bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes mellitus and carotid artery plaques exhibiting high-intensity signals on MR angiography are related to increased platelet reactivity after carotid artery stenting
Authors: Tsujimoto Masanori , Enomoto Yukiko , Kokuzawa Jouji , Iwama Toru
Published: July 2016

Background

Increased platelet reactivity after carotid artery stenting (CAS) may cause thromboembolic complications.

Objective

This study aimed to investigate the incidence of increased platelet reactivity after CAS and to determine the factors related to it.

Methods

Patients who underwent CAS were recruited prospectively. They received pre-procedural antiplatelet therapy comprising some combination of aspirin (100 mg/day), clopidogrel (75 mg/day), and/or cilostazol (200 mg/day) for a minimum of 7 days. ADP- and collagen-induced platelet aggregation were measured before and 4 days after CAS. Changes in platelet reactivity were reported as changes in the categorized platelet reactivity grade based on the effective dose 50%. Clinical characteristics of patients with and without increased platelet reactivity were compared.

Results

Among 38 consecutive patients who underwent CAS, 18 (47%) exhibited increased platelet reactivity. Diabetes mellitus (OR 15.0; 95% CI 2.1 to 106.5; p=0.007) and carotid artery plaques exhibiting high-intensity signals (HIS) on time-of-flight MR angiography (TOF-MRA) (OR 25.2; 95% CI 2.0 to 316.2; p=0.013) were independently associated with increased platelet reactivity in a multivariate analysis.

Conclusions

Increased platelet reactivity occurred in nearly half of the studied patients subjected to CAS and was independently associated with diabetes mellitus and carotid artery plaques exhibiting HIS on TOF-MRA.
Timing, growth and structure of a reactivated basin-bounding fault
Authors: Worthington Robert P. , Walsh John J.
Published: July 2016

Until recently, there have been relatively few natural examples of basement fault reactivation, demonstrating convincing hard-linkage to underlying structure and a well-constrained three-dimensional (3D) geometry and timing of reactivation. Applying various quantitative techniques to high quality 3D seismic data, we describe the Cenozoic structure and growth of a reactivated Mesozoic normal fault in the NW Porcupine Basin, west of Ireland. We demonstrate a previously unrecognized period of Mid–Late Eocene extensional reactivation with a tectonic, rather than the previously suggested compactional, origin. East–west extensional reactivation of a north–south- to NE–SW-trending basement fault led to the development of a highly segmented and systematically stepping fault array in the Cenozoic cover. A clear relationship between the displacement of hanging-wall antithetic faults and displacement along the main synthetic system is attributed to the antithetics primarily accommodating strain associated with a hanging-wall rollover anticline. Our study shows that displacement analysis provides an excellent basis for defining the kinematics of basement fault reactivation, and the importance of fault segmentation and twisting during the upwards propagation of reactivated faults. Fault timing corresponds to a period of rapid differential subsidence, the magnitude of which is too large to be attributable solely to extensional reactivation of basement faults.
Pericapillary basement membrane thickening in human skeletal muscles
Authors: Baum Oliver , Bigler Marius
Published: July 2016

The basement membrane (BM) surrounding capillaries in skeletal muscles varies physiologically in thickness according to age, physical fitness, and anatomical site in humans. Furthermore, the pericapillary BM thickness (CBMT) increases pathophysiologically during several common disease states, including peripheral arterial disease and diabetes mellitus. This review on CBM thickening in human skeletal muscles is two pronged. First, it addresses the advantages/disadvantages of grid- and tablet-based measuring and morphometric techniques that are implemented to assess the CBMT on transmission electron micrographs. Second, it deals with the biology of CBM thickening in skeletal muscles, particularly its possible causes, molecular mechanisms, and functional impact. CBM thickening is triggered by several physical factors, including diabetes-associated glycation, hydrostatic pressure, and inflammation. Increased biosynthesis of type IV collagen expression or repetitive cycles in pericyte or endothelial cell degeneration/proliferation appear to be most critical for CBM accumulation. A thickened CBM obviously poses a greater barrier for diffusion, lowers the microvascular elasticity, and impedes transcytosis of inflammatory cells. Our own morphometric data reveal the CBM enlargement to be not accompanied by the pericyte coverage. Owing to an overlap or redundancy in the capillary supply, CBM thickening in skeletal muscles might not be such a devastating occurrence as in organs with endarterial circulation (e.g., kidney and retina). CBM growth in skeletal muscles can be reversed by training or administration of antidiabetic drugs. In conclusion, CBM thickening in skeletal muscles is a microvascular remodeling process by which metabolic, hemodynamic, and inflammatory forces are integrated together and which could play a hitherto underestimated role in etiology/progression of human diseases.
Endogenous nitric oxide derived from NOS I or II in thoracic spinal cord exerts opposing tonic modulation on sympathetic vasomotor tone via disparate mechanisms in anesthetized rats
Authors: Poon Yan-Yuen , Tsai Ching-Yi , Cheng Chung-Dar , Chang Alice Y. W. , Chan Samuel H. H.
Published: July 2016

The sympathetic preganglionic neurons (SPN) in the thoracic spinal cord regulate vasomotor tone via norepinephrine released from sympathetic terminals and adrenal medulla. We assessed the hypothesis that nitric oxide synthase I (NOS I)- and NOS II-derived nitric oxide (NO) in the thoracic spinal cord differentially modulate sympathetic outflow and that the adrenal medulla may be involved in those modulatory actions. In Sprague-Dawley rats, NOS I immunoreactivity was distributed primarily in the perikaryon, proximal dendrites, or axons of SPN, and small clusters of NOS II immunoreactivity impinged mainly on the circumference of SPN. Intrathecal administration of 7-nitroindazole (7-NI), a specific NOS I antagonist, into the thoracic spinal cord significantly reduced arterial pressure, heart rate, and basal or baroreflex-mediated sympathetic vasomotor tone. On the other hand, intrathecal application of S-methylisothiourea (SMT), a specific NOS II antagonist, elevated arterial pressure with a transient reduction of heart rate, induced a surge of plasma norepinephrine, and reduced baroreflex-mediated but not basal sympathetic vasomotor tone. Bilateral adrenalectomy significantly exacerbated the cardiovascular responses to 7-NI but antagonized those to SMT. We conclude that both NOS I and NOS II are present in the thoracic spinal cord and are tonically active under physiological conditions. Furthermore, the endogenous NO generated by NOS I-containing SPN exerts a tonic excitatory action on vasomotor tone mediated by norepinephrine released from the adrenal medulla and sympathetic nerve terminals. On the other hand, NO derived from NOS II exerts a tonic inhibitory action on sympathetic outflow from the SPN that targets primarily the blood vessels.
Functional assessment of the stenotic carotid artery by CFD-based pressure gradient evaluation
Authors: Liu Xin , Zhang Heye , Ren Lijie , Xiong Huahua , Gao Zhifan , Xu Pengcheng , Huang Wenhua , Wu Wanqing
Published: July 2016

The functional assessment of a hemodynamic significant stenosis base on blood pressure variation has been applied for evaluation of the myocardial ischemic event. This functional assessment shows great potential for improving the accuracy of the classification of the severity of carotid stenosis. To explore the value of grading the stenosis using a pressure gradient (PG)—we had reconstructed patient-specific carotid geometries based on MRI images—computational fluid dynamics were performed to analyze the PG in their stenotic arteries. Doppler ultrasound image data and the corresponding MRI image data of 19 patients with carotid stenosis were collected. Based on these, 31 stenotic carotid arterial geometries were reconstructed. A combinatorial boundary condition method was implemented for steady-state computer fluid dynamics simulations. Anatomic parameters, including tortuosity (T), the angle of bifurcation, and the cross-sectional area of the remaining lumen, were collected to investigate the effect on the pressure distribution. The PG is highly correlated with the severe stenosis ( r = 0.902), whereas generally, the T and the angle of the bifurcation negatively correlate to the pressure drop of the internal carotid artery stenosis. The calculation required <10 min/case, which made it prepared for the fast diagnosis of the severe stenosis. According to the results, we had proposed a potential threshold value for distinguishing severe stenosis from mild-moderate stenosis (PG = 0.88). In conclusion, the PG could serve as the additional factor for improving the accuracy of grading the severity of the stenosis.
Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats
Authors: Wang Wen , Liu Zhi , Su Jie , Chen Wen-Sheng , Wang Xiao-Wu , Bai San-Xing , Zhang Jin-Zhou , Yu Shi-Qiang
Published: July 2016

Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3′-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI.
Phospholipase C-ε signaling mediates endothelial cell inflammation and barrier disruption in acute lung injury
Authors: Bijli Kaiser M. , Fazal Fabeha , Slavin Spencer A. , Leonard Antony , Grose Valerie , Alexander William B. , Smrcka Alan V. , Rahman Arshad
Published: July 2016

Phospholipase C-ε (PLC-ε) is a unique PLC isoform that can be regulated by multiple signaling inputs from both Ras family GTPases and heterotrimeric G proteins and has primary sites of expression in the heart and lung. Whereas the role of PLC-ε in cardiac function and pathology has been documented, its relevance in acute lung injury (ALI) is unclear. We used PLC-ε−/−mice to address the role of PLC-ε in regulating lung vascular inflammation and injury in an aerosolized bacterial LPS inhalation mouse model of ALI. PLC-ε−/−mice showed a marked decrease in LPS-induced proinflammatory mediators (ICAM-1, VCAM-1, TNF-α, IL-1β, IL-6, macrophage inflammatory protein 2, keratinocyte-derived cytokine, monocyte chemoattractant protein 1, and granulocyte-macrophage colony-stimulating factor), lung neutrophil infiltration and microvascular leakage, and loss of VE-cadherin compared with PLC-ε+/+mice. These data identify PLC-ε as a critical determinant of proinflammatory and leaky phenotype of the lung. To test the possibility that PLC-ε activity in endothelial cells (EC) could contribute to ALI, we determined its role in EC inflammation and barrier disruption. RNAi knockdown of PLC-ε inhibited NF-κB activity in response to diverse proinflammatory stimuli, thrombin, LPS, TNF-α, and the nonreceptor agonist phorbol 13-myristate 12-acetate (phorbol esters) in EC. Depletion of PLC-ε also inhibited thrombin-induced expression of NF-κB target gene, VCAM-1. Importantly, PLC-ε knockdown also protected against thrombin-induced EC barrier disruption by inhibiting the loss of VE-cadherin at adherens junctions and formation of actin stress fibers. These data identify PLC-ε as a novel regulator of EC inflammation and permeability and show a hitherto unknown role of PLC-ε in the pathogenesis of ALI.
Rapid conditional targeted ablation model for hemolytic anemia in the rat
Authors: Hanson Marina M. , Liu Fengming , Dai Shen , Kearns Alison , Qin Xuebin , Bryda Elizabeth C.
Published: July 2016

Effective methods for cell ablation are important tools for examining the anatomical, functional, and behavioral consequences of selective loss of specific cell types in animal models. We have developed an ablation system based on creating genetically modified animals that express human CD59 (hCD59), a membrane receptor, and administering intermedilysin (ILY), a toxin produced by Streptococcus intermedius, which binds specifically to hCD59 to induce cell lysis. As proof-of-concept in the rat, we generated an anemia model, SD-Tg(CD59-HBA1)Bryd, which expresses hCD59 on erythrocytes. Hemolysis is a common complication of inherited or acquired blood disorders, which can result in cardiovascular compromise and death. A rat model that can replicate hemolysis through specific ablation of erythrocytes would allow further study of disease and novel treatments. In vitro, complete lysis of erythrocytes expressing hCD59 was observed at and above 250 pM ILY, while no lysis was observed in wild-type erythrocytes at any ILY concentration (8-1,000 pM). In vivo, ILY intravenous injection (100 ng/g body wt) dramatically reduced the hematocrit within 10 min, with a mean hematocrit reduction of 43% compared with 1.4% in the saline control group. Rats injected with ILY at 500 ng/g intraperitoneally developed gross signs of anemia. Histopathology confirmed anemia and revealed hepatic necrosis, with microthrombi present. These studies validate the hCD59-ILY cell ablation technology in the rat and provide the scientific community with a new rapid conditional targeted ablation model for hemolytic anemia and hemolysis-associated sequelae.
Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer
Authors: Chong Curtis R. , Bahcall Magda , Capelletti Marzia , Kosaka Takayuki , Ercan Dalia , Sim Taebo , Sholl Lynette M. , Nishino Mizuki , Johnson Bruce E. , Gray Nathanael S. , Jänne Pasi A.
Published: July 2016

Purpose: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost and protracted timeline of drug discovery.

Experimental Design: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non–small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes.

Results: This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74–ROS1-transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nmol/L, respectively). Cabozantinib inhibited CD74–ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nmol/L, respectively), entrectinib (IC50 = 6/2,200/3,500 nmol/L), and PF-06463922 (IC50 = 1/270/2 nmol/L). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924 potently inhibited CD74–NTRK1-transformed compared with parental Ba/F3 cells (IC50 = 19 nmol/L vs. > 470 nmol/L). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response.

Conclusions: While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib. Clin Cancer Res; 23(1); 204–13. ©2016 AACR.
New Strategies in Esophageal Carcinoma: Translational Insights from Signaling Pathways and Immune Checkpoints
Authors: Wang Victoria E. , Grandis Jennifer R. , Ko Andrew H.
Published: July 2016

Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting HER2 and VEGFR in selected patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, although large-scale exome and whole-genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both esophageal adenocarcinoma and SCC and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features. Clin Cancer Res; 22(17); 4283–90. ©2016 AACR.
Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor
Authors: Zook Phillip , Pathak Harsh B. , Belinsky Martin G. , Gersz Lawrence , Devarajan Karthik , Zhou Yan , Godwin Andrew K. , von Mehren Margaret , Rink Lori
Published: July 2016

Purpose: Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate–resistant GIST cell lines and tumors.

Experimental Design: Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST.

Results: This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate–sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate–sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies.

Conclusions: These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171–80. ©2016 AACR.
HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment
Authors: Hartmann Stefan , Bhola Neil E. , Grandis Jennifer R.
Published: July 2016

Studies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread, and therapeutic failure. The EGFR is the only FDA-approved therapeutic target, yet responses to cetuximab have been limited. Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met, has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis, and angiogenesis has been investigated in HNSCC, leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review, we discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Clin Cancer Res; 22(16); 4005–13. ©2016 AACR.
Long Noncoding RNA MALAT1 Promotes Aggressive Pancreatic Cancer Proliferation and Metastasis via the Stimulation of Autophagy
Authors: Li Le , Chen Hua , Gao Yue , Wang Yong-Wei , Zhang Guang-Quan , Pan Shang-Ha , Ji Liang , Kong Rui , Wang Gang , Jia Yue-Hui , Bai Xue-Wei , Sun Bei
Published: July 2016

Recently, pancreatic ductal adenocarcinoma (PDAC) has emerged as one of the most aggressive malignant tumors with the worst prognosis. Previous studies have demonstrated that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is increased in pancreatic cancer and is identified as a diagnostic biomarker. Nonetheless, the molecular mechanism of elevated MALAT1 levels and tumor aggressiveness remains unknown. In this study, MALAT1 was found to be highly expressed in PDAC tissues, and elevated expression was associated with poorer prognoses. In addition, MALAT1 was positively linearly correlated with the expression of LC3B mRNA. Furthermore, several molecules involved in cellular autophagic flux were modulated following the downregulation of MALAT1, including LC3, P62, and LAMP-2. Mechanistically, we found that MALAT1 interacted with RNA binding protein HuR, and silencing of MALAT1 greatly enhanced the posttranscriptional regulation of TIA-1 and had further effects on inhibiting autophagy. MALAT1 was speculated to regulate tumorigenesis via HuR-TIA-1–mediated autophagic activation. Hence, we investigated the biological properties of MALAT1 in terms of tumor proliferation and metastasis by promoting autophagy in vitro. In brief, these data demonstrate that MALAT1 could facilitate the advanced progression of tumors in vivo. Our study highlights the new roles of MALAT1 on protumorigenic functioning and anticancer therapy via activating autophagy in pancreatic cancer. Mol Cancer Ther; 15(9); 2232–43. ©2016 AACR.
Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer
Authors: Brown Wells S. , Tan Li , Smith Andrew , Gray Nathanael S. , Wendt Michael K.
Published: July 2016

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial–mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1–4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096–106. ©2016 AACR.
Relationship of Annular Sizing Using Multidetector Computed Tomographic Imaging and Clinical Outcomes After Self-Expanding CoreValve Transcatheter Aortic Valve Replacement
Authors: Popma Jeffrey J. , Gleason Thomas G. , Yakubov Steven J. , Harrison J. Kevin , Forrest John K. , Maini Brijeshwar , Ruiz Carlos E. , Pinto Duane S. , Costa Marco , Resar Jon , Conte John , Crestanello Juan , Chang Yanping , Oh Jae K. , Reardon Michael J. , Adams David H.
Published: July 2016

Background—

Multidetector computed tomography is useful for determining the appropriate transcatheter heart valve (THV) size in patients with severe aortic stenosis who are suboptimal surgical candidates. The relationship between adherence to the recommended CoreValve sizing algorithm and clinical outcomes is not known.

Methods and Results—

We evaluated 1023 patients with severe aortic stenosis deemed high or extreme risk for surgery treated with the CoreValve THV. All patients underwent preprocedural multidetector computed tomography, and the scans were reviewed at a central analysis center using standardized software. Compliance to a recommended sizing algorithm was used to identify patients with below-range, in-range, and above-range THV sizing. A device annular sizing ratio (DAR) was also calculated based on the native annulus perimeter and perimeter of the selected THV. Clinical end points included the presence of paravalvular aortic regurgitation evaluated by an independent echocardiographic laboratory. Adherence to the sizing algorithm was highest with a 31-mm THV (92.6%) and lowest with the 23-mm THV (38.5%). Below-range sizing was associated with a higher rate of moderate or severe paravalvular aortic regurgitation (15.3%) than in-range (6.5%) or above-range (10.0%;
P
<0.001) sizing. Higher DARs were associated with lower rates of moderate or severe paravalvular aortic regurgitation: DAR ≤10%, 17.6%; DAR 10% to 15%, 9.9%; DAR 15% to 20%, 6.3%; and DAR >20%, 4.9%;
P
<0.001. There was no increase in clinical events associated with higher DARs.

Conclusions—

Adherence to a sizing algorithm guided by multidetector computed tomography resulted in lower rates of paravalvular aortic regurgitation after self-expanding transcatheter valve replacement without an increase in complications.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01240902.
A New Method for Determining the Optical Constants of Highly Transparent Solids
Authors: Li Xingcan , Wang Chengchao , Zhao Junming , Liu Linhua
Published: July 2016

Highly transparent substrates are of interest for a variety of applications, but it is difficult to measure their optical constants precisely, especially the absorption index in the transparent spectral region. In this paper, a combination technique (DOPTM-EM) using both the double optical pathlength transmission method (DOPTM) and the ellipsometry method (EM) is presented to obtain the optical constants of highly transparent substrates, which overcomes the deficiencies of both the two methods. The EM cannot give accurate result of optical constants when the absorption index is very weak. The DOPTM is suitable to retrieve the weak absorption index; however, two sets of solutions exist for the retrieved refractive index and absorption index, and only one is the true value that needs to be identified. In the DOPTM-EM, the optical constants are measured first by using the EM and set as the initial value in the gradient-based inverse method used in the DOPTM, which ensures only the true optical constants are retrieved. The new method simultaneously obtains the refractive index and the absorption index of highly transparent substrate without relying on the Kramers–Kronig relation. The optical constants of three highly transparent substrates (polycrystalline BaF2, CaF2, and MgF2) were experimentally determined within wavelength range from ultraviolet to infrared regions (0.2–14 µm). The presented method will facilitate the measurement of optical constants for highly transparent materials.
Taste of Clindamycin and Acetaminophen
Authors: Hashiba Kimberlee A. , Wo Shane R. , Yamamoto Loren G.
Published: July 2016

This study evaluated the taste palatability of liquid clindamycin and acetaminophen products on the market. Subjects rated the palatability of 3 clindamycin suspensions, 1 amoxicillin suspension (tasted twice), an acetaminophen elixir, and an acetaminophen suspension in a randomized blinded fashion on a 0 to 5 scale. Forty-six adults aged 20 to 82 years volunteered for this study. Means (and 95% confidence intervals) were as follows: amoxicillin-first taste 3.6 (3.3-3.9), amoxicillin-second taste 3.5 (3.2-3.7). Clindamycin Rising, Perrigo, Greenstone; 2.0 (1.6-2.5), 3.0 (2.7-3.3), and 2.2 (1.8-2.6), respectively. Acetaminophen elixir 0.6 (0.4-0.8) and acetaminophen suspension 3.4 (3.1-3.6). One clindamycin tasted significantly better than the others. Additionally, although 2 acetaminophen formulations are currently available over-the-counter, the suspension is more palatable and less costly. Medicaid drug programs that perpetuate the use of elixir should change their coverage to save money and provide patients access to better tasting acetaminophen.
An Unbiased Estimate of Global Interrater Agreement
Authors: Cousineau Denis , Laurencelle Louis
Published: July 2016

Assessing global interrater agreement is difficult as most published indices are affected by the presence of mixtures of agreements and disagreements. A previously proposed method was shown to be specifically sensitive to global agreement, excluding mixtures, but also negatively biased. Here, we propose two alternatives in an attempt to find what makes such methods so specific. The first method, RB, is found to be unbiased while at the same time rejecting mixtures, is detecting agreement with good power and is little affected by unequal category prevalence as soon as there are more than two categories.
Conceptualizing the Effect of Community and Neighborhood Factors on Type 2 Diabetes Health Outcomes
Authors: Smalls Brittany L. , Gregory Chris M. , Zoller James S. , Egede Leonard E.
Published: July 2016

The objective of this study was to validate a conceptual framework of the relationship between neighborhood factors and diabetes process and outcomes in type 2 diabetes. Structural equation modeling was used to conduct path analysis to examine relationships between neighborhood characteristics and diabetes self-care and glycemic control based on an adapted conceptual framework. Medication adherence and social cohesion has significant direct effects on glycemic control. There was an indirect effect between social support and glycemic control, where 46% of the effect was mediated by medication adherence. Last, medication adherence, food insecurity, and social cohesion had significant total effects on glycemic control. Furthermore, walking environment, social support, neighborhood safety, and neighborhood problems had significant direct effects on food insecurity. The modified conceptual model was validated using path analysis, and neighborhood characteristics had direct and indirect effects on glycemic control.
What Businesses Attract Unions? Unionization over the Life Cycle of U.S. Establishments
Authors: Dinlersoz Emin , Greenwood Jeremy , Hyatt Henry
Published: July 2016

What types of businesses attract unions? The study develops a theory of union learning and organizing to provide an answer to this question. A union monitors the productivity of establishments in an industry and uses this information to decide which ones to organize. An establishment becomes unionized if the union wins a certification election, the outcome of which can be influenced by costly actions taken by the two parties. The model offers predictions on the nature of union selection, which are examined empirically. Data on union certification elections, matched with data on establishment characteristics, are used to explore where union activity is concentrated.
The art of good governance: how images from the past provide inspiration for modern practice
Authors: de Graaf Gjalt , van Asperen Hanneke
Published: July 2016

Since the early 1990s, discourse on ‘good governance’ has become more prevalent. What ‘good governance’ means and entails, however, and when we can speak of ‘good’ governance in this discourse, is not always clear. Many scholars in public administration and other social sciences writing about good governance have used visual interpretations of good governance from centuries ago to illustrate their case in point. Here, we also use pictures from the past – Lorenzetti’s Sienese frescoes to be more precise – yet, not as an illustration, but as the core of the argument. Our main research question is: how can Lorenzetti’s frescoes of Good Governance inspire our modern-day conception of good governance? We conclude that good governance is governance by good governors, and good governors are governors guided by benevolence. We end with a discussion of what that entails for modern-day governance practice.

Points for practitioners

Governance without integrity violations is not necessarily good governance. Benevolence is needed for that.
The panel study of social support for middle-aged and elderly adults in Taiwan – Latent growth model
Authors: Li Yang-Tzu , Lee Yue-Chune , Tsui Ming-Sum , Pak Michael Chui-Man
Published: July 2016

Similar to other countries, the proportion of elderly citizens in Taiwan living with their children is declining, due to a reduced intention and ability to take care of elderly parents. The social life of elderly people is a dynamic continuum, in which their social support is correlated with social networks and social participation. Longitudinal data were used for latent growth curve modeling to estimate changes in social support for the subjects over time. The findings will be presented, followed by a discussion. The last part of the article will provide recommendations for service, research, and limitations of the study.
An improvement proposal: Protection and resettlement support act for North Korean defectors in order to propel social integration
Authors: Kim Min-jung , Kim Min-joo , Kim Jyung-soo , Kim Joon-ho
Published: July 2016

The purpose of this study is to critically examine how North Korean defectors adapt to South Korean society and how the South Korean government institutes policies to support their settlement in the perspective of social integration. In particular, economic and psychological support by the South Korean government will be analyzed among the current resettlement support policies. The aim of this study is also to suggest proper remedial actions for North Korean defectors based on empirical research on the actual conditions of North Korean defectors in South Korea.
Full Spectrum of Postnatal Tooth Phenotypes in a Novel Irf6 Cleft Lip Model
Authors: Chu E.Y. , Tamasas B. , Fong H. , Foster B.L. , LaCourse M.R. , Tran A.B. , Martin J.F. , Schutte B.C. , Somerman M.J. , Cox T.C.
Published: July 2016

Clefting of the lip, with or without palatal involvement (CLP), is associated with a higher incidence of developmental tooth abnormalities, including hypodontia and supernumerary teeth, aberrant crown and root morphologies, and enamel defects, although the underlying mechanistic link is poorly understood. As most CLP genes are expressed throughout the oral epithelium, the authors hypothesized that the expression of CLP genes may persist in the dental epithelium and thus, in addition to their earlier role in labiopalatine development, may play an important functional role in subsequent tooth patterning and amelogenesis. To address this, the authors generated a unique conditional knockout model involving the major CLP gene, Irf6, that overcomes the previously reported perinatal lethality to enable assessment of any posteruption dental phenotypes. A dental epithelium–specific Irf6 conditional knockout ( Irf6-cKO) mouse was generated via a Pitx2-Cre driver line. Dental development was analyzed by microcomputed tomography, scanning electron microscopy, histology, immunohistochemistry, and quantitative polymerase chain reaction. Irf6-cKO mice displayed variable hypodontia, occasional supernumerary incisors and molars, as well as crown and root patterning anomalies, including peg-shaped first molars and taurodontic and C-shaped mandibular second molars. Enamel density was reduced in preeruption Irf6-cKO mice, and some shearing of enamel rods was noted in posteruption incisors. There was also rapid attrition of Irf6-cKO molars following eruption. Histologically, Irf6-cKO ameloblasts exhibited disturbances in adhesion and polarity, and delayed enamel formation was confirmed immunohistochemically. Altered structure of Hertwig’s epithelial root sheath was also observed. These data support a role for IRF6 in tooth number, crown and root morphology and amelogenesis that is likely due to a functional role of Irf6 in organization and polarity of epithelial cell types. This data reinforce the notion that various isolated tooth defects could be considered part of the CLP spectrum in relatives of an affected individual.
Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations
Authors: Gowans L.J.J. , Adeyemo W.L. , Eshete M. , Mossey P.A. , Busch T. , Aregbesola B. , Donkor P. , Arthur F.K.N. , Bello S.A. , Martinez A. , Li M. , Augustine-Akpan E.A. , Deressa W. , Twumasi P. , Olutayo J. , Deribew M. , Agbenorku P. , Oti A.A. , Braimah R. , Plange-Rhule G. , Gesses M. , Obiri-Yeboah S. , Oseni G.O. , Olaitan P.B. , Abdur-Rahman L. , Abate F. , Hailu T. , Gravem P. , Ogunlewe M.O. , Buxó C.J. , Marazita M.L. , Adeyemo A.A. , Murray J.C. , Butali A.
Published: July 2016

Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10−3), 8q24 (rs987525, P = 1.22 × 10−3), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29. In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.
The return on social bonds
Authors: Nieman Mark David
Published: July 2016

This article takes a game-theoretic and latent variable approach to modeling the effect of international social hierarchies on conflict among states. I start with the premise that international states are social actors and are nested within informal social networks of friendly and conflictual relationships. Rather than lateral relationships among equals, networks among states tend to have a vertical or hierarchical structure. Although international hierarchical relationships may arise as a result of material power asymmetries, this article focuses on non-material asymmetries that stem from political legitimacy or policy innovation – a subject that has received less attention in scholarly research. I argue that, within these hierarchies, states adopt one of two roles – a dominant or a subordinate. Each resulting (dyadic) dominant–subordinate relationship is a social contract, in which the subordinate concedes some autonomy in exchange for the dominant’s protection. This social hierarchy affects the relationships among subordinates, as well as between a dominant and subordinates. The model predicts that a state’s degree of subordination reduces its probability of conflict initiation against other subordinates. Moreover, the decision to initiate conflict is influenced by the expectation that the dominant will intervene, which itself is affected by the target’s relative level of subordination to the dominant vis-à-vis the challenger. These predictions are supported by empirical analyses of the US hierarchy (1950–2000).
Echocardiographic effects of dexmedetomidine–ketamine in chinchillas (Chinchilla lanigera)
Authors: Doss Grayson A , Mans Christoph , Stepien Rebecca L
Published: July 2016

Alpha2-agonist anesthetic combinations are often used in rodent anesthesia but no information about their effects on cardiac function in chinchillas exists. The purpose of this study was to utilize echocardiography to evaluate the cardiovascular effects of dexmedetomidine–ketamine anesthesia in chinchillas. Echocardiographic examinations were performed in eight adult chinchillas under manual restraint and following dexmedetomidine (0.015 mg/kg) and ketamine (4 mg/kg) administration. Dexmedetomidine–ketamine anesthesia resulted in a significantly decreased heart rate, fractional shortening, cardiac output, and flow velocity across the aortic and pulmonic valves, and significantly increased left ventricular internal diameter in systole. The observed changes in echocardiographic parameters are similar to those previously reported in chinchillas anesthetized with isoflurane.
Effect of Implicit Perceptual-Motor Training on Decision-Making Skills and Underpinning Gaze Behavior in Combat Athletes
Authors: Milazzo Nicolas , Farrow Damian , Fournier Jean F.
Published: July 2016

This study investigated the effect of a 12-session, implicit perceptual-motor training program on decision-making skills and visual search behavior of highly skilled junior female karate fighters ( M age = 15.7 years, SD = 1.2). Eighteen participants were required to make (physical or verbal) reaction decisions to various attacks within different fighting scenarios. Fighters’ performance and eye movements were assessed before and after the intervention, and during acquisition through the use of video-based and on-mat decision-making tests. The video-based test revealed that following training, only the implicit perceptual-motor group ( n = 6) improved their decision-making accuracy significantly compared to a matched motor training (placebo, n = 6) group and a control group ( n = 6). Further, the implicit training group significantly changed their visual search behavior by focusing on fewer locations for longer durations. In addition, the session-by-session analysis showed no significant improvement in decision accuracy between training session 1 and all the other sessions, except the last one. Coaches should devote more practice time to implicit learning approaches during perceptual-motor training program to achieve significant decision-making improvements and more efficient visual search strategy with elite athletes.
Computer-Detected Attention Affects Foreign Language Listening but Not Reading Performance
Authors: Lee Shu-Ping
Published: July 2016

No quantitative study has explored the influence of attention on learning English as a foreign language (EFL). This study investigated whether computer-detected attention is associated with EFL reading and listening and reading and listening anxiety. Traditional paper-based English tests used as entrance examinations and tests of general trait anxiety, reading, listening, reading test state anxiety, and listening test state anxiety were administered in 252 Taiwan EFL college students who were divided into High Attention (Conners' Continuous Performance Test, CPT < 50) and Low Attention (CPT ≥ 50) groups. No differences were found between the two groups for traditional paper-based English tests, trait anxieties, general English reading anxiety scales, and general English listening anxiety scales. The Low Attention group had higher test state anxiety and lower listening test scores than the High Attention group, but not in reading. State anxiety during listening tests for EFL students with computer-detected low attention tendency was elevated and their EFL listening performance was affected, but those differences were not found in reading.