acrylamide Hemoglobin Adduct Levels and Ovarian Cancer Risk: A Nested Case–Control Study
Authors: Xie Jing , Terry Kathryn L. , Poole Elizabeth M. , Wilson Kathryn M. , Rosner Bernard A. , Willett Walter C. , Vesper Hubert W. , Tworoger Shelley S.
Published: February 2013

Background: Acrylamide is a probable human carcinogen formed during cooking of starchy foods. Two large prospective cohort studies of dietary acrylamide intake and ovarian cancer risk observed a positive association, although two other studies reported no association.

Methods: We measured acrylamide exposure using red blood cell acrylamide and glycidamide hemoglobin adducts among women in two large prospective cohorts: the Nurses' Health Study and Nurses' Health Study II. Between blood collection and 2010, we identified 263 incident cases of epithelial ovarian cancer, matching two controls per case. We used logistic regression models to examine the association between acrylamide exposure and ovarian cancer risk, adjusting for matching factors, family history of ovarian cancer, tubal ligation, oral contraceptive use, body mass index, parity, alcohol intake, smoking, physical activity, and caffeine intake.

Results: The multivariate-adjusted relative risk (RR) of ovarian cancer comparing the highest versus lowest tertile of total acrylamide adducts was 0.79 (95% CI, 0.50–1.24, P trend = 0.08). The comparable RR of ovarian cancer among non-smokers at blood draw was 0.85 (95% CI, 0.57–1.27, P trend = 0.14). The association did not differ by tumor histology (serous invasive versus not), P for heterogeneity = 0.86. Individual adduct types (acrylamide or glycidamide) were not associated with risk.

Conclusions: We observed no evidence that acrylamide exposure as measured by adducts to hemoglobin is associated with an increased risk of ovarian cancer.

Impact: Our finding indicates that acrylamide intake may not increase risk of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 22(4); 653–60. ©2013 AACR.
Modulation of p53 C-Terminal Acetylation by mdm2, p14ARF, and Cytoplasmic SirT2
Authors: van Leeuwen Ingeborg M.M. , Higgins Maureen , Campbell Johanna , McCarthy Anna R. , Sachweh Marijke C.C. , Navarro Ana Marín , Laín Sonia
Published: February 2013

Acetylation of C-terminal lysine residues in the p53 tumor suppressor is associated with increased stability and transcription factor activity. The function, protein level, and acetylation of p53 are downregulated by mdm2, which in its turn is inhibited by the p14ARF tumor suppressor. Here, we show that p14ARF increases the level of p53 acetylated at lysine 382 in a nuclear chromatin-rich fraction. Unexpectedly, this accumulation of p53AcK382 is dramatically enhanced in the presence of ectopic mdm2. In light of these observations, we propose that p14ARF increases the binding of p53–mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. Supporting this notion, we show that p53AcK382 can be deacetylated in the cytoplasm and that sirtuin SirT2 catalyzes this reaction. These results help understand why inhibition of both SirT1 and SirT2 is needed to achieve effective activation of p53 by small-molecule sirtuin inhibitors. Mol Cancer Ther; 12(4); 471–80. ©2013 AACR.
Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives
Authors: Dieci Maria Vittoria , Arnedos Monica , Andre Fabrice , Soria Jean Charles
Published: February 2013

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.

Significance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies. Cancer Discov; 3(3); 264–79. ©2012 AACR.
Chorioamnionitis Caused by Listeria monocytogenes: A Case Report of Ultrasound Features of Fetal Infection
Authors: Hasbún Jorge , Sepúlveda-Martínez Alvaro , Haye María T. , Astudillo Julio , Parra-Cordero Mauro
Published: February 2013

Maternal listeriosis is often associated with mild symptoms for the patient, but fetal infection can lead to severe adverse perinatal outcome. The most described antenatal symptoms are reduced fetal movements and an abnormal fetal heart rate trace. We present a case of fetal listeriosis suspected by ultrasound findings of fetal gastrointestinal compromise, neonatal diagnosis and outcome.
Word List Learning in Patients with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy
Authors: Vanhanen Matti , Hakola Panu , Ilonen Tuula , Tiihonen Jari
Published: February 2013

Background/Aims: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare hereditary disease that is characterized by a combination of progressive presenile dementia and sclerosing leukoencephalopathy with bone cysts. No quantitative information on verbal memory functioning in PLOSL patients compared with control subjects is available. Methods: 23 patients with PLOSL and 23 control subjects were examined with a version of the 10-word list-learning task. Learning curves were compared between the patients and the matched control subjects. Results: Compared with the control subjects, PLOSL patients with moderate or severe dementia were impaired in both learning trials and delayed recall on the 10-word list-learning test. Conclusion: Progressive degeneration of brain structures affecting the hippocampus and the medial temporal lobe with advanced PLOSL disease contributes to an inefficient verbal learning process.
Advanced Hepatocellular Carcinoma in Adolescence Associated with Congenital Cholestasis: A Case Description
Authors: Ladekarl Morten , Villadsen Gerda Elisabeth , Rudbeck Anne Roed , Aagenæs Øystein , Nielsen Jens Erik , Hamilton-Dutoit Stephen , Nordsmark Marianne
Published: February 2013

This case describes the clinical course and treatment of a 17-year-old male patient with advanced hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. The disease was thought to be caused by a congenital cholestatic syndrome associated with intermittent oedema in childhood, resembling the rare Aagenaes syndrome. Treatment choices in advanced HCC arising in adolescence are discussed.
Exome Sequencing and Genome-Wide Linkage Analysis in 17 Families Illustrate the Complex Contribution of TTN Truncating Variants to Dilated Cardiomyopathy
Authors: Norton Nadine , Li Duanxiang , Rampersaud Evadnie , Morales Ana , Martin Eden R. , Zuchner Stephan , Guo Shengru , Gonzalez Michael , Hedges Dale J. , Robertson Peggy D. , Krumm Niklas , Nickerson Deborah A. , Hershberger Ray E.
Published: February 2013

Background—

Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes.
TTN
truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases.

Methods and Results—

We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the
TTN
region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6
TTN
truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating
TTN
variants did not segregate with DCM. Nucleotide diversity at the
TTN
locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of
TTN
truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74.

Conclusions—

These data suggest that
TTN
truncating variants contribute to DCM cause. However, the lack of segregation of all identified
TTN
truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.
A Blood-Based Gene Expression Test for Obstructive Coronary Artery Disease Tested in Symptomatic Nondiabetic Patients Referred for Myocardial Perfusion Imaging The COMPASS Study
Authors: Thomas Gregory S. , Voros Szilard , McPherson John A. , Lansky Alexandra J. , Winn Mary E. , Bateman Timothy M. , Elashoff Michael R. , Lieu Hsiao D. , Johnson Andrea M. , Daniels Susan E. , Ladapo Joseph A. , Phelps Charles E. , Douglas Pamela S. , Rosenberg Steven
Published: February 2013

Background—

Obstructive coronary artery disease diagnosis in symptomatic patients often involves noninvasive testing before invasive coronary angiography. A blood-based gene expression score (GES) was previously validated in nondiabetic patients referred for invasive coronary angiography but not in symptomatic patients referred for myocardial perfusion imaging (MPI).

Methods and Results—

This prospective, multicenter study obtained peripheral blood samples for GES before MPI in 537 consecutive patients. Patients with abnormal MPI usually underwent invasive coronary angiography; all others had research coronary computed tomographic angiography, with core laboratories defining coronary anatomy. A total of 431 patients completed GES, coronary imaging (invasive coronary angiography or computed tomographic angiography), and MPI. Mean age was 56±10 years (48% women). The prespecified primary end point was GES receiver-operating characteristics analysis to discriminate ≥50% stenosis (15% prevalence by core laboratory analysis). Area under the receiver-operating characteristics curve for GES was 0.79 (95% confidence interval, 0.73–0.84;
P
<0.001), with sensitivity, specificity, and negative predictive value of 89%, 52%, and 96%, respectively, at a prespecified threshold of ≤15 with 46% of patients below this score. The GES outperformed clinical factors by receiver-operating characteristics and reclassification analysis and showed significant correlation with maximum percent stenosis. Six-month follow-up on 97% of patients showed that 27 of 28 patients with adverse cardiovascular events or revascularization had GES >15. Site and core-laboratory MPI had areas under the curve of 0.59 and 0.63, respectively, significantly less than GES.

Conclusions—

GES has high sensitivity and negative predictive value for obstructive coronary artery disease. In this population clinically referred for MPI, the GES outperformed clinical factors and MPI.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01117506.
Yield and Diagnostic Value of Stress Myocardial Perfusion Imaging in Patients Without Known Coronary Artery Disease Presenting With Syncope
Authors: AlJaroudi Wael A. , Alraies M. Chadi , Wazni Oussama , Cerqueira Manuel D. , Jaber Wael A.
Published: February 2013

Background—

American College of Cardiology/American Heart Association appropriate use criteria recommend performing stress myocardial perfusion imaging (MPI) for intermediate- to high-risk patients presenting with syncope but not for low-risk patients. However, there are limited data to support these recommendations. We investigated the yield of stress MPI for the evaluation of syncope in patients at risk but without known coronary artery disease.

Methods and Results—

Using the Cleveland Clinic Institutional Review Board–approved MPI database, we identified consecutive patients without known coronary artery disease who underwent stress MPI between 2006 and 2012 for diagnostic workup of syncope. Patients were stratified into low-, intermediate-, and high-risk groups using the Framingham risk score. For patients with abnormal MPI, left heart catheterization were reviewed if performed. There were 700 patients (mean age, 62±15 years; 55% female) who had undergone stress MPI for syncope; 659 patients (94%) had normal perfusion. Of the 41 patients with abnormal MPI, 18 had left heart catheterization (9 were false-positive); there were 23 remaining patients with abnormal MPI (16 having moderate to severe perfusion defect size) but who did not have a left-side angiogram and could have undiagnosed significant coronary artery disease. The diagnostic yield of stress MPI was similarly low among all cardiovascular risk categories.

Conclusions—

Stress MPI for evaluation of syncope in patients without known coronary artery disease has a low-diagnostic yield among all risk categories; thus, reaffirmation and revision of the appropriateness criteria should be considered.
Relationship of Delayed Enhancement by Magnetic Resonance to Myocardial Perfusion by Positron Emission Tomography in Hypertrophic Cardiomyopathy
Authors: Bravo Paco E. , Zimmerman Stefan L. , Luo Hong-Chang , Pozios Iraklis , Rajaram Mahadevan , Pinheiro Aurélio , Steenbergen Charles , Kamel Ihab R. , Wahl Richard L. , Bluemke David A. , Bengel Frank M. , Abraham M. Roselle , Abraham Theodore P.
Published: February 2013

Background—

Presence of delayed enhancement (DE) on cardiac magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy. We investigated the relationship between DE on CMR and myocardial ischemia in hypertrophic cardiomyopathy.

Methods and Results—

Hypertrophic cardiomyopathy patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography to quantify myocardial blood flow and coronary flow reserve. The summed difference score for regional myocardial perfusion was also assessed. Patients in the DE group (n=35) had greater left ventricular wall thickness (2.09±0.44 versus 1.78±0.34 cm;
P
=0.03). Stress myocardial blood flow (2.25±0.46 versus 1.78±0.43 mL/min per gram;
P
=0.01) and coronary flow reserve (2.78±0.32 versus 2.01±0.52;
P
<0.001) were significantly lower in DE-positive patients. Summed difference score (7.3±6.6 versus 0.9±1.4;
P
<0.0001) was significantly higher in patients with DE. A coronary flow reserve <2.00 was seen in 18 patients (51%) with DE but in none of the DE-negative patients (
P
<0.0001). CMR and positron emission tomography showed visually concordant DE and regional myocardial perfusion abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal regional myocardial perfusion, and 3 DE-negative patients had (apical) regional myocardial perfusion abnormalities.

Conclusions—

We found a close relationship between DE by CMR and microvascular function in most of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in hypertrophic cardiomyopathy patients.
β
2
-Adrenergic Receptor Stimulation Improves Endothelial Progenitor Cell–Mediated Ischemic Neoangiogenesis
Authors: Galasso Gennaro , De Rosa Roberta , Ciccarelli Michele , Sorriento Daniela , Del Giudice Carmine , Strisciuglio Teresa , De Biase Chiara , Luciano Rossella , Piccolo Raffaele , Pierri Adele , Di Gioia Giuseppe , Prevete Nella , Trimarco Bruno , Piscione Federico , Iaccarino Guido
Published: February 2013

Rationale:

Endothelial progenitor cells (EPCs) are present in the systemic circulation and home to sites of ischemic injury where they promote neoangiogenesis. β
2
-Adrenergic receptor (β
2
AR) plays a critical role in vascular tone regulation and neoangiogenesis.

Objective:

We aimed to evaluate the role of β
2
AR on EPCs’ function.

Methods and Results:

We firstly performed in vitro analysis showing the expression of β
2
AR on EPCs. Stimulation of wild-type EPCs with β-agonist isoproterenol induced a significant increase of Flk-1 expression on EPCs as assessed by fluorescence-activated cell sorter. Moreover, β
2
AR stimulation induced a significant increase of cell proliferation, improved the EPCs migratory activity, and enhanced the EPCs’ ability to promote endothelial cell network formation in vitro. Then, we performed in vivo studies in animals model of hindlimb ischemia. Consistent with our in vitro results, in vivo EPCs’ treatment resulted in an improvement of impaired angiogenic phenotype in β
2
AR KO mice after induction of ischemia, whereas no significant amelioration was observed when β
2
AR knock out (KO) EPCs were injected. Indeed, wild-type–derived EPCs’ injection resulted in a significantly higher blood flow restoration in ischemic hindlimb and higher capillaries density at histological analysis as compared with not treated or β
2
AR KO EPC-treated mice.

Conclusions:

The present study provides the first evidence that EPCs express a functional β
2
AR. Moreover, β
2
AR stimulation results in EPCs proliferation, migration, and differentiation, enhancing their angiogenic ability, both in vitro and in vivo, leading to an improved response to ischemic injury in animal models of hindlimb ischemia.
Bacterial Signatures in Thrombus Aspirates of Patients With Myocardial Infarction
Authors: Pessi Tanja , Karhunen Vesa , Karjalainen Pasi P. , Ylitalo Antti , Airaksinen Juhani K. , Niemi Matti , Pietila Mikko , Lounatmaa Kari , Haapaniemi Teppo , Lehtimäki Terho , Laaksonen Reijo , Karhunen Pekka J. , Mikkelsson Jussi
Published: February 2013

Background—

Infectious agents, especially bacteria and their components originating from the oral cavity or respiratory tract, have been suggested to contribute to inflammation in the coronary plaque, leading to rupture and the subsequent development of coronary thrombus. We aimed to measure bacterial DNA in thrombus aspirates of patients with ST-segment–elevation myocardial infarction and to check for a possible association between bacteria findings and oral pathology in the same cohort.

Methods and Results—

Thrombus aspirates and arterial blood from patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention (n=101; 76% male; mean age, 63.3 years) were analyzed with real-time quantitative polymerase chain reaction with specific primers and probes to detect bacterial DNA from several oral species and
Chlamydia pneumoniae.
The median value for the total amount of bacterial DNA in thrombi was 16 times higher than that found in their blood samples. Bacterial DNA typical for endodontic infection, mainly oral viridans streptococci, was measured in 78.2% of thrombi, and periodontal pathogens were measured in 34.7%. Bacteria-like structures were detected by transmission electron microscopy in all 9 thrombus samples analyzed; whole bacteria were detected in 3 of 9 cases. Monocyte/macrophage markers for bacteria recognition (CD14) and inflammation (CD68) were detected in thrombi (8 of 8) by immunohistochemistry. Among the subgroup of 30 patients with myocardial infarction examined by panoramic tomography, a significant association between the presence of periapical abscesses and oral viridans streptococci DNA–positive thrombi was found (odds ratio, 13.2; 95% confidence interval, 2.11–82.5;
P
=0.004).

Conclusions—

Dental infection and oral bacteria, especially viridans streptococci, may be associated with the development of acute coronary thrombosis.
Regulation of Conflict of Laws in the United Arab Emirates
Authors: Elhawary Ahmed Mohmed
Published: February 2013

Abstract

This article aims at giving an outline of the regulation of conflict of laws contained in the Emirati Code of Civil Transactions, while adopting a comparative approach to Private international law rules in other Arab as well as Western countries. The article is divided into two main parts. The first consists of an overview of the regulation of conflict of laws in the UAE, addressing the origins, method and scope of the regulation. The second contains an analysis of the conflict of law provisions in the Emirati law, addressing the conceptual approach, general rules and special rules of conflict of laws.
Triple Ṭalāq in One Session: An Analysis of the Opinions of Classical, Medieval, and Modern Muslim Jurists under Islamic Law
Authors: Munir Muhammad
Published: February 2013

Abstract

This work analyzes one of the hottest and most tricky issues of the Muslim Family Law, i.e., whether in cases of divorce (ṭalāq), three repudiations spoken in one session equal one or three repudiations. There had been no disagreement regarding this issue among the four Sunni Schools of Jurisprudence until the end of the 7th century Hijrah when Ibn Taimiyah and Ibn al-Qayim challenged the position of the ğamhūr (majority of Islamic scholars). Before them only the Shīʿa and the Ẓāhirites had treated three pronouncements in one session as one. The ğamhūr has given very strong arguments in support of their point of view, whereas Ibn Taimiyah and Ibn al-Qayim have advanced very weak arguments in support of their view. The Shīʿa Imāmiyah School of Thought holds two opinions. According to one view, three ṭalāqs in one session amount to one, while the second point of view holds that three repudiations in one session do not amount to any ṭalāq.
A Critique of Intellectual Property Research
Authors: Nesheiwat Faris K.
Published: February 2013

Abstract

This article is first of its kind in that it provides a survey of intellectual property (IP) literature and suggestions for future research on IP issues for Arab countries using Jordan as a case study. A review of IP literature, which identifies how international scholars perceived the effect of harmonised IP standards on access to common knowledge, is followed by a review of literature pertaining to Jordan. Areas of controversy and questions are identified. Finally, an outline of outstanding questions and gaps in the existing IP literature on Jordan is offered as a template for the creation of future research objectives.
Imposing Zakāt on Legal Entities and its Applications in Islamic Financial Institutions
Authors: Noor Azman Mohd , Haron Muhamad Nasir
Published: February 2013

Abstract

Zakāt (obligation to donate a certain proportion of wealth each year to charitable causes) is imposed on particular assets owned by Muslims. However, as there has been a tremendous development in trade locally and globally, and with the growth of Islamic banking and finance and the increased demand for Sharīʿah-compliant services and supplies, a number of contemporary Muslim scholars have suggested that zakāt be imposed on legal entities. This implies that the calculation is based on the company’s net asset value. Based on this proposition, one need not know the identities of the shareholders: i.e., whether they are government-linked companies, foreign parent companies, individual proprietors, Muslims or non-Muslims. This article aims to examine the validity of imposing zakāt on legal entities from the Sharīʿah’s perspective.
Two Surprising Aspects of Islamic Saudi Liberalism in Public and Private Law
Authors: Koraytem Tabet
Published: February 2013

Abstract

Saudi Arabia is often defined as a country where the rule of law is challenged by archaism with reference to Islamic criminal punishments or by anarchy with reference to its pluralism combining Western and Islamic laws (and sometimes tribal customs). Both opinions are wrong thanks to two fundamental rules of Ḥanbalism (the Kingdom’s Islamic School of Law). The first rule says: “No obedience to a creature in the disobedience of the Creator”, and the second says: “The Rule in profane activities (muʿāmalāt) is lawfulness until one indication from the Sharīʿah Guides [i.e., Qurʾān and the Prophet’s sayings or Ḥadīth] dismisses it from [the application of] this Rule”. Thanks to these rules and the way in which they have been developed in public and private law, we will see that Saudi law finally appears less contradictory than laws in other Arab countries, and therefore less challenging to the rule of law.
Weighing Reasons
Authors: Kearns Stephen , Star Daniel
Published: February 2013

This paper is a response to two sets of published criticisms of the 'Reasons as Evidence’ thesis concerning normative reasons, proposed and defended in earlier papers. According to this thesis, a fact is a normative reason for an agent to Φ just in case this fact is evidence that this agent ought to Φ. John Broome and John Brunero have presented a number of challenging criticisms of this thesis which focus, for the most part, on problems that it appears to confront when it comes to the topic of the weighing of reasons. Our paper responds to all of the criticisms that these critics have provided, shedding fresh light on this interesting topic in the process.
Subordination and Objectification
Authors: Maitra Ishani
Published: February 2013

This essay discusses Rae Langton’s recent collection of essays, Sexual Solipsism: Philosophical Essays on Pornography and Objectification. After introducing some of the major themes of the collection, I raise questions about two of the central concepts in the book. The first question has to do with Langton’s notion of subordination. I ask why she takes pornography to be a subordinating speech act, rather than a subordinating practice, and argue that the latter view has several advantages. The remaining questions have to do with Langton’s notion of objectification. Looking first at the moral dimension of objectification, I raise some concerns about Langton’s strategy for distinguishing instances of objectification from non-instances. Then, turning to Langton’s discussion of the epistemic dimension of objectification, I ask under what circumstances certain belief-forming mechanisms, such as desire-driven projection, are objectifying, on her view.
Muslim Motives for Conquering the Byzantine Empire 634–720: The Evidence from Eastern Christian Sources
Authors: Whealey Alice
Published: February 2013

This article examines the motives of the earliest Muslim attacks on the Byzantine Empire in the seventh and eighth centuries by examining the earliest Christian (Byzantine) and Muslim sources that describe these attacks. The article assesses the strengths of these accounts and culls from them the possible religious motivations behind the first Muslim attacks on the Byzantine Empire. One question particularly addressed is the goal of the Muslim attacks: to bring down the Byzantine Empire entirely, or merely to wrest from it Palestine and the surrounding territories that were of significance to the Muslim invaders. In either case, Whealey argues that the motives were religious in nature.
Reassessment, Unification, and Enlargement of the Sources of Slavic Pre-Christian Religion
Authors: Santos Marinas Enrique
Published: February 2013

This article discusses the texts included in a new compilation entitled Sources of Slavic Pre-Christian Religion produced by scholars at the University Complutense in Madrid, Spain. This compilation responds to the challenges of previous historiographical difficulties inherent in the indirect sources available and in the previous incomplete collections of sources. Thus, this is the first work to consolidate all known sources on pagan practices of all the Slavic peoples—East, West, and South—and to include all known provenances of sources, including Latin, Greek, Slavonic, Old Icelandic, Arabic, and Persian. The resulting compilation reveals a more complex and sophisticated pre-Christian religion than previously assumed. In this article, Santos Marinas explains the reasoning behind the selection of the texts for this compilation and offers notable examples of some of the included sources on Slavic pre-Christian practices, particularly from Byzantine and Latin texts, that provide new insights into the sacred practices of the early medieval Slavic peripheries of Christendom.
Dressing a Wolf in Sheep’s Clothing: Toward Understanding the Composition of the Life of Alexander Nevskii
Authors: Ostrowski Donald
Published: February 2013

The Life of Alexander Nevskii is written in two styles: a hagiographic style and a secular style. Scholarly views are divided over whether the Life was written by one person in two different styles or by two persons, either a hagiographic writer and secular editor or a secular writer and hagiographic editor. The present article hypothesizes that the Life was probably written initially in a secular style as a military tale (the “wolf”) in the second half of the thirteenth century. This military tale was the foundational layer for the subsequent writing of the Life. Some time later, probably in the second half of the fourteenth century (before 1377), an ecclesiastical redactor edited the text of the military tale adding phrases in a hagiographic style (the “sheep’s clothing”), thus creating a chronicle tale about the life of Alexander Nevskii. In the second half of the fifteenth century, a further editing took place as anti-Tatar interpolations were added, thus creating the First Redaction of the Life of Alexander Nevskii. Following a text critical analysis, this article reconstructs the First Redaction of the Life, in which the two styles are delineated. Then the article provides a translation into English of the hypothetical version of the non-extant military tale about Alexander Nevskii.