bluuebunny/crossref_metadata_2025 huggingface dataset:
Belief Propagation-Based Cognitive Routing in Maritime Ad Hoc Networks
Authors: Ghafoor Huma , Noh Youngtae , Koo Insoo
Published: April 2016

Cognitive routing for maritime wireless ad hoc networks is proposed in this paper to find a stable path between source and destination. This is ship-to-ship communication where two ships can communicate when they not only have consensus on a common idle channel but also are in the transmission range of each other. We apply belief propagation algorithm for collaborative spectrum sensing. Every user (ship) exchanges its local decisions with its neighbors to compute the final belief about the state of the channel. These beliefs are applied for estimating the link duration for total number of hops between source and destination. Then, a path is selected which maximizes the path duration among all the paths in the network to reach the destination. We apply both flood-based and geographical routing protocols to find a route between source and destination for different scenarios. We simulate our scheme for different ocean settings and evaluate path durations for different number of ships. The results report a significant increase in path duration as the number of nodes increases in the network. In addition, we verify that path duration increases with an increase in probability of primary user being idle via extensive simulations. Hence, our scheme provides stable path selection for communication among users onboard.
Statistical Analysis of Loss of Offsite Power Events
Authors: Volkanovski Andrija , Ballesteros Avila Antonio , Peinador Veira Miguel
Published: April 2016

This paper presents the results of the statistical analysis of the loss of offsite power events (LOOP) registered in four reviewed databases. The reviewed databases include the IRSN (Institut de Radioprotection et de Sûreté Nucléaire) SAPIDE database and the GRS (Gesellschaft für Anlagen- und Reaktorsicherheit mbH) VERA database reviewed over the period from 1992 to 2011. The US NRC (Nuclear Regulatory Commission) Licensee Event Reports (LERs) database and the IAEA International Reporting System (IRS) database were screened for relevant events registered over the period from 1990 to 2013. The number of LOOP events in each year in the analysed period and mode of operation are assessed during the screening. The LOOP frequencies obtained for the French and German nuclear power plants (NPPs) during critical operation are of the same order of magnitude with the plant related events as a dominant contributor. A frequency of one LOOP event per shutdown year is obtained for German NPPs in shutdown mode of operation. For the US NPPs, the obtained LOOP frequency for critical and shutdown mode is comparable to the one assessed in NUREG/CR-6890. Decreasing trend is obtained for the LOOP events registered in three databases (IRSN, GRS, and NRC).
Clinicopathological Significance of Vimentin and Cytokeratin Protein in the Genesis of Squamous Cell Carcinoma of Cervix
Authors: Husain Nazik Elmalaika O. S. , Babiker Ali Yousif , Albutti Aqel S. , Alsahli Mohammed A. , Aly Salah M. , Rahmani Arshad H.
Published: April 2016

Cervical cancer is one of the commonest types of cancers worldwide especially in developing countries. Intermediate filaments protein family has shown a role in the diagnosis of various cancers, but a few studies are available about the vimentin and cytokeratin roles in the cervical cancer. This case control study aimed to interpret the expression of vimentin and cytokeratin proteins in the development and progression of cervical cancer and its correlation with clinicopathological features. The cytoplasmic expression of vimentin was observed in 40% of cases, but not in inflammatory lesions of cervix. It was noticed that vimentin expression was increasing significantly with high grade of the tumour. Cytokeratin expression was observed in 48.33% and it was noticed that the expression was 62.5% in well differentiated (G1), 45% in moderately differentiated (G2), and 41.66% in poorly differentiated carcinoma, yet statistically insignificant. The expression of vimentin and cytokeratin proteins was not significantly associated with age groups. The current findings concluded a possible role of vimentin in the development and progression of cervical cancer and vimentin marker will be useful in the diagnosis and grading of cervical cancer.
The Expert Patient and Chronic Respiratory Diseases
Authors: Boulet Louis-Philippe
Published: April 2016

The concept of “expert patient” has been developed in the last two decades to define a patient who has a significant knowledge of his/her disease and treatment in addition to self-management skills. However, this concept has evolved over the last years, and these patients are now considered, not only to be more efficient in the management of their own condition and communicating effectively with health professionals, but to also act as educators for other patients and as resources for the last, provide feedback on care delivery, and be involved in the production and implementation of practice guidelines, as well as in the development and conduct of research initiatives. There are some barriers, however, to the integration of this new contributor to the health care team, and specific requirements need to be considered for an individual to be considered as an expert. This new player has, however, a potentially important role to improve current care, particularly in respiratory health.
Long-Term Observation of Triplex Surgery for Cataract after Phakic 6H Implantation for Super High Myopia
Authors: Liu Xin , Fan Fan , Wang Xiaoying , Lu Yi , Zheng Tianyu , Zhou Peng , Zhou Xingtao , Luo Yi
Published: April 2016

Purpose. To analyze the safety, effectiveness, and stability of triplex surgery for phakic 6H anterior chamber phakic intraocular lens explantation and phacoemulsification with in-the-bag IOL implantation for super high myopia in long-term observations.Methods. This retrospective case series evaluated 16 eyes of 10 patients who underwent triplex surgery. Best corrected visual acuity (BCVA), endothelial cell density (ECD), and associated adverse events were evaluated.Results. The mean follow-up time after the triplex surgery was 46 ± 14 months. The mean logMAR BCVA was significantly improved after triplex surgery (P= 0.047). One eye developed endophthalmitis five days postoperatively and underwent pars plana vitrectomy (PPV). Five eyes with preoperative severe endothelial cell loss developed corneal decompensation and underwent keratoplasty at a mean time of 9.4 ± 2.6 months after the triplex surgery. One eye had graft failure and underwent a second keratoplasty. The eye developed rhegmatogenous retinal detachment and underwent PPV with silicone oil 18 months later. ECD before the triplex surgery was not significantly different compared with that at last follow-up (P= 0.495) apart from these five eyes. Three eyes (18.8%) developed posterior capsule opacification.Conclusions. Triplex surgery was safe and effective for phakic 6H related complicated cataracts. Early extraction before severe ECD loss is recommended.
Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity
Authors: Wozniak Krystyna M. , Vornov James J. , Wu Ying , Nomoto Kenichi , Littlefield Bruce A. , DesJardins Christopher , Yu Yanke , Lai George , Reyderman Larisa , Wong Nancy , Slusher Barbara S.
Published: April 2016

Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332–9. ©2016 AACR.
Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling
Authors: Yeo Syn Kok , Wen Jian , Chen Song , Guan Jun-Lin
Published: April 2016

Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the coexistence of distinct breast cancer stem-like cells (BCSC) as identified by ALDH+ and CD29hiCD61+ markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29hiCD61+ BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary stem cell–associated genes, whereas ALDH+ BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumor-initiating properties of both ALDH+ and CD29hiCD61+ BCSC, as achieved by impairing either the Stat3 or TGFβ/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgfβ-R1 inhibitor LY-2157299 inhibited the formation of both epithelial and mesenchymal BCSC colonies. In vivo, this combination treatment was sufficient to limit tumor growth and reduce BCSC number. Overall, our findings reveal a differential dependence of heterogeneous BCSC populations on divergent signaling pathways, with implications on how to tailor drug combinations to improve therapeutic efficacy. Cancer Res; 76(11); 3397–410. ©2016 AACR.
mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM
Authors: Bhoopathi Praveen , Lee Nathaniel , Pradhan Anjan K. , Shen Xue-Ning , Das Swadesh K. , Sarkar Devanand , Emdad Luni , Fisher Paul B.
Published: April 2016

Advanced stages of neuroblastoma, the most common extracranial malignant solid tumor of the central nervous system in infants and children, are refractive to therapy. Ectopic expression of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) promotes broad-spectrum antitumor activity in vitro, in vivo in preclinical animal models, and in a phase I clinical trial in patients with advanced cancers without harming normal cells. mda-7/IL-24 exerts cancer-specific toxicity (apoptosis or toxic autophagy) by promoting endoplasmic reticulum stress and modulating multiple signal transduction pathways regulating cancer cell growth, invasion, metastasis, survival, and angiogenesis. To enhance cancer-selective expression and targeted anticancer activity of mda-7/IL-24, we created a tropism-modified cancer terminator virus (Ad.5/3-CTV), which selectively replicates in cancer cells producing robust expression of mda-7/IL-24. We now show that Ad.5/3-CTV induces profound neuroblastoma antiproliferative activity and apoptosis in a caspase-3/9–independent manner, both in vitro and in vivo in a tumor xenograft model. Ad.5/3-CTV promotes these effects through a unique pathway involving apoptosis-inducing factor (AIF) translocation into the nucleus. Inhibiting AIF rescued neuroblastoma cells from Ad.5/3-CTV–induced cell death, whereas pan-caspase inhibition failed to promote survival. Ad.5/3-CTV infection of neuroblastoma cells increased ATM phosphorylation instigating nuclear translocation and increased γ-H2AX, triggering nuclear translocation and intensified expression of AIF. These results were validated further using two ATM small-molecule inhibitors that attenuated PARP cleavage by inhibiting γ-H2AX, which in turn inhibited AIF changes in Ad.5/3-CTV–infected neuroblastoma cells. Taken together, we elucidate a novel pathway for mda-7/IL-24–induced caspase-independent apoptosis in neuroblastoma cells mediated through modulation of AIF, ATM, and γ-H2AX. Cancer Res; 76(12); 3572–82. ©2016 AACR.
MYC Is a Crucial Mediator of TGFβ-Induced Invasion in Basal Breast Cancer
Authors: Cichon Magdalena A. , Moruzzi Megan E. , Shqau Tiziana A. , Miller Erin , Mehner Christine , Ethier Stephen P. , Copland John A. , Radisky Evette S. , Radisky Derek C.
Published: April 2016

Basal subtype breast cancers have a particularly poor prognosis, with high invasiveness and resistance to most targeted therapies. TGFβ and MYC drive central features of basal breast cancer: TGFβ is an autocrine and paracrine signaling factor that drives cell invasion and metastasis, and MYC is a central regulator of cellular proliferation that is upregulated in many cancer types. We show here that genetic or pharmacologic inhibition of MYC in MCF10A basal breast cells results in increased sensitivity to TGFβ-stimulated invasion and metastasis and also show that this signaling loop is dependent on activation of SRC. Analysis of human breast cancer datasets and additional experiments with breast cancer cell lines further suggest the relevance of this signaling loop in basal, but not luminal, breast cancers. Our results imply precaution should be taken when utilizing therapeutic inhibitors of MYC with basal breast cancer patients as this could lead to increased metastasis; however, simultaneous pharmacologic inhibition of SRC and MYC for these patients could facilitate the antiproliferative effects of MYC inhibition while blocking the consequent promotion of metastasis. Cancer Res; 76(12); 3520–30. ©2016 AACR.
Systematic Review and Meta-study Synthesis of Qualitative Studies Evaluating Facilitators and Barriers to Participation in Colorectal Cancer Screening
Authors: Honein-AbouHaidar Gladys N. , Kastner Monika , Vuong Vincent , Perrier Laure , Daly Corinne , Rabeneck Linda , Straus Sharon , Baxter Nancy N.
Published: April 2016

Screening reduces the incidence, morbidity, and mortality of colorectal cancer, yet participation tends to be low. We undertook a systematic review and meta-study synthesis of qualitative studies to identify facilitators and barriers to colorectal cancer screening participation. We searched major bibliographic databases for records published in all languages from inception to February 2015. Included primary studies that elicited views and perceptions towards colorectal cancer screening were appraised for relevance and quality. We used a two-stage synthesis to create an interpretation of colorectal cancer screening decisions grounded in primary studies; a thematic analysis to group themes and systematically compare studies and a meta-synthesis to generate an expanded theory of colorectal cancer screening participation. Ninety-four studies were included. The decision to participate in colorectal cancer screening depended on an individual's awareness of colorectal cancer screening. Awareness affected views of cancer, attitudes towards colorectal cancer screening modalities, and motivation for screening. Factors mediating awareness included public education to address misconceptions, primary care physician efforts to recommend screening, and the influence of friends and family. Specific barriers to participation in populations with lower participation rates included language barriers, logistical challenges to attending screening tests, and cultural beliefs. This study identifies key barriers, facilitators, and mediators to colorectal cancer screening participation. Cancer Epidemiol Biomarkers Prev; 25(6); 907–17. ©2016 AACR.
ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients
Authors: Chen Ming-Huang , Weng Jing-Jie , Cheng Chi-Tung , Wu Ren-Chin , Huang Shih-Chiang , Wu Chiao-En , Chung Yi-Hsiu , Liu Chun-Yu , Chang Mu-Hsin , Chen Ming-Han , Chiang Kun-Chun , Yeh Ta-Sen , Su Yeu , Yeh Chun-Nan
Published: April 2016

Purpose: Intrahepatic cholangiocarcinoma is a fatal primary liver cancer resulting from diagnosis at an advanced stage. Understanding the mechanisms of drug resistance and metastasis of cholangiocarcinoma may improve the disease prognosis. Enhanced aldehyde dehydrogenase (ALDH) activity is suggested to be associated with increased drug resistance and the metastasis. This study aims to investigate the roles of the ALDH isoforms in cholangiocarcinoma.

Experimental Design: Aldefluor assays, RT-PCR, and Western blot analysis were used to identify the major ALDH isoforms contributing to Aldefluor activity in human cholangiocarcinoma cell lines. We manipulated isoform expression in HuCCT1 cells to elucidate the role of ALDH1A3 in the malignant progression of these cells. Finally, we used immunohistochemical staining to evaluate the clinical significance of ALDH1A3 in 77 hepatectomized cholangiocarcinoma patients and an additional 31 patients with advanced cholangiocarcinoma who received gemcitabine-based therapy.

Results: ALDHhigh cholangiocarcinoma cells not only migrated faster but were more resistant to gemcitabine. Among the 19 ALDH isoforms studied, ALDH1A3 was found to be the main contributor to Aldefluor activity. In addition, we also found that knockdown of ALDH1A3 expression in HuCCT1 cells markedly reduced not only their sensitivity to gemcitabine, which might be attributed to a decreased expression of ribonucleotide reductase M1, but also their migration. Most importantly, this enzyme was also identified as an independent poor prognostic factor for patients with intrahepatic cholangiocarcinoma, as well as a prognostic biomarker of gemcitabine-treated patients.

Conclusions: ALDH1A3 plays an important role in enhancing malignant behavior of cholangiocarcinoma and serves as a new therapeutic target. Clin Cancer Res; 22(16); 4225–35. ©2016 AACR.
A Promyelocytic Leukemia Protein–Thrombospondin-2 Axis and the Risk of Relapse in Neuroblastoma
Authors: Dvorkina Maria , Nieddu Valentina , Chakelam Shalini , Pezzolo Annalisa , Cantilena Sandra , Leite Ana Paula , Chayka Olesya , Regad Tarik , Pistorio Angela , Sementa Angela Rita , Virasami Alex , Barton Jack , Montano Ximena , Lechertier Tanguy , Brindle Nicola , Morgenstern Daniel , Lebras Morgane , Burns Alan J. , Saunders Nigel J. , Hodivala-Dilke Kairbaan , Bagella Luigi , De The Hugues , Anderson John , Sebire Neil , Pistoia Vito , Sala Arturo , Salomoni Paolo
Published: April 2016

Purpose: Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations.

Experimental Design: Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro. Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann–Whitney tests, respectively. Gene expression was assessed using chip microarrays.

Results: PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas.

Conclusions: Our work reveals a novel PML-I–TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398–409. ©2016 AACR.
VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells
Authors: Tiper Irina V. , Temkin Sarah M. , Spiegel Sarah , Goldblum Simeon E. , Giuntoli Robert L. , Oelke Mathias , Schneck Jonathan P. , Webb Tonya J.
Published: April 2016

Purpose: Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell–mediated antitumor responses.

Experimental Design: To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a conditioned media model was established, wherein the supernatants from ovarian cancer cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d-expressing antigen-presenting cells (APC) and cocultured with NKT hybridomas. Ovarian cancer–associated VEGF was inhibited by treatment with bevacizumab and genistein; conditioned medium was collected, and CD1d-mediated NKT-cell responses were assayed by ELISA.

Results: Ovarian cancer tissue and ascites contain lymphocytic infiltrates, suggesting that immune cells traffic to tumors, but are then inhibited by immunosuppressive molecules within the tumor microenvironment. OV-CAR-3 and SK-OV-3 cell lines produce high levels of VEGF and GD3. Pretreatment of APCs with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 blocked CD1d-mediated NKT-cell activation. Inhibition of VEGF resulted in a concomitant reduction in GD3 levels and restoration of NKT-cell responses.

Conclusions: We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model. These studies suggest that the combination of immune modulation with antiangiogenic treatment has therapeutic potential in ovarian cancer. Clin Cancer Res; 22(16); 4249–58. ©2016 AACR.
Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation
Authors: Flores M. Luz , Castilla Carolina , Gasca Jessica , Medina Rafael , Pérez-Valderrama Begoña , Romero Francisco , Japón Miguel A. , Sáez Carmen
Published: April 2016

Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCδ silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCδ seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/β-catenin pathway. PKCδ silencing induces activation of Wnt/β-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3β inactivation and consequently in the stabilization of β-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/β-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCδ. Finally, we observe that high Gleason score prostate tumors lose PKCδ expression and this correlates with higher activation of β-catenin, inactivation of GSK3β, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/β-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCδ expression. Mol Cancer Ther; 15(7); 1713–25. ©2016 AACR.
Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update
Authors: Snoek Kitty G. , Reiss Irwin K.M. , Greenough Anne , Capolupo Irma , Urlesberger Berndt , Wessel Lucas , Storme Laurent , Deprest Jan , Schaible Thomas , van Heijst Arno , Tibboel Dick ,   for the CDH EURO Consortium
Published: April 2016

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH.
Novel BEST1 Mutations and Special Clinical Features of Best Vitelliform Macular Dystrophy
Authors: Liu Jingshu , Zhang Yongjin , Xuan Yi , Liu Wei , Wang Min
Published: April 2016

Purpose: To describe the clinical features and to analyze BEST1 mutations in patients with Best vitelliform macular dystrophy (BVMD). Methods: Thirteen individuals affected by BVMD from 6 unrelated Chinese families were studied. Complete ophthalmological examinations were performed, and the BEST1 gene was screened in all participants and 100 controls. Follow-ups were arranged within 12 months. Results: All 6 probands showed typical fundus appearances of BVMD. One of the 6 had a history of angle closure glaucoma, and another showed a unilateral focal choroidal excavation on optical coherence tomography. One patient experienced progression of the macular lesion during the follow-up. The asymptomatic mutation carriers had normal fundus but abnormal Arden ratios on electro-oculograms. Besides 4 previously reported mutations (p.Ser16Phe, p.Ser144Asn, p.Glu292Lys, p.Glu300Lys), 2 novel disease-causing mutations (p.Thr307Asp, p.Arg47His) were identified, of which p.Arg47His has been reported in adult-onset vitelliform macular dystrophy. Conclusions: Our findings have expanded the mutational and clinical spectrum of BVMD in a Chinese population. Clinical presentations of angle closure glaucoma and/or focal choroidal excavation may be related to BVMD, underlining the necessity of multimodal studies and risk assessment of angle closure glaucoma in BEST1 mutation carriers. BVMD and adult-onset vitelliform macular dystrophy may share a common etiology in some cases.
Using ROADMAP Data to Identify Enhancers Associated with Disorders of Sex Development
Authors: Ohnesorg Thomas , Croft Brittany , Tan Jacqueline , Sinclair Andrew H.
Published: April 2016

Despite recent advances in our understanding, most cases of disorders of sex development (DSD) cannot be explained by mutations in known genes. In genome-wide screens of DSD patients, we and others detected duplications or deletions of potential regulatory regions of known or suspected DSD genes. It is therefore likely that a significant proportion of DSD cases may be explained by disrupted transcriptional regulation of gonad genes. Despite many recent technological advances, limited availability of relevant tissues - especially human embryonic material - can make the identification of long-range regulatory elements extremely difficult. In an attempt to overcome this limitation, we evaluated the usefulness of publicly available DNaseI hypersensitivity data from the Roadmap Epigenomics Project. For this feasibility study we used the ‘gene desert' around the SOX9 gene and a genomic locus downstream of GATA4. Over 60% of our selected candidate regions had significant enhancer activity in luciferase assays. We show that this approach facilitates the detection of strong enhancer candidates worthy of further analysis.
Management of the multiple phases of heparin-induced thrombocytopenia
Authors: Cuker Adam
Published: April 2016

The clinical course of heparin-induced thrombocytopenia (HIT) may be separated into five sequential phases: 1. suspected HIT, 2. acute HIT, 3. subacute HIT A, 4. subacute HIT B, and 5. remote HIT. Each phase confronts the clinician with a unique set of management questions. In this review, the phases of HIT are defined and key management questions associated with each phase are discussed. Among patients with Suspected HIT, I use the 4Ts score to determine which patients have a sufficiently high probability of HIT to justify discontinuation of heparin and initiation of a non-heparin parenteral anticoagulant. An algorithm for selecting an appropriate non-heparin anticoagulant based on the patient’s clinical stability, renal and hepatic function, drug availability, and physician comfort is provided. In patients with Acute HIT, I generally avoid prophylactic platelet transfusion and inferior vena cava filter insertion because of a potential increased risk of thrombosis. I perform 4-limb screening compression ultrasonography. In patients with symptomatic thromboembolism or asymptomatic proximal deep-vein thrombosis, I treat with anticoagulation for three months. In patients without thrombosis, I discontinue anticoagulation upon platelet count recovery. I do not transition patients to an oral anticoagulant until platelet count recovery (i. e. Subacute HIT A). I increasingly choose direct oral anticoagulants over vitamin K antagonists in this setting because of their greater convenience and safety. In Subacute HIT B and Remote HIT, I use heparin for cardiovascular surgery, whereas I use bivalirudin in patients with Acute HIT and Subacute HIT A in whom surgery cannot be delayed.
Non-vitamin K antagonist oral anticoagulants for heparin-induced thrombocytopenia. A systematic review of 54 reported cases
Authors: Shatzel Joseph J. , Crapster-Pregont Meg , Deloughery Thomas G.
Published: April 2016

Supplementary Material to this article is available at www.thrombosis-online.com.
Efficacy of Rivaroxaban for thromboprophylaxis after Knee Arthroscopy (ERIKA)
Authors: Camporese Giuseppe , Bernardi Enrico , Noventa Franco , Bosco Mario , Monteleone Giuseppe , Santoro Luca , Bortoluzzi Cristiano , Freguja Stefano , Nardin Michela , Marullo Matteo , Zanon Giacomo , Mazzola Claudio , Damiani Guido , Maniscalco Pietro , Imberti Davide , Lodigiani Corrado , Becattini Cecilia , Tonello Chiara , Agnelli Giancarlo
Published: April 2016

Without thromboprophylaxis, knee arthroscopy (KA) carries a low to moderate risk of venous thromboembolism. Over 5 million arthroscopies are performed worldwide yearly. It was our study objective to assess the efficacy and safety of rivaroxaban for thromboprophylaxis after therapeutic KA. Patients undergoing KA in nine Italian teaching or community hospitals were allocated to once-daily rivaroxaban (10 mg) or placebo for seven days in a phase II, multicentre, double-blind, placebo-controlled randomised trial. The primary efficacy outcome was a composite of all-cause death, symptomatic thromboembolism and asymptomatic proximal DVT at three months; major bleeding represented the primary safety outcome. All patients underwent whole-leg ultrasonography at day 7(+1), or earlier if symptomatic. A total of 241 patients were randomised (122 rivaroxaban, 119 placebo), and 234 completed the study. The primary efficacy outcome occurred in 1/120 of the rivaroxaban group and in 7/114 of the placebo group (0.8% vs 6.1%, respectively, p=0.03; absolute risk difference, −5.3%, 95% CI, −11.4 to −0.8; crude relative risk 0.14, 95% CI, 0.02 to 0.83; number-needed-to-treat=19). No major bleedings were observed. We found no association between different arthroscopic procedures and thrombotic events. Small sample size, high exclusion rate, and low number of anterior cruciate ligament reconstruction procedures are the main limitations of our study. In conclusion, a seven-day course of 10-mg rivaroxaban may be safely employed for thromboprophylaxis after KA. Whether prophylaxis after KA should be given to all patients, or to selected “high-risk” subjects, remains to be determined. A larger trial to verify our preliminary results is warranted.
Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries
Authors: Le Luong , Duckles Hayley , Schenkel Torsten , Mahmoud Marwa , Tremoleda Jordi , Wylezinska-Arridge Marzena , Ali Majid , Bowden Neil , Villa-Uriol Mari-Cruz , Van der Heiden Kim , Xing Ruoyu , Gijsen Frank , Wentzel Jolanda , Lawrie Allan , Feng Shuang , Arnold Nadine , Gsell Willy , Lungu Angela , Hose Rodney , Spencer Tim , Halliday Ian , Ridger Victoria , Evans Paul
Published: April 2016

Blood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.
Transcatheter Aortic Valve Implantation in Lower-Risk Patients With Aortic Stenosis
Authors: Abdelghani Mohammad , Serruys Patrick W.
Published: April 2016

Transcatheter aortic valve implantation underwent progressive improvements until it became the default therapy for inoperable patients, and a recommended therapy in high-risk operable patients with symptomatic severe aortic stenosis. In the lower-risk patient strata, a currently costly therapy that still has important complications with questionable durability is competing with the established effective and still-improving surgical replacement. This report tries to weigh the clinical evidence, the recent technical improvements, the durability, and the cost-effectiveness claims supporting the adoption of transcatheter aortic valve implantation in intermediate-low risk patients. The importance of appropriate patients’ risk stratification and a more comprehensive approach to estimate that risk are also emphasized in the present report.
Cardiovascular Disease in Women
Authors: Garcia Mariana , Mulvagh Sharon L. , Bairey Merz C. Noel , Buring Julie E. , Manson JoAnn E.
Published: April 2016

Cardiovascular disease continues to be the leading cause of death among women in the United States, accounting for ≈1 of every 3 female deaths. Sex-specific data focused on cardiovascular disease have been increasing steadily, yet is not routinely collected nor translated into practice. This comprehensive review focuses on novel and unique aspects of cardiovascular health in women and sex differences as they relate to clinical practice in the prevention, diagnosis, and treatment of cardiovascular disease. This review also provides current approaches to the evaluation and treatment of acute coronary syndromes that are more prevalent in women, including myocardial infarction associated with nonobstructive coronary arteries, spontaneous coronary artery dissection, and stress-induced cardiomyopathy (Takotsubo Syndrome). Other cardiovascular disease entities with higher prevalence or unique considerations in women, such as heart failure with preserved ejection fraction, peripheral arterial disease, and abdominal aortic aneurysms, are also briefly reviewed. Finally, recommendations for cardiac rehabilitation are addressed.
Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells
Authors: Green Linden A. , Njoku Victor , Mund Julie , Case Jaime , Yoder Mervin , Murphy Michael P. , Clauss Matthias
Published: April 2016

Rationale:

Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony–forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs.

Objective:

The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs.

Methods and Results:

Here, we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation–induced premature senescence involves an abrogation of tmTNF/TNF receptor 2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TNF-α–converting enzyme via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression.

Conclusions:

Thus, we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity.
Irregular Shape of Intracranial Aneurysm Indicates Rupture Risk Irrespective of Size in a Population-Based Cohort
Authors: Lindgren Antti E. , Koivisto Timo , Björkman Joel , von und zu Fraunberg Mikael , Helin Katariina , Jääskeläinen Juha E. , Frösen Juhana
Published: April 2016

Background and Purpose—

Size and shape of saccular intracranial aneurysms (sIA) reflect the condition of the sIA wall and were risk factors for rupture in previous follow-up studies. We investigated how well size or shape identify rupture-prone sIAs.

Methods—

In a population-based registry, we investigated the characteristics of ruptured sIAs treated in a single neurosurgical center (1980–2014). In addition to univariate analysis, logistic regression was used in multivariate analysis, and sensitivity and specificity of size or shape were calculated using receiver operating characteristic curves.

Results—

Ruptured sIAs were on average larger than unruptured sIAs (median, 7 versus 4 mm;
P
<0.000), but location and patient background affected the size at rupture. Of the ruptured sIAs, 38% were smaller than 7 mm and 18% were smaller than 4 mm. Of those sIAs that had ruptured at a small (<7 mm) size, 87% had an irregular shape. In multivariate analysis, irregular shape had the strongest association with presentation as ruptured sIA (odds ratio, 7.1; 95% confidence interval, 6.0–8.3), with better sensitivity (91%) and specificity (76%), in contrast to smoking (odds ratio, 0.7; 95% confidence interval, 0.6–0.9; sensitivity, 28%; specificity 57%) and Population, Hypertension, Age, Size of sIA, Earlier SAH from another sIA, Site of sIA score (odds ratio, 1.5; 95% confidence interval, 1.4–1.6).

Conclusions—

Irregular or multilobular shape is strongly associated with rupture in sIAs of all sizes and independent of location and patient background. Especially sIAs with irregular shape should be considered as high rupture risk lesions, even if small in diameter and in nonsmoking patients with low PHASES scores.
Association of Ideal Cardiovascular Health With Vascular Brain Injury and Incident Dementia
Authors: Pase Matthew P. , Beiser Alexa , Enserro Danielle , Xanthakis Vanessa , Aparicio Hugo , Satizabal Claudia L. , Himali Jayandra J. , Kase Carlos S. , Vasan Ramachandran S. , DeCarli Charles , Seshadri Sudha
Published: April 2016

Background and Purpose—

The American Heart Association developed the ideal cardiovascular health (CVH) index as a simple tool to promote CVH; yet, its association with brain atrophy and dementia remains unexamined.

Methods—

Our aim was to investigate the prospective association of ideal CVH with vascular brain injury, including the 10-year risks of incident stroke and dementia, as well as cognitive decline and brain atrophy on magnetic resonance imaging, measured for ≈7 years. We studied 2750 stroke- and dementia-free Framingham Heart Study Offspring cohort participants (mean age, 62±9 years; 45% men). Ideal CVH was quantified on a 7-point scale with 1 point awarded for each of the following: nonsmoking status, ideal body mass index, regular physical activity, healthy diet, as well as optimum blood pressure, cholesterol, and fasting blood glucose. Both recent (baseline) and remote (6.9 years earlier) ideal CVH scores were examined.

Results—

Recent ideal CVH was associated with stroke (hazard ratio, 0.80; 95% confidence interval, 0.67–0.95), vascular dementia (hazard ratio, 0.49; 95% confidence interval, 0.30–0.81), frontal brain atrophy (
P
=0.003), and cognitive decline on tasks measuring visual memory and reasoning (
P
<0.05). In addition to predicting stroke, vascular dementia, whole-brain atrophy, and cognitive decline, remote ideal CVH was associated with the incidence of all-cause dementia (hazard ratio, 0.80; 95% confidence interval, 0.67–0.97) and Alzheimer disease (hazard ratio, 0.79; 95% confidence interval, 0.64–0.98).

Conclusions—

Adherence to the American Heart Association’s ideal CVH factors and behaviors, particularly in midlife, may protect against cerebrovascular disease and dementia.
Toward an Indonesian Postcolonial Christology
Authors: Harmakaputra Hans Abdiel
Published: April 2016

‘Indonesian theology’ has not yet flourished as a theological discourse. Unlike liberation theology, black theology, feminist and womanist theology, or other Asian theologies such as South Korean and Indian theology, there is no consensus on what ‘Indonesian theology’ is. Some theologians have tried to build up this perspective for several decades, yet the result is still far from clear. The intent of this article is to describe several examples of Indonesian readings on the figure of Jesus Christ and to identify several key elements using postcolonial theological analytical frameworks that could contribute to the construction of ‘Indonesian Postcolonial Christology’. After discussing three examples of Christological works, I found three key elements related to three loci of Indonesian context: the reality of oppression, multi-cultural, and multi-faith milieu. In addition, this article will give special attention to how this framework correlates with liberation theology.
Short-Term Probabilistic Forecasts of the 31 May 2013 Oklahoma Tornado and Flash Flood Event Using a Continuous-Update-Cycle Storm-Scale Ensemble System
Authors: Yussouf Nusrat , Kain John S. , Clark Adam J.
Published: April 2016

A continuous-update-cycle storm-scale ensemble data assimilation (DA) and prediction system using the ARW model and DART software is used to generate retrospective 0–6-h ensemble forecasts of the 31 May 2013 tornado and flash flood event over central Oklahoma, with a focus on the prediction of heavy rainfall. Results indicate that the model-predicted probabilities of strong low-level mesocyclones correspond well with the locations of observed mesocyclones and with the observed damage track. The ensemble-mean quantitative precipitation forecast (QPF) from the radar DA experiments match NCEP’s stage IV analyses reasonably well in terms of location and amount of rainfall, particularly during the 0–3-h forecast period. In contrast, significant displacement errors and lower rainfall totals are evident in a control experiment that withholds radar data during the DA. The ensemble-derived probabilistic QPF (PQPF) from the radar DA experiment is more skillful than the PQPF from the no_radar experiment, based on visual inspection and probabilistic verification metrics. A novel object-based storm-tracking algorithm provides additional insight, suggesting that explicit assimilation and 1–2-h prediction of the dominant supercell is remarkably skillful in the radar experiment. The skill in both experiments is substantially higher during the 0–3-h forecast period than in the 3–6-h period. Furthermore, the difference in skill between the two forecasts decreases sharply during the latter period, indicating that the impact of radar DA is greatest during early forecast hours. Overall, the results demonstrate the potential for a frequently updated, high-resolution ensemble system to extend probabilistic low-level mesocyclone and flash flood forecast lead times and improve accuracy of convective precipitation nowcasting.
Assessment of Change in Psychoanalysis
Authors: Pires António Pazo , Gonçalves João , Sá Vânia , Silva Andrea , Sandell Rolf
Published: April 2016

A systematic method is presented whereby material from a full course of psychoanalytic treatment is analyzed to assess changes and identify patterns of change. Through an analysis of session notes, changes were assessed using the CHange After Psychotherapy scales (CHAP; Sandell 1987a), which evaluate changes in five rating variables (symptoms, adaptive capacity, insight, basic conflicts, and extratherapeutic factors). Change incidents were identified in nearly every session. Early in the analysis, relatively more change incidents related to insight were found than were found for the other types of change. By contrast, in the third year and part of the fourth year, relatively more change incidents related to basic conflicts and adaptive capacity were found. While changes related to symptoms occurred throughout the course of treatment, such changes were never more frequent than other types of change. A content analysis of the change incidents allowed a determination of when in the treatment the patient’s main conflicts (identified clinically) were overcome. A crossing of quantitative data with clinical and qualitative data allowed a better understanding of the patterns of change.