bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Aluminium and EGCG on Fibrillation and Aggregation of Human Islet Amyloid Polypeptide
Authors: Xu Zhi-Xue , Zhang Qiang , Ma Gong-Li , Chen Cong-Heng , He Yan-Ming , Xu Li-Hui , Zhang Yuan , Zhou Guang-Rong , Li Zhen-Hua , Yang Hong-Jie , Zhou Ping
Published: December 2016

The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (−)-epigallocatechin gallate (EGCG) is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III)/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III) and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III) and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III) could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III)/EGCG complex in molar ratio of 1 : 1 as Al(EGCG)(H2O)2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes.
The Time Course of Markers of Neutrophil Extracellular Traps in Patients Undergoing Revascularisation for Acute Myocardial Infarction or Stable Angina Pectoris
Authors: Helseth Ragnhild , Solheim Svein , Arnesen Harald , Seljeflot Ingebjørg , Opstad Trine Baur
Published: December 2016

Background and Aims. Neutrophil extracellular traps (NETs) have been identified in acute myocardial infarction. We assessed the time profile and association with infarct size for NETs markers in ST-elevation myocardial infarction (STEMI) and stable angina pectoris (AP). Methods. In 20 patients with STEMI and 10 with AP undergoing percutaneous coronary intervention (PCI), blood samples were collected before PCI (only AP group) and after 3 and 12 hours, days 1, 3, 5, 7, and 14 for measurement of NETs markers. Results. Double-stranded deoxyribonucleic acid (dsDNA) and nucleosome levels were higher in STEMI than AP until day 3 and 12 hours (p<0.03, all). DsDNA declined after day 5 in both groups (p<0.04, all), while nucleosomes declined until day 3 only in the AP group (p<0.05, all). DsDNA correlated with peak troponin T and creatine kinase MB (CKMB) at day 5 (r=0.48, p=0.03, both) and with MRI-measured infarct size at days 5 and 7 (r=0.61, p=0.01 and r=0.52, p=0.04, resp.), while nucleosomes correlated with infarct size at day 5 (r=0.58, p=0.02). Conclusions. High levels of NETs markers were observed in STEMI shortly after revascularisation and were partly associated with infarct size. The decline thereafter in both groups indicates a role for NETs in both acute and chronic atherothrombosis.
Effects of Frequency and Acceleration Amplitude on Osteoblast Mechanical Vibration Responses: A Finite Element Study
Authors: Wang Liping , Hsu Hung-Yao , Li Xu , Xian Cory J.
Published: December 2016

Bone cells are deformed according to mechanical stimulation they receive and their mechanical characteristics. However, how osteoblasts are affected by mechanical vibration frequency and acceleration amplitude remains unclear. By developing 3D osteoblast finite element (FE) models, this study investigated the effect of cell shapes on vibration characteristics and effect of acceleration (vibration intensity) on vibrational responses of cultured osteoblasts. Firstly, the developed FE models predicted natural frequencies of osteoblasts within 6.85–48.69 Hz. Then, three different levels of acceleration of base excitation were selected (0.5, 1, and 2 g) to simulate vibrational responses, and acceleration of base excitation was found to have no influence on natural frequencies of osteoblasts. However, vibration response values of displacement, stress, and strain increased with the increase of acceleration. Finally, stress and stress distributions of osteoblast models under 0.5 g acceleration inZ-direction were investigated further. It was revealed that resonance frequencies can be a monotonic function of cell height or bottom area when cell volumes and material properties were assumed as constants. These findings will be useful in understanding how forces are transferred and influence osteoblast mechanical responses during vibrations and in providing guidance for cell culture and external vibration loading in experimental and clinical osteogenesis studies.
Direct Current-Induced Calcium Trafficking in Different Neuronal Preparations
Authors: Wieraszko Andrzej , Ahmed Zaghloul
Published: December 2016

The influence of direct current (DC) stimulation on radioactive calcium trafficking in sciatic nerve in vivo and in vitro, spinal cord, and synaptosomes was investigated. The exposure to DC enhanced calcium redistribution in all of these preparations. The effect was dependent on the strength of the stimulation and extended beyond the phase of exposure to DC. The DC-induced increase in calcium sequestration by synaptosomes was significantly reduced by cobalt and rupture of synaptosomes by osmotic shock. Although both anodal and cathodal currents were effective, the experiments with two electrodes of different areas revealed that cathodal stimulation exerted stronger effect. The exposure to DC induced not only relocation but also redistribution of calcium within segments of the sciatic nerve. Enzymatic removal of sialic acid by preincubation of synaptosomes with neuroaminidase, or carrying out the experiments in sodium-free environment, amplified DC-induced calcium accumulation.
Integrative Evaluation of Automated Massage Combined with Thermotherapy: Physical, Physiological, and Psychological Viewpoints
Authors: Kim Do-Won , Lee Dae Woon , Schreiber Joergen , Im Chang-Hwan , Kim Hansung
Published: December 2016

Various types of massages are reported to relieve stress, pain, and anxiety which are beneficial for rehabilitation; however, more comprehensive studies are needed to understand the mechanism of massage therapy. In this study, we investigated the effect of massage therapy, alone or in combination with infrared heating, on 3 different aspects: physical, physiological, and psychological. Twenty-eight healthy university students were subjected to 3 different treatment conditions on separate days, one condition per day: control, massage only, or massage with infrared heating. Physical (trunk extension [TE]; maximum power of erector spinae), physiological (heart-rate variability [HRV]; electroencephalogram [EEG]), and psychological (state-trait anxiety inventory [STAI]; visual analogue scale [VAS]) measurements were evaluated and recorded before and after each treatment condition. The results showed that massage therapy, especially when combined with infrared heating, significantly improved physical functioning, increased parasympathetic response, and decreased psychological stress and anxiety. In the current study, we observed that massage therapy contributes to various physical, physiological, and psychological changes, where the effect increases with thermotherapy.
Horizontally Transferred Genetic Elements in the Tsetse Fly Genome: An Alignment-Free Clustering Approach Using Batch Learning Self-Organising Map (BLSOM)
Authors: Nakao Ryo , Abe Takashi , Funayama Shunsuke , Sugimoto Chihiro
Published: December 2016

Tsetse flies (Glossinaspp.) are the primary vectors of trypanosomes, which can cause human and animal African trypanosomiasis in Sub-Saharan African countries. The objective of this study was to explore the genome ofGlossina morsitans morsitansfor evidence of horizontal gene transfer (HGT) from microorganisms. We employed an alignment-free clustering method, that is, batch learning self-organising map (BLSOM), in which sequence fragments are clustered based on the similarity of oligonucleotide frequencies independently of sequence homology. After an initial scan of HGT events using BLSOM, we identified 3.8% of the tsetse fly genome as HGT candidates. The predicted donors of these HGT candidates included known symbionts, such asWolbachia, as well as bacteria that have not previously been associated with the tsetse fly. We detected HGT candidates from diverse bacteria such asBacillusand Flavobacteria, suggesting a past association between these taxa. Functional annotation revealed that the HGT candidates encoded loci in various functional pathways, such as metabolic and antibiotic biosynthesis pathways. These findings provide a basis for understanding the coevolutionary history of the tsetse fly and its microbes and establish the effectiveness of BLSOM for the detection of HGT events.
Cost Estimation and Efficiency Analysis of Korean CANDU Spent Fuel Disposal Alternatives in Consideration of Future Price Volatility
Authors: Bang Sungsig , Chung Yanghon , Chun Dongphil , Kwon Chulhong , Hong Sungjun
Published: December 2016

In Korea, spent fuel is temporarily stored in spent fuel pools at nuclear reactor sites and it is predicted to become saturated between 2020 and 2024. For this reason, four disposal alternatives (KRS-1, A-KRS-1, A-KRS-21, and A-KRS-22) have been developed in order to carry out the direct disposal of the CANDU spent fuel. The objective of this study is to conduct cost efficiency analysis of the disposal alternatives in consideration of price volatility for the radioactive waste repository. To derive future price volatility, this study used the ARIMA model. As a result, A-KRS-1 is the most efficient in terms of price per bundle using 2015 price. As for the results using ARIMA model, except in the case of KRS-1, the cost per bundle of A-KRS-1, A-KRS-21, and A-KRS-22 is decreased. Cost estimation using ARIMA model shows little change or decreases in cost while cost estimation using inflation rates for 2020 resulted in approximately 7.2% increases compared to 2015 for all options. As for the results of scenario analysis, A-KRS-1 earned 8,160 points, while A-KRS-22 followed closely behind with 7,980 points among the total 24,300 points. The results of this study provide invaluable policy data for any nation considering the construction of spent nuclear fuel repository.
Profiles of Inflammatory Cytokines in the Vitreous Fluid from Patients with Rhegmatogenous Retinal Detachment and Their Correlations with Clinical Features
Authors: Takahashi Shizuka , Adachi Kobu , Suzuki Yukihiko , Maeno Atsuko , Nakazawa Mitsuru
Published: December 2016

Purpose. To characterize the profiles for inflammatory cytokines in the vitreous fluid from patients with rhegmatogenous retinal detachment (RRD) by comparing those of other vitreoretinal diseases and to analyze the correlation between intravitreal cytokines and clinical features.Materials and Methods. Vitreous fluid was obtained at the time of surgery from 28 RRD eyes. Vitreous fluid was similarly collected from patients with macular hole (MH), epiretinal membrane, proliferative diabetic retinopathy (PDR), and retinal vein occlusion as controls. Twenty-seven cytokines were measured. Intravitreal cytokine profiles in RRD were characterized by comparing these with those in other vitreoretinal diseases. We also analyzed the correlations between vitreous cytokines and clinical features.Results. There were statistical differences in the MCP-1, MIP-1β, and IP-10 between the RRD and MH, while the IL-6 and IL-8 exhibited levels that were between those for the PDR and MH. MIP-1βwas significantly correlated to both the extent and duration of the RRD, while IL-8 was significantly correlated to the extent of the RRD.Conclusions. MCP-1, MIP-1β, and IP-10 may modify the pathologic features of RRD. The levels of these cytokines are related in part to the clinical features and the level of photoreceptor damage.
Influence of Androgen Receptor Gene CAG and GGC Polymorphisms on Male Sexual Function: A Cross-Sectional Study
Authors: Tirabassi Giacomo , Corona Giovanni , Falzetti Sara , delli Muti Nicola , Maggi Mario , Balercia Giancarlo
Published: December 2016

Background. No study has assessed the possible involvement of GGC androgen receptor (AR) polymorphism in sexual function. Our aim is to evaluate the association between CAG and GGC AR polymorphisms in this function.Methods. We retrospectively examined eighty-five outpatients. Clinical, biochemical, and genetic parameters were considered. Sexual assessment was performed using the International Index of Erectile Function (IIEF) which evaluates erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), and overall satisfaction (OS).Results. In the whole sample, CAG repeats were inversely correlated with EF, OF, and total IIEF-15 score, whereas GGC tracts did not show any significant correlation with sexual function. CAG relationship with IIEF items retained significance only in the eugonadal but not in the hypogonadal cohort. On the other hand, GGC tracts were not found to be significantly correlated with IIEF variables in either eugonadal or hypogonadal subjects. In eugonadal subjects, logistic regression pointed out that a higher number of CAG triplets were associated with lower values of EF, OF, SD, OS, and total IIEF independently from other confounders.Conclusions. GGC polymorphism seems not to exert any influence on sexual function, whereas CAG polymorphism appears to affect sexual parameters only in eugonadal subjects.
Monocyte-Derived Macrophages Are Impaired in Myelodysplastic Syndrome
Authors: Han Yu , Wang Huaquan , Shao Zonghong
Published: December 2016

Background. The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic stem cell diseases characterized by cytopenia, dysplasia in one or more of the major myeloid lineages, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia (AML). Macrophages are innate immune cells that ingest and degrade abnormal cells, debris, and foreign material and orchestrate inflammatory processes. We analyzed the role of macrophages from MDS patients in vitro. Methods. Macrophages were induced from peripheral blood of patients with MDS via granulocyte macrophage colony-stimulating factor (GM-CSF). Phagocytic capacity of macrophages was measured with carboxyfluorescein succinimidyl ester and fluorescent microspheres. CD206 and signal regulatory protein alpha (SIRPα) on macrophages were detected by flow cytometry. Inducible nitric oxide synthase (iNOS) was measured by ELISA method. Results. Compared with normal control group, the number of monocytes increased in MDS patients. However, the monocytes showed impaired ability to induce macrophages and the number of macrophages induced from MDS samples was lower. Further, we demonstrated that the ex vivo phagocytic function of macrophages from MDS patients was impaired and levels of reorganization receptors CD206 and SIRPα were lower. Levels of iNOS secreted by macrophages in MDS were increased. Conclusions. Monocyte-derived macrophages are impaired in myelodysplastic syndromes.
To Identify Predictors of Central Lymph Node Metastasis in Patients with Clinically Node-Negative Conventional Papillary Thyroid Carcinoma
Authors: Yuan Jiru , Zhao Gang , Du Jialin , Chen Xiaoyi , Lin Xiaodong , Chen Zhengbo , Wu Zeyu
Published: December 2016

Objective. The aim of this study was to identify the risk factors associated with central lymph node metastasis (CLNM) in patients with clinically node-negative conventional papillary thyroid carcinoma (cN0CPTC).Methods. A total of 190 cN0CPTC patients who underwent thyroidectomy with prophylactic central neck dissection (pCND) in the Department of General Surgery at Guangdong General Hospital between March 2014 and December 2015 were assessed retrospectively. The relations of CLNM with clinicopathologic characteristics of cN0CPTC were analyzed by univariate and multivariate logistic regression.Results. The incidence of CLNM in patients with cN0CPTC was 63.2% (120 of 190 cases). Univariate analysis showed that age <45 years (P=0.000), tumor size >2 cm (P=0.009), multifocality (P=0.001), and bilaterality (P=0.000) were significantly associated with the increased incidence of CLNM in cN0CPTC. No significant correlations were found between CLNM and other variables such as gender (P=0.150), capsular invasion (P=0.973), extrathyroidal invasion (P=0.616), and lymphadenectomy (P=0.062). Multivariate logistic regression analysis revealed that age <45 years (P=0.000), tumor size >2 cm (P=0.025), and bilaterality (P=0.000) were independent risk factors of CLNM in patients with cN0CPTC.Conclusions. Metastatic disease to central compartment lymph nodes is prevalent in patients with cN0CPTC. Age <45 years, tumor size >2 cm, and bilaterality are independent risk factors of CLNM, which allow for selective CND in patients with cN0CPTC.
Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis
Authors: Tanaka Miwa , Homme Mizuki , Yamazaki Yukari , Shimizu Rikuka , Takazawa Yutaka , Nakamura Takuro
Published: December 2016

Alveolar soft part sarcoma (ASPS) is a slowly growing, but highly metastatic, sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here, we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. High expression of glycoprotein nmb (GPNMB), a transcriptional target of ASPSCR1-TFE3, was observed at the sites of intravasation. ASPS tumor cells also demonstrated enhanced transendothelial migration activity, which was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, a key step in cancer metastasis. The present model also enabled the evaluation of TFE/MITF family transcription factor function, which demonstrated that ASPSCR1-TFEB possessed definitive albeit less marked oncogenic activity than that of ASPSCR1-TFE3. Collectively, our mouse model provides a tool to understand oncogenic, angiogenic, and metastatic mechanisms of ASPS. It also identifies important motifs within the ASPSCR1-TFE3 fusion protein and provides a platform for developing novel therapeutic strategies for this disorder. Cancer Res; 77(4); 897–907. ©2016 AACR.
The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics
Authors: Martens-de Kemp Sanne R. , Brink Arjen , van der Meulen Ida H. , de Menezes Renée X. , te Beest Dennis E. , Leemans C. René , van Beusechem Victor W. , Braakhuis Boudewijn J.M. , Brakenhoff Ruud H.
Published: December 2016

Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that influence the response to cisplatin in HNSCC cells. By siRNA-mediated knockdown, we identified the Fanconi anemia/BRCA pathway as the predominant pathway for cisplatin response in HNSCC cells. We also identified the involvement of the SHFM1 gene in the process of DNA cross-link repair. Furthermore, expression profiles based on these genes predict the prognosis of radiation- and chemoradiation-treated head and neck cancer patients. This genome-wide functional analysis designated the genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Cisplatin imaging as well as biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway in the tumors are the prime candidates. Mol Cancer Ther; 16(3); 540–50. ©2016 AACR.
Folate-Hapten–Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer
Authors: Bandara N. Achini , Bates Cody D. , Lu Yingjuan , Hoylman Emily K. , Low Philip S.
Published: December 2016

The overexpression of folate receptors (FR) on many human cancers has led to the development of folate-linked drugs for the imaging and therapy of FR-expressing cancers. In a recent phase I clinical trial of late-stage renal cell carcinoma patients, folate was exploited to deliver an immunogenic hapten, fluorescein, to FR+ tumor cells in an effort to render the cancer cells more immunogenic. Although >50% of the patients showed prolonged stable disease, all patients eventually progressed, suggesting that the folate-hapten immunotherapy was insufficient by itself to treat the cancer. In an effort to identify a companion therapy that might augment the folate-hapten immunotherapy, we explored coadministration of two approved cancer drugs that had been previously shown to also stimulate the immune system. We report that sunitinib and axitinib (VEGF receptor inhibitors that simultaneously mitigate immune suppression) synergize with the folate-hapten–targeted immunotherapy to reduce tumor growth in three different syngeneic murine tumor models. We further demonstrate that the combination therapy not only enhances tumor infiltration of CD4+ and CD8+ effector cells, but surprisingly reduces tumor neovasculogenesis more than predicted. Subsequent investigation of the mechanism for this unexpected suppression of neovasculogenesis revealed that it is independent of elimination of any tumor cells, but instead likely derives from a reduction in the numbers of FR+ tumor-associated macrophages and myeloid-derived suppressor cells, that is, immunosuppressive cells that release significant quantities of VEGF. These data suggest that a reduction in stromal cells of myeloid origin can inhibit tumor growth by suppressing neovasculogenesis. Mol Cancer Ther; 16(3); 461–8. ©2016 AACR.
Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome
Authors: Raynal Noël J.-M. , Da Costa Elodie M. , Lee Justin T. , Gharibyan Vazganush , Ahmed Saira , Zhang Hanghang , Sato Takahiro , Malouf Gabriel G. , Issa Jean-Pierre J.
Published: December 2016

Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397–407. ©2016 AACR.
Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca2+-eNOS Pathway in Rats
Authors: Yang Weiwei , Li Shuzhen , Liao Lin , Zheng Xiaodong , Li Jiali , Zheng Yaqin , Zhang Xiuling , Zhu Daling
Published: December 2016

Aims: Nobiletin, a natural polymethoxylated flavonoid compound, has various beneficial properties, such as anticancer, anti-inflammatory, and antioxidant effects, and it also improves memory. Therefore, we investigated the effects and mechanisms of nobiletin on rat isolated mesenteric arteries (MAs). Methods: We examined vasodilation induced by nobiletin on rat isolated MA rings with a tension study, the expression and activity of endothelial nitric oxide synthase (eNOS) with Western blotting, NO production with DAF- FMDA fluorescence, and intracellular Ca2+ concentration ([Ca2+]i) with Fluo-3AM. Results and Conclusion: Our study showed that nobiletin elicited a dose-dependent vasodilation in phenylephrine precontracted MA rings, but it did not elicit the same response in pulmonary artery rings. Vasodilation was related to endothelium and activated partly by eNOS. Vasodilation was inhibited by denudation of the endothelium or inhibition of eNOS activity. Nobiletin increased NO production by promoting the phosphorylation of eNOS at Ser-1177 without changing the level of eNOS expression in rat mesenteric artery endothelial cells (RMAECs). Nobiletin increased the concentration of endothelial [Ca2+]i, which enhances eNOS activity in RMAECs. In summary, vasodilation induced by nobiletin was dependent on the endothelium and partly on eNOS activation, which is mediated by high endothelial [Ca2+]i. Results suggest nobiletin may offer a therapeutic benefit and could potentially be used as a vasodilator for the treatment of hypertension.
Conduction Abnormalities after Transcatheter Aortic Valve Implantation and Diastolic Dysfunction
Authors: Priesler Ofir , Biner Simon , Finkelstein Ariel , Michowitz Yoav
Published: December 2016

Objectives: Transcatheter aortic valve implantation (TAVI) is frequently associated with the development of conduction abnormalities. We assessed the effect of conduction abnormalities on diastolic function following TAVI. Methods: In total, 101 consecutive post-TAVI patients were included, each with echocardiographic follow-up at 1 and 6 months. Diastolic properties were correlated with the occurrence of a long PR interval and wide QRS, and their change from baseline. The measured diastolic parameters included E/A ratio, E wave deceleration time, E wave to e′ ratio, left atrial (LA) volume, and systolic pulmonary artery pressure (SPAP). The clinical outcome was all-cause mortality. Results: Overall, TAVI was associated with a consistent decrease in SPAP at the 1- and 6-month follow-up. LA volumes were increased at 1 month post-TAVI in patients with a wide compared to normal QRS (p = 0.03) and at 6 months in patients with a normal compared to prolonged PR (p = 0.03). PR prolongation above 40 ms was associated with lower SPAP at the 1- but not 6-month follow-up. Survival was not influenced by conduction abnormalities. Conclusions: TAVI is associated with a reduction in SPAP. A postprocedural wide QRS and normal PR interval may unfavorably influence the left-sided filling performance, resulting in an increased LA volume. Other diastolic parameters, as well as survival, are not significantly affected by postprocedural conduction abnormalities.
Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1
Authors: Kristofikova Zdenka , Ricny Jan , Soukup Ondrej , Korabecny Jan , Nepovimova Eugenie , Kuca Kamil , Ripova Daniela
Published: December 2016

Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.
Generalization of Context-Specific Training in Individuals with Mild Cognitive Impairment: An Event-Related Potential Study
Authors: Chan Sam C.C. , Lam Tommy L.H. , Fong Kenneth N.K. , Pang Marco Y.C. , Chan Chetwyn C.H.
Published: December 2016

Background: This study examined the neural processes associated with the generalization of the effect of context-specific (CS) training to noncontextual situations among individuals with mild cognitive impairment (MCI). Methods: Fourteen and 16 participants with MCI were randomly allocated to a Chinese calligraphy writing (CW) training or a control group, respectively. The CW participants learned how to write Chinese strokes in a semicursive style to construct characters, tapping on working memory functions. The control group, on the other hand, learned how to use a tablet computer without emphasis on working memory functions. They then performed two 2-back tasks with CS semicursive strokes and non-context-specific (NCS) digits. Event-related electroencephalogram signals were concurrently recorded. Results: The CW participants had a significantly shorter reaction time in the CS than in the NCS task (p < 0.05). They showed significantly longer latency in working memory updating (N200; t11 = 4.70, p = 0.05) and shorter latency in the evaluation of visual representation (P300; t12 = 4.67; p = 0.05) than the control group when performing the 2-back CS task. Shorter P300 latency was also revealed in the 2-back NCS task (t12 = 5.15, p = 0.041), suggesting a possible generalization of the training effect among the CW participants. Conclusion: The results suggest that CS working memory is likely to be generalized to NCS domains among individuals with MCI. Future research should extend the scope of the generalization and apply it beyond experimental conditions.
Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects
Authors: Akizawa Tadao , Tsubakihara Yoshiharu , Nangaku Masaomi , Endo Yukihiro , Nakajima Hiromu , Kohno Tomoko , Imai Yukiko , Kawase Natsumi , Hara Katsutoshi , Lepore John , Cobitz Alexander
Published: December 2016

Background: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. Methods: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated. Results: Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL. Conclusion: Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels.
Venous Thrombotic Recurrence After Cerebral Venous Thrombosis
Authors: Palazzo Paola , Agius Pierre , Ingrand Pierre , Ciron Jonathan , Lamy Matthias , Berthomet Aline , Cantagrel Paul , Neau Jean-Philippe
Published: December 2016

Background and Purpose—

After cerebral venous thrombosis (CVT), the risk of venous thrombotic events was estimated at 2% to 3% for a new CVT and 3% to 8% for extracranial events. However, because of the paucity of prospective studies, the clinical course of CVT is still largely unknown. We aimed to prospectively evaluate the rate of thrombosis recurrence in a cohort of CVT patients with a long-term follow-up and to detect predisposing factors for recurrence.

Methods—

Consecutive CVT patients with complete clinical, radiological, biological, and genetic data were systematically followed up. New venous thrombotic events were detected after hospital readmission and imaging confirmation.

Results—

One-hundred eighty-seven patients (mean age 45±18 years, 67% women) with angiographically confirmed CVT were included. Cause was found in 73% of patients. Coagulation abnormality and JAK2 gene mutation were detected in 20% and 9%, respectively. Median follow-up length was 73 months (range 1–247 months). Mean duration of the oral anticoagulant treatment was 14 months. Mortality rate was 2.5% per year, with 2% in-hospital mortality. During follow-up, CVT reoccurred in 6 patients, whereas 19 subjects had a symptomatic extracranial venous thrombotic event, with cumulative venous thrombotic recurrence rates of 3% at 1 year, 8% at 2 years, 12% at 5 years, and 18% at 10 years. A previous venous thrombotic event (hazard ratio, 2.8;
P
=0.018), presence of cancer or malignant hemopathies (hazard ratio, 3.2;
P
=0.039), and unknown CVT causes (hazard ratio, 2.81;
P
=0.024) were independently associated with recurrence.

Conclusions—

In our cohort of CVT patients followed on average for >6 years, subjects with a previous venous thrombotic event, cancer/malignant hemopathies, and unknown CVT causes were found to be at higher risk of recurrence.
Charles Brockden Brown and the Conundrum of Complicity
Authors: Zimmerman David
Published: December 2016

Charles Brockden Brown’s four major novels, all written between 1798 and 1800, are devoted to the conundrum of moral complicity—the impossibility of pinpointing moral accountability for harms in a world where intersubjective life makes it impossible to separate one person’s action from the actions of others. This essay argues that for Brown, this conundrum constituted the narrative precondition of fictional storytelling and served as the source of his fiction’s formal innovation, theoretical self-consciousness, and gothic weirdness. This essay suggests, too, that the conundrum of complicity served as the prompt for a synoptic mode of reading that Brown introduced to American fiction.
Uncle Tom across the Sea (and Back): Pierre Faubert and the Haitian Response to Harriet Beecher Stowe
Authors: Albanese Mary Grace
Published: December 2016

The transnational material network of Harriet Beecher Stowe’s Uncle Tom’s Cabin (1852) has enjoyed substantial critical analysis: however, most scholarship tends to focus on the novel’s influence in Europe. Haiti plays a much greater role in the novel than any European country, yet in contrast to Britain, France, or Hungary, the first black republic is seldom considered a serious actor within Uncle Tom’s reception history. This essay considers how Stowe’s cautionary specter of the “San Domingo hour” was translated to Haiti and, in turn, the diverse ways in which Haitians responded to l’Oncle Tom. Ultimately, this essay argues that Haiti, far from being an isolated figure, was aware of, responded to, and cannily attempted to retranslate its own image both at home and abroad. This essay contributes to a long-neglected archive of Haitian cultural production while more broadly asking how Haitian writers revised Stowe’s conceptualization of nationhood.
Use of cidofovir in pediatric patients with adenovirus infection
Authors: Ganapathi Lakshmi , Arnold Alana , Jones Sarah , Patterson Al , Graham Dionne , Harper Marvin , Levy Ofer
Published: December 2016

Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity.  

Methods: We conducted a retrospective 5-year review at Boston Children’s Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction.  

Results:Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV.

Conclusions:  CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.
Preliminary results on the control of Aedes spp. in a remote Guatemalan community vulnerable to dengue, chikungunya and Zika virus: community participation and use of low-cost ecological ovillantas for mosquito control
Authors: Ulibarri Gerard , Betanzos Angel , Betanzos Mireya , Rojas Juan Jacobo
Published: December 2016

Objective: To study the effectiveness of an integrated intervention of health worker training, a low-cost ecological mosquito ovitrap, and community engagement on Aedes spp. mosquito control over 10 months in 2015 in an urban remote community in Guatemala at risk of dengue, chikungunya and Zika virus transmission.

Methods: We implemented a three-component integrated intervention consisting of: web-based training of local health personnel in vector control, cluster-randomized assignment of an ecological modified ovitrap (ovillantas: ovi=egg, llanta=tire) or standard ovitraps to capture Aedes spp. mosquito eggs (no efforts have been taken to determine the exact Aedes species at this moment), and community engagement to promote participation of community members and health personnel in the understanding and maintenance of ovitraps for mosquito control. The intervention was implemented in local collaboration with Guatemala’s  Ministry of Health’s Vector Control Programme, and in international collaboration with the National Institute of Public Health in Mexico.

Findings: Eighty percent of the 25 local health personnel enrolled in the training programme received accreditation of their improved knowledge of vector control. When ovillantas were used in a cluster of ovitraps (several in proximity), significantly more eggs were trapped by  ecological ovillantas than standard ovitraps over the 10 month (42 week) study period (t=5.2577; p<0.05). Repetitive filtering and recycling of the attractant solution (or water) kept the ovillanta clean, free from algae growth. Among both community members and health workers, the levels of knowledge, interest, and participation in community mosquito control and trapping increased. Recommendations for enhancing and sustaining community mosquito control were identified.

Conclusion: Our three-component integrated intervention proved beneficial to this remote community at risk of mosquito-borne diseases such as dengue, chikungunya, and Zika. The combination of training of health workers, cluster use of low-cost ecological ovillanta to destroy the second generation of mosquitoes, and community engagement ensured the project met local needs and fostered collaboration and participation of the community, which can help improve sustainability. The ovillanta intervention and methodology may be modified to target other species such as Culex, should it be established that such mosquitoes carry Zika virus in addition to Aedes.
Hemodynamic monitoring in the critically ill: an overview of current cardiac output monitoring methods
Authors: Huygh Johan , Peeters Yannick , Bernards Jelle , Malbrain Manu L. N. G.
Published: December 2016

Critically ill patients are often hemodynamically unstable (or at risk of becoming unstable) owing to hypovolemia, cardiac dysfunction, or alterations of vasomotor function, leading to organ dysfunction, deterioration into multi-organ failure, and eventually death. With hemodynamic monitoring, we aim to guide our medical management so as to prevent or treat organ failure and improve the outcomes of our patients. Therapeutic measures may include fluid resuscitation, vasopressors, or inotropic agents. Both resuscitation and de-resuscitation phases can be guided using hemodynamic monitoring. This monitoring itself includes several different techniques, each with its own advantages and disadvantages, and may range from invasive to less- and even non-invasive techniques, calibrated or non-calibrated. This article will discuss the indications and basics of monitoring, further elaborating on the different techniques of monitoring.
Laboratory Evidence on the Effects of Sponsorship on the Competitive Preferences of Men and Women
Authors: Baldiga Nancy R. , Coffman Katherine B.
Published: December 2016

Sponsorship programs have been proposed as one way to promote female advancement in competitive career fields. A sponsor is someone who advocates for a protégé, and in doing so, takes a stake in her success. We use a laboratory experiment to explore two channels through which sponsorship has been posited to increase advancement in a competitive workplace. In our setting, being sponsored provides a vote of confidence and/or creates a link between the protégé’s and sponsor’s payoffs. We find that both features of sponsorship significantly increase willingness to compete among men on average, while neither of these channels significantly increases willingness to compete among women on average. As a result, sponsorship does not close the gender gap in competitiveness or earnings. We discuss how these insights from the laboratory could help to inform the design of sponsorship programs in the field.

Data, as supplemental material, are available at https://doi.org/10.1287/mnsc.2016.2606 .

This paper was accepted by Uri Gneezy, behavioral economics.
0/1 Polytopes with Quadratic Chvátal Rank
Authors: Rothvoß Thomas , Sanità Laura
Published: December 2016

For a polytope P, the Chvátal closure P′ ⊆ P is obtained by simultaneously strengthening all feasible inequalities cx ⩽ β (with integral c) to cx ⩽ ⌊β⌋. The number of iterations of this procedure that are needed until the integral hull of P is reached is called the Chvátal rank. If P ⊆ [0, 1]n, then it is known that O(n2 log n) iterations always suffice and at least (1 + 1/e − o(1))n iterations are sometimes needed, leaving a huge gap between lower and upper bounds.

We prove that there is a polytope contained in the 0/1 cube that has Chvátal rank Ω(n2), closing the gap up to a logarithmic factor. In fact, even a superlinear lower bound was mentioned as an open problem by several authors. Our choice of P is the convex hull of a semi-random Knapsack polytope and a single fractional vertex. The main technical ingredient is linking the Chvátal rank to simultaneous Diophantine approximations w.r.t. the ‖·‖1-norm of the normal vector defining P.