bluuebunny/crossref_metadata_2025 huggingface dataset:
How Supraphysiological Oxygen Levels in Standard Cell Culture Affect Oxygen‐Consuming Reactions
Authors: Stuart Jeffrey A. , Fonseca Joao , Moradi Fereshteh , Cunningham Cassandra , Seliman Bishoy , Worsfold Cydney R. , Dolan Sarah , Abando John , Maddalena Lucas A.
Published: September 2018

Most mammalian tissue cells experience oxygen partial pressures in vivo equivalent to 1–6% O2 (i.e., physioxia). In standard cell culture, however, headspace O2 levels are usually not actively regulated and under these conditions are ~18%. This drives hyperoxia in cell culture media that can affect a wide variety of cellular activities and may compromise the ability of in vitro models to reproduce in vivo biology. Here, we review and discuss some specific O2‐consuming organelles and enzymes, including mitochondria, NADPH oxidases, the transplasma membrane redox system, nitric oxide synthases, xanthine oxidase, and monoamine oxidase with respect to their sensitivities to O2 levels. Many of these produce reactive oxygen and/or nitrogen species (ROS/RNS) as either primary end products or byproducts and are acutely sensitive to O2 levels in the range from 1% to 18%. Interestingly, many of them are also transcriptional targets of hypoxia‐inducible factors (HIFs) and chronic cell growth at physioxia versus 18% O2 may alter their expression. Aquaporins, which facilitate hydrogen peroxide diffusion into and out of cells, are also regulated by HIFs, indicating that O2 levels may affect intercellular communication via hydrogen peroxide. The O2 sensitivities of these important activities emphasize the importance of maintaining physioxia in culture.
Suitability Investigation of Recycled Concrete Aggregates for Concrete Production: An Experimental Case Study
Authors: Taffese Woubishet Zewdu
Published: September 2018

In developing countries, construction and demolition waste (CDW) is disposed to landfill, causing social, environmental, and economic crises. In these nations, CDW exponentially increase due to their rapid economic growth, industrialization, and urbanization. This paper aims to examine the possibility of recycling concrete waste for production of new concrete in Ethiopia. Physical and mechanical characteristics of recycled concrete aggregate (RCA) acquired from concrete waste are thoroughly examined. Though the RCA exhibited relatively lesser performance compared with the natural coarse aggregate (NCA), it reveals the same properties as of normal‐weight aggregates in several instances. The performance of concrete specimens which employ RCA up to 20% is evaluated from workability, strength, and permeability aspects. The utilization of RCA slightly affects the workability and the water permeability properties of the concretes. Replacement of 10% of the NCA by the RCA enhances the compressive strength of the hardened concrete by 8%. The difference between the splitting tensile strength of the concretes which employ RCA and conventional aggregates is trivial. Generally, this work demonstrates the practicability of concrete waste recycling to produce new concrete or construction materials in Ethiopian context.
Updates on the Status of Vitamin D as a Risk Factor for Respiratory Distress Syndrome
Authors: Gatera Vesara Ardhe , Abdulah Rizky , Musfiroh Ida , Judistiani Raden Tina Dewi , Setiabudiawan Budi
Published: September 2018

To update the guidelines regarding vitamin D status in respiratory distress syndrome, we reviewed recent human and animal studies on the benefits of vitamin D in respiratory distress. We searched PubMed and ProQuest for studies on the use of vitamin D from 2009 to 2017. The common parameters in these studies included the use of lung tissue, phospholipids, blood, and plasma to assess the effects of vitamin D on respiratory syndrome. The metabolized form of vitamin D used in these studies was 1,25(OH)2D3 in animal studies and 25(OH)D in human studies. Vitamin D supplementation decreases the risk of respiratory distress syndrome, improves the quality of life, and is relatively effective and safe for preterm neonates as well as during lung maturation. However, although vitamin D supplementation may offer benefits for respiratory distress syndrome, the optimal dosing strategies for specific types of risk factors in the lungs must be clarified to confirm the therapeutic efficacy.
miR‐26a Potentially Contributes to the Regulation of Fatty Acid and Sterol Metabolism In Vitro Human HepG2 Cell Model of Nonalcoholic Fatty Liver Disease
Authors: Ali Omaima , Darwish Hebatallah A. , Eldeib Kamal M. , Abdel Azim Samy A.
Published: September 2018

Nonalcoholic fatty liver disease (NAFLD) is a metabolic‐related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). This study aimed at assessing the regulatory and protective role of miR‐26a on lipid metabolism and progression of NAFLD in human HepG2 cells loaded with free fatty acids (FFA). Lentivirus expressing miR‐26a or negative control miR was used to transduce HepG2 cells and to establish stable cell lines. Gain or loss of function using an miR‐26a inhibitor was used to compare triglyceride content (TG), total cholesterol level (CL), total antioxidant capacity (TAC), malondialdehyde (MDA) and the level of apoptosis. In addition, quantitative reverse transcription polymerase chain reaction (qPCR) was used to assess the mRNA levels of lipogenesis, TG synthesis, storage genes, inflammatory and fibrogenic markers, and autophagic besides endoplasmic reticulum (ER) stress markers after gaining or losing the function of miR‐26a. miR‐26a levels decreased in response to FFA in human HepG2 cells. After the establishment of a stable cell line, the upregulation of miR‐26a resulted in the downregulation of TG, CL, and MDA levels, through regulating mRNA levels of genes involved in lipid homeostasis, ER stress marker, inflammatory and fibrogenic markers. Nevertheless, there was a marked increment in the mRNA expression of autophagic marker genes. Moreover, miR‐26a overexpression protects the cells from apoptosis, whereas inhibition of miR‐26a, using an anti‐miR‐26a oligonucleotide, decreased the expression of miR‐26a which potentially contributes to altered lipid metabolism in HepG2 cells loaded with FFA. In conclusion, these findings suggested that miR‐26a has a crucial role in regulating fatty acid and cholesterol homeostasis in HepG2 cells, along with the offered protection against the progression of NAFLD in vitro. Hence, miRNAs could receive growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets.
ABCC4 Variants Modify Susceptibility to Kawasaki Disease in a Southern Chinese Population
Authors: Che Di , Pi Lei , Fang Zhenzhen , Xu Yufen , Cai Minmin , Fu Lanyan , Zhou Huazhong , Zhang Li , Gu Xiaoqiong
Published: September 2018

A previous family-based linkage study revealed that Kawasaki disease (KD) was associated with variations of the ATP-binding cassette subfamily C member 4 (ABCC4) gene in most European populations. However, significant differences exist among ethnic populations in European and Chinese subjects; therefore, whether ABCC4 variants indicate susceptibility to KD in Chinese children is unclear. The purpose of this research was to evaluate correlations between ABCC4 gene polymorphisms and susceptibility to KD in a Southern Chinese population. We genotyped six polymorphisms (rs7986087, rs868853, rs3765534, rs1751034, rs3742106, and rs9561778) in 775 KD patients and 774 healthy controls. Ninety-five percent confidence intervals (95% CIs) and odds ratios (ORs) were used to assess the strength of each association. We found that the rs7986087 T variant genotype was associated with significantly higher susceptibility to KD (adjusted OR = 1.30, 95% CI = 1.05–1.60 for rs7986087 CT/TT). However, the rs868853 T variant genotype was associated with significantly lower susceptibility to KD (adjusted OR = 0.74, 95% CI = 0.59–0.92 for rs868853 CT/CC). Compared with the patients with 0–4 ABCC4 risk genotypes, the patients with 5-6 ABCC4 risk genotypes had a significantly increased risk of KD (adjusted OR = 1.63, 95% CI = 1.07–2.47), and this risk was more significant in the subgroups of females, subjects aged 12–60 months, and individuals with coronary artery lesions. These results indicate that specific single-nucleotide polymorphisms in the ABCC4 gene may increase susceptibility to KD in a Southern Chinese population.
Human-Robot Interaction and Demonstration Learning Mode Based on Electromyogram Signal and Variable Impedance Control
Authors: Wu Rui , Zhang He , Peng Tao , Fu Le , Zhao Jie
Published: September 2018

In this research, properties of variable admittance controller and variable impedance controller were simulated by MATLAB firstly, which reflected the good performance of these two controllers under trajectory tracking and physical interaction. Secondly, a new mode of learning from demonstration (LfD) that conforms to human intuitive and has good interaction performances was developed by combining the electromyogram (EMG) signals and variable impedance (admittance) controller in dragging demonstration. In this learning by demonstration mode, demonstrators not only can interact with manipulator intuitively, but also can transmit end-effector trajectories and impedance gain scheduling to the manipulator for learning. A dragging demonstration experiment in 2D space was carried out with such learning mode. Experimental results revealed that the designed human-robot interaction and demonstration mode is conducive to demonstrators to control interaction performance of manipulator directly, which improves accuracy and time efficiency of the demonstration task. Moreover, the trajectory and impedance gain scheduling could be retained for the next learning process in the autonomous compliant operations of manipulator.
Incidence and Risk Factors of Intraocular Foreign Body-Related Endophthalmitis in Southern China
Authors: Duan Fang , Yuan Zhaohui , Liao Jingyu , Zheng Yongxin , Yang Yao , Lin Xiaofeng
Published: September 2018

Purpose. To investigate the incidence and risk factors of intraocular foreign body- (IOFB-) related endophthalmitis.Methods. A total of 1701 patients diagnosed with IOFB between January 1, 2005 and June 30, 2015 were included. Two groups of patients were defined according to the presence or absence of endophthalmitis, and a comparison of personal information, IOFB characteristics, and wound location were performed.Results. In total, 279 patients (16.4%) developed endophthalmitis, older age (P=0.01) was a risk factor. IOFBs retained in the crystal lens or wall of the eyeball conferred lower risks (P=0.01and 0.04, respectively) compared to the vitreous chamber. The coexistence of different IOFB types and plant IOFBs conferred higher risks (P=0.02and 0.03, respectively), while glass/plastic IOFBs conferred a lower risk (P=0.03) compared to metallic IOFBs.Conclusions. Age, IOFB locations, and types were related to development of endophthalmitis, while IOFB number, size, or timing of primary repairs was not related.
A Rapid Detection Method for Bridges Based on Impact Coefficient of Standard Bumping
Authors: Liu Xiaolan , Zhang Xianmin , Wang Yadong
Published: September 2018

The evaluation method of load transfer efficiency using falling weight deflectometer is unworkable in remote mountain areas and transportation difficult region. Therefore, a novation method of load transfer efficiency evaluation is proposed using the index of amplitude ratio. Finite element method is applied to study the influence of dowel bar parameters (diameter, length, spacing, and elastic modulus) and pavement structures parameters (thickness and modulus) on load transfer efficiency, frequency, and the ratio of amplitude. Results of finite element model show that the effects of dowel bar and pavement structure parameters on load transfer efficiency and the ratio of amplitude are similar. The load transfer efficiency, frequency, and the ratio of amplitude enhance with the increase of dowel bar diameter, length, and elastic modulus and the decrease of dowel bar spacing. The subgrade modulus has more significant influence on the load transfer efficiency, frequency, and the ratio of amplitude than other pavement parameters. Polynomial function method is utilized to established load transfer mode between deflection-based load transfer efficiency and the ratio of amplitude. The feasibility and reliability of new method is verified by static and dynamic load test. All results are helpful for the development of highway engineering and airport engineering.
Effect of Natural Antioxidants on the Stability of Linseed Oil and Fish Stored under Anaerobic Conditions
Authors: Śpitalniak-Bajerska Kinga , Szumny Antoni , Kucharska Alicja Zofia , Kupczyński Robert
Published: September 2018

Vegetable and animal oils are susceptible to the oxidation of their lipid components on storage. Polyphenols from apple peels are investigated as potential natural antioxidants used for stabilizing polyunsaturated fatty acid and preventing oxidation. The aim of this study was assessing the antioxidant efficacy of apple pomace as natural antioxidant in linseed and fish oils, stored in anaerobic conditions. Apple pomace was added to the linseed and fish oils stored for eight weeks to evaluate the antioxidant activity of their polyphenolic components. The total phenolic content, activity of DPPH, ABTS•+, FRAP, acid value (AV), peroxide value (PV), and fatty acid profile were analyzed in storage tests. We found that apple pomace, regardless of the oil content of the formulation, was capable of blanking 2,2-diphenyl-1-picrylhydrazyl radicals. The highest ability to reduce Fe3+ ions occurred in the samples containing 30% of the fish oil. The use of apple pomace comprising polyphenolic compounds improves the stability of linseed and fish oils in storage tests. Polyphenols in apple pomace show a high antioxidant potential, as indicated by their values of DPPH, ABST•+, and FRAP. The addition of apple pomace resulted in limiting the acid and peroxide values of the samples during storage.
Acupuncture and Related Therapies for Obesity: A Network Meta‐Analysis
Authors: Zhang Yanji , Li Jia , Mo Guoyan , Liu Jing , Yang Huisheng , Chen Xianglin , Liu Hui , Cai Teng , Zhang Xian , Tian Xiangmin , Zhou Zhongyu , Huang Wei
Published: September 2018

Obesity is a worldwide public health problem. Currently, increasing evidence suggests acupuncture and related therapies are effective for obesity. This network meta‐analysis (NMA) was performed to compare the effectiveness of different acupuncture and related therapies. We searched potential randomized controlled trials (RCTs) in three international databases. Thirty‐four trials involving 2283 participants were included. Pairwise meta‐analysis showed that acupuncture and related therapies were superior to lifestyle modification and placebo in reducing weight and body mass index (BMI). Based on decreases in body weight, results from NMA showed that acupoint catgut embedding (standard mean difference [SMD]: 1.26; 95% credible interval [95% CI], 0.46–2.06), acupuncture (SMD: 2.72; 95% CrI, 0.06–5.29), and combination of acupuncture and related theories (SMD: 3.65; 95% CrI, 0.96–6.94) were more effective than placebo. Another NMA result indicated that acupoint catgut embedding (SMD: 0.63; 95% CI, 0.25–1.11), acupuncture (SMD: 1.28; 95% CrI, 0.43–2.06), combination of acupuncture and related therapies (SMD: 1.44; 95% CrI, 0.64–2.38), and electroacupuncture (SMD: 0.60; 95% CrI, 0.03–1.22) were superior to lifestyle modification in decreasing BMI. Combination of acupuncture and related therapies was ranked the optimal method for both reducing weight and BMI. Further studies will clarify which combination of acupuncture and related therapies is better.
Relationships among Antibodies against Extractable Nuclear Antigens, Antinuclear Antibodies, and Autoimmune Diseases in a Brazilian Public Hospital
Authors: Banhuk Fernanda Weyand , Pahim Bruna Corrêa , Jorge Alex Sandro , Menolli Rafael Andrade
Published: September 2018

One characteristic of autoimmune diseases (ADs) is the production of autoantibodies for extractable nuclear autoantigens, which may aid in the discrimination of the different types of autoimmune diseases and is related to different antinuclear antibody (ANA) patterns. The present study verified the profile of patient samples tested for extractable nuclear antigens (ENA) antibodies in a public hospital and correlated the ENA results with ANA patterns and patient diagnoses. The study reviewed data in the medical records of patients who underwent anti-ENA tests at a public hospital in the West of the State of Paraná from February 2011 to January 2017. Patients were classified according to age, ethnicity, gender, anti-ENA test results, ANA results, and the presence or absence of AD. Thirty-six (20.9%) samples of the 172 anti-ENA tests were positive, seven (4.1%) samples were undetermined, and 129 (75%) exhibited negative results. The ANA reagent was found in 84.3% of the anti-ENA-positive samples. The anti-SSA/Ro autoantibody exhibited the highest frequency in the group, 41.7% (15/36). The most common pattern was nuclear fine speckled, which was found in 24.3% of the samples. The association results indicated a significant relationship between ANA titer and diagnosis in the anti-ENA- and ANA-positive patients. The anti-ENA-negative patients were diagnosed with an AD in 35% (45/129) of the cases, and 75% (27/36) of the anti-ENA-positive patients were diagnosed with an AD. Systemic lupus erythematosus and scleroderma were the most common pathologies in the antigen-positive patients. The anti-ENA test is a good marker to aid in the complex clinical diagnosis of patients with autoimmune diseases.
On the Blended Solutions of Polynomial-Like Iterative Equation with Multivalued Functions
Authors: Liu Jinghua , Duan Hongjuan , Yu Zhiheng
Published: October 2018

Theblendedsolutions are more general than theunblendedsolutions for polynomial-like iterative equation with multivalued functions. In this paper we study theblendedsolutions of polynomial-like iterative equation with multivalued functions.
PD-L1 Mediates Dysfunction in Activated PD-1+ NK Cells in Head and Neck Cancer Patients
Authors: Concha-Benavente Fernando , Kansy Benjamin , Moskovitz Jessica , Moy Jennifer , Chandran Uma , Ferris Robert L.
Published: October 2018

Inhibitory immune-checkpoint receptors (ICRs), including programmed death 1 (PD-1), have been characterized as exhaustion markers on T cells that infiltrate the tumor microenvironment (TME) of many cancer types, including head and neck cancer (HNC). However, expression and function of ICRs, including PD-1, on natural killer (NK) cells remains less defined. NK cells are innate immune effector cells that lyse epidermal growth factor receptor–overexpressing HNC cells via cetuximab-mediated antibody-dependent cytotoxicity. Cetuximab is clinically effective but only in 10% to 15% of patients. Therefore, it is necessary to investigate how immunomodulation with cetuximab or PD-1 blockade might enhance NK cell responses in the TME and improve monoclonal antibody therapeutic efficacy. We observed that expression of PD-1 on NK cells marks an activated phenotype, which was suppressed only after binding programmed death ligand-1 (PD-L1). HNC patients who exhibit higher circulating PD-1+ NK cells associate with better clinical outcome, and these cells are enriched in the TME. Cetuximab-mediated NK cell activation increased PD-1 expression on NK cells in vitro, which was confirmed in vivo in a prospective neoadjuvant cetuximab trial. In contrast, PD-L1 ligation of PD-1+ NK cells diminished their activation status, whereas PD-1 blockade increased cetuximab-mediated NK cell activation and cytotoxicity, but only against HNC targets with high PD-L1 expression. Therefore, blocking the PD-1–PD-L1 axis may be a useful strategy to reverse immune evasion of HNC tumors with high PD-L1 expression during cetuximab therapy by reversing NK cell dysfunction.
Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus
Authors: Liu Limin , Wang Herui , Cui Jing , Zhang Qi , Zhang Wei , Xu Wanlin , Lu Hao , Liu Shengwen , Shen Shukun , Fang Francia , Li Lei , Yang Wenjun , Zhuang Zhengping , Li Jiang
Published: October 2018

Background/Aims: Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that mediates cell cycle regulation and metabolism. Mounting evidence has indicated that PP2A inhibition exhibits considerable anticancer potency in multiple types of human cancers. However, the efficacy of PP2A inhibition remains unexplored in mucoepidermoid carcinoma (MEC), especially in locally advanced and metastatic cases with limited systemic treatment. In this study, we demonstrated the therapeutic potency of LB100 in mucoepidermoid carcinoma. Methods: In this study, the expression of PP2A was evaluated using immunohistochemical (IHC) staining. The effects associated with LB100 alone and in combination with cisplatin for the treatment of mucoepidermoid carcinoma were investigated both in vitro, regarding metabolism, proliferation, and migration, and in vivo in a mucoepidermoid carcinoma xenograft model. In addition, with LB100 treatment and in response to an insulin stimulus, the expression levels and phosphorylation levels of targets in the PI3K-AKT pathway were determined using western blot analysis and immunoblotting. Results: The expression of protein phosphatase 2A was significantly upregulated in the clinical specimens of high-grade MECs compared with those of low-/medium-grade MECs and normal controls. In this article, we report that a small molecule PP2A inhibitor, LB100, decreased cellular viability and glycolytic activity and induced G2/M cell cycle arrest. Importantly, LB100 enhanced the efficacy of cisplatin in mucoepidermoid carcinoma cells both in vitro and in vivo. PP2A inhibition by LB100 increased the phosphorylation of insulin receptor substrate 1(IRS-1) on serine residues, downregulated the expression of phosphatidylinositol 3-kinase (PI3K) p110 alpha subunit and dephosphorylated AKT at Ser473 and Thr308 in mucoepidermoid carcinoma cells in response to insulin stimulus. Conclusion: These results highlight the translational potential of PP2A inhibition to synergize with cisplatin in mucoepidermoid carcinoma treatment.
How Long Non-Coding RNAs and MicroRNAs Mediate the Endogenous RNA Network of Head and Neck Squamous Cell Carcinoma: a Comprehensive Analysis
Authors: Zhao Guomiao , Fu Yaru , Su Zhifang , wu Rongling
Published: October 2018

Background/Aims: Long non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs) to compete for microRNAs (miRNAs) in cancer metastasis. Head and neck squamous cell carcinoma (HNSCC) is one of the most common human cancers and rare biomarkers could predict the clinical prognosis of this disease and its therapeutic effect. Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify differentially expressed mRNAs (DEmRNAs) that might be key genes. GO enrichment and protein–protein interaction (PPI) analyses were performed to identify the principal functions of the DEmRNAs. An lncRNA-miRNA-mRNA network was constructed to understand the regulatory mechanisms in HNSCC. The prognostic signatures of mRNAs, miRNAs, and lncRNAs were determined by Gene Expression Profiling Interactive Analysis (GEPIA) and using Kaplan–Meier survival curves for patients with lung squamous cell carcinoma. Results: We identified 2,023 DEmRNAs, 1,048 differentially expressed lncRNAs (DElncRNAs), and 82 differentially expressed miRNAs (DEmiRNAs). We found that eight DEmRNAs, 53 DElncRNAs, and 16 DEmiRNAs interacted in the ceRNA network. Three ceRNAs (HCG22, LINC00460 and STC2) were significantly correlated with survival. STC2 transcript levels were significantly higher in tumour tissues than in normal tissues, and the STC2 expression was slightly upregulated at different stages of HNSCC. Conclusion: LINC00460, HCG22 and STC2 exhibited aberrant levels of expression and may participate in the pathogenesis of HNSCC.
Randomized Trial of a Distal Embolic Protection Device During Percutaneous Intervention of Saphenous Vein Aorto-Coronary Bypass Grafts
Authors: Baim Donald S. , Wahr Dennis , George Barry , Leon Martin B. , Greenberg Joel , Cutlip Donald E. , Kaya Unsal , Popma Jeffrey J. , Ho Kalon K.L. , Kuntz Richard E.
Published: September 2018

Background

—

Stents provide effective treatment for stenotic saphenous venous aorto-coronary bypass grafts, but their placement carries a 20% incidence of procedure-related complications, which potentially are related to the distal embolization of atherosclerotic debris. We report the first multicenter randomized trial to evaluate use of a distal embolic protection device during stenting of such lesions.

Methods and Results

—

Of 801 eligible patients, 406 were randomly assigned to stent placement over the shaft of the distal protection device, and 395 were assigned to stent placement over a conventional 0.014-inch angioplasty guidewire (control group). The primary end point—a composite of death, myocardial infarction, emergency bypass, or target lesion revascularization by 30 days—was observed in 65 patients (16.5%) assigned to the control group and 39 patients (9.6%) assigned to the embolic protection device (
P
=0.004). This 42% relative reduction in major adverse cardiac events was driven by myocardial infarction (8.6% versus 14.7%,
P
=0.008) and “no-reflow” phenomenon (3% versus 9%,
P
=0.02). Clinical benefit was seen even when platelet glycoprotein IIb/IIIa receptor blockers were administered (61% of patients), with composite end points occurring in 10.7% of protection device patients versus 19.4% of control patients (
P
=0.008).

Conclusions

—

Use of this distal protection device during stenting of stenotic venous grafts was associated with a highly significant reduction in major adverse events compared with stenting over a conventional angioplasty guidewire. This demonstrates the importance of distal embolization in causing major adverse cardiac events and the value of embolic protection devices in preventing such complications.
Maternal Hypercholesterolemia During Pregnancy Promotes Early Atherogenesis in LDL Receptor-Deficient Mice and Alters Aortic Gene Expression Determined by Microarray
Authors: Napoli Claudio , de Nigris Filomena , Welch John S. , Calara Federico B. , Stuart Robert O. , Glass Christopher K. , Palinski Wulf
Published: September 2018

Background

—

Maternal hypercholesterolemia during pregnancy is associated with markedly enhanced fatty streak formation in human fetal aortas and accelerated progression of atherosclerosis in normocholesterolemic children.

Methods and Results

—

To establish the causal role of maternal hypercholesterolemia in a genetically homogeneous murine model and to test the hypothesis that pathogenic events during fetal development result in persistent changes in arterial gene expression, female LDL receptor-deficient (LDLR
−/−
) mice were fed regular chow or high-fat diets supplemented with 0.075% or 1.25% cholesterol during pregnancy. Lesion sizes were determined in the aortic origin of their chow-fed offspring at 3 months. Maternal hypercholesterolemia more than doubled lesion sizes in male offspring (
P
<0.0001 for the 0.0075% cholesterol group). Microarray analysis of the expression of 11 000 murine genes in the nonatherosclerotic descending aorta by Affymetrix gene chips suggested that 139 genes were significantly regulated in offspring of hypercholesterolemic mothers. A subset of 12 of the upregulated transcripts was subjected to secondary analysis by semiquantitative PCR of pooled RNA and 4 genes were found to be upregulated >1.7-fold. Quantitative PCR for one of these genes using RNA from individual mice yielded similar results. Comparative immunostaining for several of the above genes also indicated increased protein content in offspring of hypercholesterolemic mothers.

Conclusions

—

These findings establish an atherogenic effect of maternal hypercholesterolemia in genetically uniform mice and indicate that changes in aortic gene expression persist long after fetal exposure to hypercholesterolemia. In addition to elucidating pathogenic mechanisms initiated during fetal development, this approach may identify genes in morphologically normal arteries that influence the susceptibility to classical risk factors of atherosclerosis.
Recombinant Leptin Promotes Atherosclerosis and Thrombosis in Apolipoprotein E–Deficient Mice
Authors: Bodary Peter F. , Gu Shufang , Shen Yuechun , Hasty Alyssa H. , Buckler Joshua M. , Eitzman Daniel T.
Published: September 2018

Objective—

The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice.

Methods and Results—

Sixteen-week-old, male apolipoprotein E–deficient mice were treated with injections of recombinant leptin (125 μg per day IP; n=10) or vehicle (n=10) for 4 weeks. Leptin treatment resulted in reduced epididymal fat (352±30.7 versus 621±61.5 mg;
P
=0.005) and fasting insulin (0.57±0.25 versus 1.7±0.22 ng/mL;
P
=0.014). Despite these metabolic benefits, leptin treatment resulted in an increase in atherosclerosis (8.0±0.95% versus 5.4±0.59% lesion surface coverage;
P
<0.05). Leptin treatment also resulted in a shortened time to occlusive thrombosis after vascular injury (21±2.1 versus 34.6±5.4 minutes;
P
=0.045).

Conclusions—

These studies indicate that exogenous leptin promotes atherosclerosis and thrombosis and support the concept that elevations of leptin may increase the risk for cardiovascular disease.
Heart Rate Recovery Immediately After Treadmill Exercise and Left Ventricular Systolic Dysfunction as Predictors of Mortality
Authors: Watanabe Junko , Thamilarasan Maran , Blackstone Eugene H. , Thomas James D. , Lauer Michael S.
Published: September 2018

Background

An attenuated heart rate recovery after exercise has been shown to be predictive of mortality. In prior studies, recovery heart rates were measured while patients were exercising lightly, that is, during a cool-down period. It is not known whether heart rate recovery predicts mortality when measured in the absence of a cool-down period or after accounting for left ventricular systolic function.

Methods and Results

We followed 5438 consecutive patients without a history of heart failure or valvular disease referred for exercise echocardiography for 3 years. Heart rate recovery was defined as the difference in heart rate between peak exercise and 1 minute later; a value ≤18 beats per minute was considered abnormal. Patients assumed the left lateral decubitus position after exercise. An abnormal heart rate recovery was present in 805 patients (15%); during follow-up, 190 died. An abnormal heart rate recovery was predictive of death (9% versus 2%, hazard ratio [HR] 3.9, 95% CI 2.9 to 5.3,
P
<0.0001) and predicted death whether or not left ventricular systolic dysfunction (ejection fraction ≤40%) was present. After adjusting for age, sex, exercise capacity, left ventricular systolic function, presence or absence of myocardial ischemia, and other confounders, an abnormal heart rate recovery remained predictive of death (adjusted HR 2.09, 95% CI 1.49 to 2.82,
P
<0.001).

Conclusions

Even in the absence of a cool-down period and even after accounting for left ventricular systolic function, heart rate recovery is a powerful and independent predictor of death.
Local Expression of Interleukin-1 Receptor Antagonist by Plasmid DNA Improves Mortality and Decreases Myocardial Inflammation in Experimental Coxsackieviral Myocarditis
Authors: Lim Byung-Kwan , Choe Seong-Choon , Shin Jae-Ok , Ho Seong-Hyun , Kim Jong-Mook , Yu Seung-Shin , Kim Sunyoung , Jeon Eun-Seok
Published: September 2018

Background

—

The inflammatory cytokines have an important role in the pathogenesis of viral myocarditis. Inerleukin-1 (IL-1) is one of the major cytokines that modulate the outcome of viral infection. Among the methods for in vivo gene transfer, direct injection of plasmid DNA is one that is simple and feasible. In this study, we expressed human IL-1 receptor antagonist (hIL-1Ra) in the mouse heart by direct injection of a novel plasmid vector and evaluated its effects on coxsackieviral (CVB3) myocarditis.

Methods and Results

—

A plasmid vector expressing hIL-1Ra (total 40 μg/mouse) was injected into the heart apex of 8-week-old inbred female Balb/C mice (day 3). On day 0, mice (IL-1Ra-CVB3, n=35) were infected intraperitoneally with 10
4
PFU of CVB3; control mice (pCK-CVB3, n=15) were injected with empty vector on day −3 and infected on day 0. hIL-1Ra was expressed in the heart, reached its peak on day 5, and persisted for 2 weeks. The 14-day survival rate of IL-1Ra-CVB3 was higher (77%) than that of controls (30%,
P
<0.01). Myocardial virus titers on day 3 were lower in IL-1Ra-CVB3 mice. Myocardial inflammation on day 7 and fibrosis on day 14 were markedly decreased in IL-1Ra-CVB3.

Conclusion

—

These results showed that direct injection of the expression plasmid vector into the heart was an effective method to transfer the cytokine gene in vivo, and expressed IL-1Ra in the heart can modulate the deleterious effect of the host immune response in viral myocarditis.
Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction
Authors: Lewis Gregory D. , Semigran Marc J. , Givertz Michael M. , Malhotra Rajeev , Anstrom Kevin J. , Hernandez Adrian F. , Shah Monica R. , Braunwald Eugene
Published: September 2018

Iron deficiency is present in ≈50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with heart failure have not been defined. Although results of intravenous iron repletion trials have been promising, regularly treating patients with intravenous iron products is both expensive and poses logistical challenges for outpatients. Herein, we describe the rationale for the Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) trial. This National Institute of Health-sponsored trial will investigate oral iron polysaccharide compared with matching placebo with the primary end point of change in exercise capacity as measured by peak oxygen consumption at baseline and at 16 weeks.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02188784.
Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure
Authors: Sabbah Hani N. , Gupta Ramesh C. , Kohli Smita , Wang Mengjun , Hachem Souheila , Zhang Kefei
Published: September 2018

Background—

Elamipretide (MTP-131), a novel mitochondria-targeting peptide, was shown to reduce infarct size in animals with myocardial infarction and improve renal function in pigs with acute and chronic kidney injury. This study examined the effects of chronic therapy with elamipretide on left ventricular (LV) and mitochondrial function in dogs with heart failure (HF).

Methods and Results—

Fourteen dogs with microembolization-induced HF were randomized to 3 months monotherapy with subcutaneous injections of elamipretide (0.5 mg/kg once daily, HF+ELA, n=7) or saline (control, HF-CON, n=7). LV ejection fraction, plasma n-terminal pro-brain natriuretic peptide, tumor necrosis factor-α, and C-reactive protein were measured before (pretreatment) and 3 months after initiating therapy (post-treatment). Mitochondrial respiration, membrane potential (Δψm), maximum rate of ATP synthesis, and ATP/ADP ratio were measured in isolated LV cardiomyocytes obtained at post-treatment. In HF-CON dogs, ejection fraction decreased at post-treatment compared with pretreatment (29±1% versus 31±2%), whereas in HF+ELA dogs, ejection fraction significantly increased at post-treatment compared with pretreatment (36±2% versus 30±2%;
P
<0.05). In HF-CON, n-terminal pro-brain natriuretic peptide increased by 88±120 pg/mL during follow-up but decreased significantly by 774±85 pg/mL in HF+ELA dogs (
P
<0.001). Treatment with elamipretide also normalized plasma tumor necrosis factor-α and C-reactive protein and restored mitochondrial state-3 respiration, Δψm, rate of ATP synthesis, and ATP/ADP ratio (ATP/ADP: 0.38±0.04 HF-CON versus 1.16±0.15 HF+ELA;
P
<0.001).

Conclusions—

Long-term therapy with elamipretide improves LV systolic function, normalizes plasma biomarkers, and reverses mitochondrial abnormalities in LV myocardium of dogs with advanced HF. The results support the development of elamipretide for the treatment of HF.
Induction Therapy With Antithymocyte Globulin in Patients Undergoing Cardiac Transplantation Is Associated With Decreased Coronary Plaque Progression as Assessed by Intravascular Ultrasound
Authors: Azarbal Babak , Cheng Richard , Vanichsarn Christopher , Patel Jignesh K. , Czer Lawrence S. , Chang David H. , Kittleson Michelle M. , Kobashigawa Jon A.
Published: September 2018

Background—

Antithymocyte globulin (ATG) is used as induction therapy after cardiac transplant for enhancing immunosuppression and delaying the initiation of nephrotoxic drugs. It is unknown if ATG induction is associated with decreased coronary plaque progression by intravascular ultrasound (IVUS).

Methods and Results—

Patients transplanted between March 2010 and December 2012 with baseline and 1-year IVUS were included. All patients transplanted were included in a secondary analysis. Change in plaque progression was measured in a blinded fashion on matched coronary segments and contrasted between patients induced with ATG and those who were not. One hundred and three patients were included in IVUS arms. Mean age at transplant was 55.8±12.6 years, and 33.0% were female. Patients induced with ATG were more sensitized (54.3% versus 14.3%). Plaque progression was attenuated in patients who received ATG by changes in maximal intimal area (1.0±1.2 versus 2.3±2.6 mm
2
;
P
=0.001), maximal percent stenosis (6.3±7.9 versus 12.8±12.3%; =0.003), maximal intimal thickness (0.2±0.2 versus 0.3±0.3 mm;
P
=0.035), and plaque volume (0.5±0.7 versus 1.0±1.3 mm
3
/mm;
P
=0.016). Rapid plaque progression by maximal percent stenosis (≥20%) occurred less frequently in the ATG arm (4.3% versus 26.3;
P
=0.003). Survival (
P
=0.242) and any treated rejection (
P
=0.166) were not statistically different between groups. Patients receiving ATG had a higher rate of first-year infection (
P
=0.003), perhaps related to increased intravenous antibiotic use immediately postoperatively, and a trend toward more biopsy-proven rejection (
P
=0.073).

Conclusions—

Induction therapy with ATG is associated with reduced first-year coronary plaque progression as assessed by IVUS, despite an increased prevalence of sensitized patients with a trend toward more rejection.
Clinical and Echocardiographic Outcomes After Bariatric Surgery in Obese Patients With Left Ventricular Systolic Dysfunction
Authors: Vest Amanda R. , Patel Parag , Schauer Philip R. , Satava Mary Ellen , Cavalcante João L. , Brethauer Stacy , Young James B.
Published: September 2018

Background—

Obesity is a risk factor for development of left ventricular systolic dysfunction (LVSD) and can complicate LVSD management, especially for individuals in whom cardiac transplantation is indicated. Bariatric surgery is increasingly recognized as a safe and effective intervention to achieve marked weight loss, but experience is limited in the LVSD population.

Methods and Results—

We retrospectively reviewed patients with obesity and left ventricular ejection fraction (LVEF) <50% who underwent bariatric surgery at a tertiary center 2004 to 2013. An analysis of outcomes and efficacy compared 42 surgical patients with LVSD to 2588 without known LVSD. The LVSD group had greater baseline prevalence of comorbidities and showed a slight excess of early postoperative heart failure and myocardial infarction. However, patients with LVSD achieved good weight loss efficacy (mean decrease 22.6%) and no excess in mortality at 1 year. An overlapping cohort of 38 patients with LVSD had both pre- and postoperative echocardiographic images available for review by 2 blinded readers. Obese nonsurgical controls were matched on age, sex, initial LVEF, and interval between echocardiograms. There was a mean pre- to postoperative LVEF improvement of +5.1% ±8.3 (
P
=0.0005) for surgical subjects, but not for controls (+3.4%±10.5,
P
=0.056). Among surgical subjects, 11 patients had an LVEF improvement of >10%, whereas only 6 improved by >10% among nonsurgical controls.

Conclusions—

At experienced centers, bariatric surgery may be a safe and effective intervention for obese patients with LVSD. Bariatric surgery was associated with an improvement in LVEF, although the magnitude of change was on the cusp of clinical significance.
Relation of QRS Duration to Clinical Benefit of Cardiac Resynchronization Therapy in Mild Heart Failure Patients Without Left Bundle Branch Block
Authors: Biton Yitschak , Kutyifa Valentina , Cygankiewicz Iwona , Goldenberg Ilan , Klein Helmut , McNitt Scott , Polonsky Bronislava , Ruwald Anne Christine , Ruwald Martin H. , Moss Arthur J. , Zareba Wojciech
Published: September 2018

Background—

There are conflicting data regarding the efficacy of cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and without left bundle branch block.

Methods and Results—

We evaluated the long-term clinical outcomes of 537 non–left bundle branch block patients with mild HF enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study by QRS duration or morphology further stratified by PR interval. At 7 years of follow-up, the cumulative probability of HF hospitalization or death was 45% versus 56% among patients randomized to implantable cardioverter–defibrillator and CRT with defibrillator (CRT-D), respectively (
P
=0.209). Multivariable-adjusted subgroup analysis by QRS duration showed that patients from the lower quartile QRS duration group (≤134 ms) experienced 2.4-fold (
P
=0.015) increased risk for HF hospitalization or death with CRT-D versus implantable cardioverter–defibrillator only therapy, whereas the effect of CRT-D in patients from the upper quartiles group (QRS>134 ms) was neutral (hazard ratio [HR] =0.97,
P
=0.86;
P
value for interaction =0.024). In a second analysis incorporating PR interval, patients with prolonged QRS (>134 ms) and prolonged PR (>230 ms) were protected with CRT-D (HR=0.31,
P
=0.003), whereas the association was neutral with prolonged QRS (>134 ms) and shorter PR (≤230 ms;, HR=1.19,
P
=0.386;
P
value for interaction =0.002). The effect was neutral, regardless of morphology, right bundle branch block (HR=1.01,
P
=0.975), and intraventricular conduction delay (HR=1.31,
P
=0.172).

Conclusions—

Overall, patients with mild HF but without left bundle branch block morphology did not derive clinical benefit with CRT-D during long-term follow-up. Relatively shorter QRS was associated with a significantly increased risk with CRT-D relative to implantable cardioverter–defibrillator -only.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110.
Relationship Between Anticoagulation Intensity and Thrombotic or Bleeding Outcomes Among Outpatients With Continuous-Flow Left Ventricular Assist Devices
Authors: Nassif Michael E. , LaRue Shane J. , Raymer David S. , Novak Eric , Vader Justin M. , Ewald Gregory A. , Gage Brian F.
Published: September 2018

Background—

We evaluated thrombotic and bleeding outcomes in patients with continuous-flow left ventricular assist devices (CF-LVADs), stratified by anticoagulation intensity. Previous studies of outpatients with CF-LVADs have suggested that target international normalized ratio (INR) values <2.5 (range, 2–3) may be used. However, recent studies reported an increase in pump thrombosis among CF-LVADs, especially within the first 6 months of implant.

Methods and Results—

We retrospectively reviewed 249 outpatients at our center who received a CF-LVAD between January 2005 and August 2013. Using Poisson models, we analyzed their 10 927 INRs to determine INR-specific rates of thrombotic (ischemic stroke and suspected pump thrombosis) and hemorrhagic (gastrointestinal bleeding and hemorrhagic stroke) events occurring outside of the hospital. In multivariate analyses, we adjusted for age, sex, atrial fibrillation, coronary disease, and LVAD type as time-dependent Cox proportional hazard models. During a mean follow-up of 17.6±13.6 months, thrombotic events occurred in 46 outpatients. The highest event rate (0.40 thrombotic events per patient-year) was in the INR range of <1.5, but INR values of 1.5 to 1.99 also had high rates (0.16 thrombotic events per patient-year). INR was inversely associated with thrombotic events (hazard ratio, 0.40; 95% confidence interval, 0.22–0.72;
P
=0.002). The optimal INR based on weighted mortality of thrombotic and bleeding events was 2.6.

Conclusions—

INR is inversely related to thrombotic events occurring outside of the hospital among patients supported with CF-LVADs. INR values <2.0 increase the rate of thrombotic events occurring outside of the hospital among patients supported with CF-LVADs.
Continuous Rapid Quantification of Stroke Volume Using Magnetohydrodynamic Voltages in 3T Magnetic Resonance Imaging
Authors: Gregory T. Stan , Oshinski John , Schmidt Ehud J. , Kwong Raymond Y. , Stevenson William G. , Ho Tse Zion Tsz
Published: September 2018

Background—

To develop a technique to noninvasively estimate stroke volume in real time during magnetic resonance imaging (MRI)–guided procedures, based on induced magnetohydrodynamic voltages (VMHD) that occur in ECG recordings during MRI exams, leaving the MRI scanner free to perform other imaging tasks. Because of the relationship between blood flow (BF) and VMHD, we hypothesized that a method to obtain stroke volume could be derived from extracted VMHD vectors in the vectorcardiogram (VCG) frame of reference (VMHD
VCG
).

Methods and Results—

To estimate a subject-specific BF–VMHD model, VMHD
VCG
was acquired during a 20-s breath-hold and calibrated versus aortic BF measured using phase-contrast magnetic resonance in 10 subjects (n=10) and 1 subject diagnosed with premature ventricular contractions. Beat-to-beat validation of VMHD
VCG
-derived BF was performed using real-time phase-contrast imaging in 7 healthy subjects (n=7) during 15-minute cardiac exercise stress tests and 30 minutes after stress relaxation in 3T MRIs. Subject-specific equations were derived to correlate VMHD
VCG
with BF at rest and validated using real-time phase-contrast. An average error of 7.22% and 3.69% in stroke volume estimation, respectively, was found during peak stress and after complete relaxation. Measured beat-to-beat BF time history derived from real-time phase-contrast and VMHD was highly correlated using a Spearman rank correlation coefficient during stress tests (0.89) and after stress relaxation (0.86).

Conclusions—

Accurate beat-to-beat stroke volume and BF were estimated using VMHD
VCG
extracted from intra-MRI 12-lead ECGs, providing a means to enhance patient monitoring during MR imaging and MR-guided interventions.