bluuebunny/crossref_metadata_2025 huggingface dataset:
Murine DX5+NKT Cells Display Their Cytotoxic and Proapoptotic Potentials against Colitis-Inducing CD4+CD62LhighT Cells through Fas Ligand
Authors: Werner Jens M. , Damian Michael , Farkas Stefan A. , Schlitt Hans J. , Geissler Edward K. , Hornung Matthias
Published: September 2018

Introduction. It has been previously shown that immunoregulatory DX5+NKT cells are able to prevent colitis induced by CD4+CD62LhighT lymphocytes in a SCID mouse model. The aim of this study was to further investigate the underlying mechanism in vitro.Methods. CD4+CD62Lhighand DX5+NKT cells from the spleen of Balb/c mice were isolated first by MACS, followed by FACS sorting and cocultured for up to 96 h. After polyclonal stimulation with anti-CD3, anti-CD28, and IL-2, proliferation of CD4+CD62Lhighcells was assessed using a CFSE assay and activity of proapoptotic caspase-3 was determined by intracellular staining and flow cytometry. Extrinsic apoptotic pathway was blocked using an unconjugated antibody against FasL, and activation of caspase-3 was measured.Results. As previously shown in vivo, DX5+NKT cells inhibit proliferation of CD4+CD62Lhighcells in vitro after 96 h coculture compared to a CD4+CD62Lhighmonoculture (proliferation index: 1.39 ± 0.07 vs. 1.76 ± 0.12;P=0.0079). The antiproliferative effect of DX5+NKT cells was likely due to an induction of apoptosis in CD4+CD62Lhighcells as evidenced by increased activation of the proapoptotic caspase-3 after 48 h (38 ± 3% vs. 28 ± 3%;P=0.0451). Furthermore, DX5+NKT cells after polyclonal stimulation showed an upregulation of FasL on their cell surface (15 ± 2% vs. 2 ± 1%;P=0.0286). Finally, FasL was blocked on DX5+NKT cells, and therefore, the extrinsic apoptotic pathway abrogated the activation of caspase-3 in CD4+CD62Lhighcells.Conclusion. Collectively, these data confirmed that DX5+NKT cells inhibit proliferation of colitis-inducing CD4+CD62Lhighcells by induction of apoptosis. Furthermore, DX5+NKT cells likely mediate their cytotoxic and proapoptotic potentials via FasL, confirming recent reports about iNKT cells. Further studies will be necessary to evaluate the therapeutical potential of these immunoregulatory cells in patients with colitis.
Stabilization of Heterogeneous Multiagent Systems via Harmonic Control
Authors: Liu Xianzhu , Ji Zhijian , Hou Ting
Published: September 2018

Stabilizing multiagent systems including unstable agents shows the advantage of cooperation. This paper addresses the problem of stabilization of heterogeneous multiagent systems. Under cycle graphs, a sufficient condition for the stabilization problem via harmonic control is provided and an algorithm of designing the interconnection gains is presented. Furthermore, a sufficient and necessary condition for stabilization problem via harmonic control under cycle graphs is first given when the graph contains less than 5 nodes.
Uniqueness and Novel Finite-Time Stability of Solutions for a Class of Nonlinear Fractional Delay Difference Systems
Authors: Luo Danfeng , Luo Zhiguo
Published: September 2018

This paper focuses on the uniqueness and novel finite-time stability of solutions for a kind of fractional-order nonlinear difference equations with time-varying delays. Under some new criteria and by applying the generalized Gronwall inequality, the new constructive results have been established in the literature. As an application, two typical examples are delineated to demonstrate the effectiveness of our theoretical results.
Dorsal Root Ganglion Maintains Stemness of Bone Marrow Mesenchymal Stem Cells by Enhancing Autophagy through the AMPK/mTOR Pathway in a Coculture System
Authors: Zhang Shuaishuai , Li Junqin , Jiang Huijie , Gao Yi , Cheng Pengzhen , Cao Tianqing , Li Donglin , Wang Jimeng , Song Yue , Liu Bin , Wu Hao , Wang Chunmei , Yang Liu , Pei Guoxian
Published: September 2018

Our previous studies found that sensory nerve tracts implanted in tissue-engineered bone (TEB) could result in better osteogenesis. To explore the mechanism of the sensory nerve promoting osteogenesis in TEB in vitro, a transwell coculture experiment was designed between dorsal root ganglion (DRG) cells and bone marrow mesenchymal stem cells (BMSCs). BMSC proliferation was determined by CCK8 assay, and osteo-, chondro-, and adipogenic differentiation were assessed by alizarin red, alcian blue, and oil red staining. We found that the proliferation and multipotent differentiation of BMSCs were all enhanced in the coculture group compared to the BMSCs group. Crystal violet staining showed that the clone-forming ability of BMSCs in the coculture group was also enhanced and mRNA levels of Sox2, Nanog, and Oct4 were significantly upregulated in the coculture group. Moreover, the autophagy level of BMSCs, regulating their stemness, was promoted in the coculture group, mediated by the AMPK/mTOR pathway. In addition, AMPK inhibitor compound C could significantly downregulate the protein expression of LC3 and the mRNA level of stemness genes in the coculture group. Finally, we found that the NK1 receptor antagonist, aprepitant, could partly block this effect, which indicated that substance P played an important role in the effect. Together, we conclude that DRG could maintain the stemness of BMSCs by enhancing autophagy through the AMPK/mTOR pathway in a transwell coculture system, which may help explain the better osteogenesis after implantation of the sensory nerve into TEB.
Rolling Supply Chain Scheduling considering Suppliers, Production, and Delivery Lot-Size
Authors: Huang Rong-Hwa , Yu Tung-Han , Lee Chen-Yun
Published: September 2018

Supply chain management and integration play a key factor in contemporary manufacturing concept. Companies seek to integrate itself within a cooperative and mutual benefiting supply chain. Supply chain scheduling, as an important aspect of supply chain management, highly emphasizes on minimizing stock costs and delivery costs. Most previous researches on supply chain scheduling problems assume make-to-order production, which includes delivery cost in lot-size. This practice simplifies the complexity of the problem. Instead, this research discusses make-to-contract production, where the supply chain has a rolling planning horizon that changes according to contracts. Within a planning horizon, two types of interval are defined. The first is frozen interval, in which the manufacturing decision cannot be changed. The second is free interval, where schedules can be adjusted depending on new contracts. This research aims to build a robust rolling supply management schedule to satisfy customers’ needs, by considering supplier, production, and delivery lot-size simultaneously. The objective is to effectively decide a combination of supplier, production, and delivery lot-size that minimizes total cost consisting of supplier cost, finish good stock cost, and delivery cost. Based on the concept, this study designs a problem-solving process that combines the methods of rolling planning horizon and genetic algorithm. Delivery size (DS), finish good stock (FS), and early delivery cost (ED) are the three methods applied; each will provide a guideline to produce a feasible solution. By further considering the fluctuations in practical needs and performing an overall evaluation, a robust and optimal supply chain scheduling plan can be decided, including the optimal lot-sizes of supplier, production, and delivery. In the effectiveness test which considers 3 types of customer demands and 11 types of company cost structures, the simulated data test results suggest that the proposed methods in this study have excellent performance.
Attitude towards Mental Illness among Primary Healthcare Providers: A Community-Based Study in Rural China
Authors: Ma Zhenyu , Huang Hui , Nie Guanghui , Silenzio Vincent M. B. , Wei Bo
Published: September 2018

Objective. There are no studies that have explored attitudes towards mental illness that are held by rural primary healthcare (PHC) providers. The aim of this study was to conduct evidential and comparative research about attitudes towards mental illness among primary healthcare providers from different mental health service models in China rural communities.Methods. A self-administered questionnaire was conducted with a total of 361 rural primary healthcare providers engaged in mental health service delivery.Results. Total attitude score mark of rural primary healthcare providers shows that most PHC providers still held pessimistic and negative attitude towards mental illness patients. 71.3% of respondents agreed that “the mental patients often impulsively perform destruction of property”; 72.9% agreed that “mental patients are burdens to the families and society.” There are also positive correlations between attitudes and abilities of primary healthcare providers to mental illness.Conclusion. This study provides baseline evidence that primary healthcare providers in rural China hold negative attitudes towards mental illness. It is critical to improve negative attitudes and understanding about the importance of the management of severe mental illness among rural primary healthcare workers in mental health services. We should take comprehensive methods to enrich primary healthcare providers’ professional knowledge about mental illness and eliminate discrimination and inappropriate perception against the mental illness.
Automatic High-Frequency Trading: An Application to Emerging Chilean Stock Market
Authors: Crawford Broderick , Soto Ricardo , San Martín Marco Alarcón , de la Fuente-Mella Hanns , Castro Carlos , Paredes Fernando
Published: September 2018

This research seeks to design, implement, and test a fully automatic high-frequency trading system that operates on the Chilean stock market, so that it is able to generate positive net returns over time. A system that implements high-frequency trading (HFT) is presented through advanced computer tools as an NP-Complete type problem in which it is necessary to optimize the profitability of stock purchase and sale operations. The research performs individual tests of the algorithms implemented, reviewing the theoretical net return (profitability) that can be applied on the last day, month, and semester of real market data. Finally, the research determines which of the variants of the implemented system performs best, using the net returns as a basis for comparison. The use of particle swarm optimization as an optimization algorithm is shown to be an effective solution since it is able to optimize a set of disparate variables but is bounded to a specific domain, resulting in substantial improvement in the final solution.
Electroacupuncture Improves Baroreflex and γ-Aminobutyric Acid Type B Receptor-Mediated Responses in the Nucleus Tractus Solitarii of Hypertensive Rats
Authors: Zhang Qi , Tan Ying-Ying , Liu Xiao-hua , Yao Fan-Rong , Cao Dong-Yuan
Published: September 2018

Electroacupuncture (EA) has been reported to benefit hypertension, but the underlying mechanisms are still unclear. We hypothesized that EA attenuates hypertension, in part, through modulation of γ-aminobutyric acid (GABA) receptor function in the nucleus tractus solitarii (NTS). In the present study, the long-term effect of EA on GABA receptor function and expression was examined in the NTS of two-kidney, one-clip (2K1C) renovascular hypertensive rats. EA (0.1–0.4 mA, 2 and 15 Hz) was applied at Zusanli (ST36) acupoints overlying the deep fibular nerve for 30 min once a day for two weeks. The results showed that long-term EA treatment improved blood pressure (BP) and markedly restored the baroreflex response in 2K1C hypertensive rats. The increased pressor and depressor responses to microinjection of GABAB receptor agonist and antagonist into the NTS in the hypertensive rats were blunted by the EA treatment. Moreover, EA treatment attenuated the increased GABAB receptor expression in the NTS of hypertensive rats. In contrast, EA had no significant effect on the GABAA receptor function and expression in the NTS of 2K1C hypertensive rats. These findings suggest that the beneficial effects of EA on renovascular hypertension may be through modulation of functional GABAB receptors in the NTS.
Sevoflurane Inhibits the Th2 Response and NLRP3 Expression in Murine Allergic Airway Inflammation
Authors: Wang Lixia , Zha Binshan , Shen Qiying , Zou Hongyun , Cheng Cheng , Wu Huimei , Liu Rongyu
Published: September 2018

Background. Our colleagues have demonstrated an impressive therapeutic role of sevoflurane in a murine allergic airway inflammation model, but the mechanisms underlying this effect remain undefined. In this study, we tried to investigate the effect of sevoflurane on the resolution of allergic airway inflammation and to assess whether NLRP3 or the NLRP3 inflammasome is involved in this process. Methods. Female (C57BL/6) mice were sensitized and challenged with ovalbumin (OVA). Then, some of the mice received MCC950 (10 mg/kg; i.p.) or 3% sevoflurane. Total and differential inflammatory cell numbers, proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), the peribronchial inflammation density, and mucus production were evaluated. In addition, we analysed the protein levels of NLRP3, the apoptosis-associated speck-like protein containing the caspase activation and recruitment domain (ASC), pro-caspase-1, and caspase-1 in the lung tissue. Results. We found that OVA-induced inflammatory cell recruitment to peribronchial regions, goblet cell hyperplasia, the serum levels of IgE, inflammatory cells, and the Th2 cytokine secretion in BALF was potently suppressed by sevoflurane with an efficacy comparable with that suppressed by MCC950 treatment. Furthermore, sevoflurane, similar to MCC950, clearly inhibited the OVA-induced activity of NLRP3 in the lungs. In addition, we found that OVA challenge failed to increase the expression of ASC, pro-caspase-1, and caspase-1 in the lungs and the levels of IL-18 and IL-1β in BALF. Conclusion. Taken together, our data showed that sevoflurane ameliorated allergic airway inflammation by inhibiting Th2 responses and NLRP3 expression. The NLRP3 independent of inflammasomes participated in the pathogenesis of allergic asthma in this model.
Adoptive Transfers of CD4+CD25+ Tregs Raise Foxp3 Expression and Alleviate Mouse Enteritis
Authors: Wang Kai , Zhu Tongjia , Wang Haijun , Yang Jinxin , Du Shuaishuai , Dong Guoying , Pei Zhihua , Hu Guixue
Published: September 2018

CD4+CD25+Foxp3+ Tregs control the immune response and maintain immune homeostasis. This study examined whether Tregs can affect mouse enteritis and the Foxp3 (Forkhead transcription factor) transcriptional pathway. Mouse CD4+CD25+ Treg cells were labelled using CFSE (5,6-carboxyfluorescein diacetate succinimidyl ester) and transferred to enteritis model mice. The mice were randomly divided into an enteritis group, a Treg-infusion group, a Treg-inhibiting group, and a control group. Histopathology, ELISA, flow cytometry, western blot, immunohistochemistry, and immunofluorescence were performed. Our results demonstrated that CD4+CD25+ Tregs were successfully transferred. The disease activity index (DAI) scores in the Tregs-infusion group were lower than those of the enteritis and Tregs-inhibiting groups. The number of goblet cells and inflammatory cells was reduced, and the levels of IL-1β, TNF-α, NO, and PGE2 were significantly decreased in the Tregs-infusion group compared to those in the enteritis group (p<0.05). The number of CD4+CD25+Foxp3+ Tregs and CD4+IL-17A+ Th17 cells in the mesenteric lymph nodes differed significantly from the enteritis and Tregs-inhibiting groups (p<0.05). There were more Foxp3+ Tregs and Smad3 and NFAT2 infiltrated into the duodenum after adoptive transfer of CD4+CD25+ Tregs, which was a significant difference relative to the enteritis group (p<0.05). This study demonstrated that adoptive transfer of CD4+CD25+ Tregs can decrease mouse enteritis. Foxp3 expression may be improved through the Smad3 and NFAT2 signalling pathways.
Gynura procumbens Improved Fertility of Diabetic Rats: Preliminary Study of Sperm Proteomic
Authors: Kamaruzaman Khaidatul Akmar , Aizat Wan Mohd , Mat Noor Mahanem
Published: September 2018

Gynura procumbens (GP) is a medicinal herb that has long been known as anti‐inflammatory and antihyperglycaemic. Recently, this herbal extract has been associated with a profertility effect, suggesting its applicability in treating both diabetes and male infertility. In this study, the effects of GP aqueous extract (GPAE) on diabetic rats were investigated through evaluating testes histology and androgen hormone levels as well as the implantation sites of female rats on copulation with the treated male rats. Three dosages of GPAE were used (150, 300, and 450 mg/kg), and there were three control groups [normal, diabetic, and metformin‐treated diabetic]. Testes histology, androgen hormone levels, and number of implantation sites of the GPAE‐treated groups matched those of the normal group in contrast to the diabetic and metformin‐treated diabetic controls. Sperm proteomics analysis identified 666 proteins, but only 88 were consistently found in all the control and 450‐mg/kg GPAE‐treated groups. Four proteins, including cysteine‐rich secretory protein 1, carboxylesterase 5A, zona pellucida binding protein, and phosphatidylethanolamine‐binding protein 1, were significantly upregulated with GPAE treatment compared with the diabetic control, matching the protein levels of the normal group. These proteins were mainly involved in sperm maturation, sperm capacitation, and sperm‐egg interaction, suggesting that GP treatment was able to restore the fertility of male diabetic rats at molecular protein level. In conclusion, GP treatment effectively treats infertility of male diabetic rats, possibly through the upregulation of proteins related to sperm maturation and sperm‐egg interaction.
Investigating the Antiproliferative and Antioxidant Properties of Pancratium maritimum L. (Amaryllidaceae) Stems, Flowers, Bulbs, and Fruits Extracts
Authors: Leporini Mariarosaria , Catinella Giorgia , Bruno Maurizio , Falco Tiziana , Tundis Rosa , Loizzo Monica R.
Published: September 2018

Pancratium maritimum stems, flowers, bulbs, and fruits extracts were investigated for their antiproliferative and antioxidant properties. Total phenols and total flavonoids were also determined. The in vitro antiproliferative activity was tested against seven cancer cell lines such as C32, HeLa, MDA‐MB‐231, PC3, A549, MCF‐7, and LNCaP by using SRB assay. Interesting results were obtained with stems ethanol extract (ET1) against C32 cells (IC50 of 27.1 μg/mL) and fruits aqueous extract (AQ) against MCF‐7 cell line (IC50 of 36.5 μg/mL). To define the antioxidant activity, four tests such as DPPH, ABTS FRAP, and β‐carotene bleaching tests were used. The most promising ABTS scavenging capacity was observed with fruits ethanol extract (ET1) that showed an IC50 value of 6.9 μg/mL. According to the correlation results, the phenols and flavonoids content could provide a fundamental contribution to the antioxidant and antiproliferative activity of P. maritimum extracts.
Sensitivity Analysis on Thermal Conductivity Characteristics of a Water-Based Bionanofluid Flow Past a Wedge Surface
Authors: Chan Sze Qi , Aman Fazlina , Mansur Syahira
Published: September 2018

Thermobioconvection boundary layer flow in a suspension of water-based bionanofluid holding both nanoparticles and motile microorganisms past a wedge surface was studied. The governing nonlinear partial differential equations on reference of the Buongiorno model were transformed into a set of coupled nonlinear ordinary differential equations. Shooting technique was then used to solve the transformed nonlinear ordinary differential equations numerically. The solutions were found to be contingent on several values of the governing parameters. As highlighted, the velocity profile as well as the skin friction coefficient was affected by the pressure gradient parameter, the function of the wedge angle parameter. On the other hand, the temperature, nanoparticle concentration, and density of motile microorganism’s distributions together with its corresponding local Nusselt number, local Sherwood number, and local density of the motile microorganisms change with the thermophoresis and Brownian motion parameter and so Lewis number, Schmidt number, and bioconvection Péclet number. An experimental scheme together with sensitivity analysis on the basis of Response Surface Methodology (RSM) was applied to examine the dependency of the response parameters of interest to the input parameters’ change. Obviously, local Nusselt number was more sensitive towards the Brownian motion parameter when the Brownian motion parameter was at 0.2 and 0.3. However local Sherwood number was more sensitive towards the Lewis number for all values of Brownian motion parameter. Compatibility found by comparing results between RSM and shooting technique gave confidence for the model’s accuracy. The findings would provide initial guidelines for future device fabrication. Finally, the numerical results obtained were thoroughly inspected and verified with the existing values reported by some researchers.
Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair
Authors: Sánchez-Quesada Cristina , López-Biedma Alicia , Toledo Estefania , Gaforio José J.
Published: September 2018

Anti‐inflammatory effects of virgin olive oil (VOO) have been described recently, along with its wound healing effect. One of the main minor compounds found in VOO is squalene (SQ), which also possesses preventive effects against skin damage and anti‐inflammatory properties. The inflammatory response is involved in wound healing and manages the whole process by macrophages, among others, as the main innate cells with a critical role in the promotion and resolution of inflammation for tissue repair. Because of that, this work is claimed to describe the role that squalene exerts in the immunomodulation of M1 proinflammatory macrophages, which are the first cells implicate in recent injuries. Pro‐ and anti‐inflammatory cytokines were analysed using TPH1 cell experimental model. SQ induced an increase in the synthesis of anti‐inflammatory cytokines, such as IL‐10, IL‐13, and IL‐4, and a decrease in proinflammatory signals, such as TNF‐α and NF‐κB in M1 proinflammatory macrophages. Furthermore, SQ enhanced remodelling and repairing signals (TIMP‐2) and recruitment signals of eosinophils and neutrophils, responsible for phagocytosis processes. These results suggest that SQ is able to promote wound healing by driving macrophage response in inflammation. Therefore, squalene could be useful at the resolution stage of wound healing.
Resistance Exercise Training in McArdle Disease: Myth or Reality?
Authors: Pietrusz Aleksandra , Scalco Renata S. , Quinlivan Ros
Published: September 2018

McArdle disease is a metabolic myopathy mainly characterised by symptom onset during physical activities or isometric muscle contraction. Resistance (also termed strength) training is a type of physical exercise focusing on the use of resistance (e.g., lifting weights) to induce muscular contraction, which builds muscle mass and strength. Historically people with McArdle disease were advised to avoid resistance exercises and any other form of physical activity involving high mechanical loads such as prolonged isometric contraction. Paradoxically, a clinical trial exploring the benefits of strength training in this patient population was published. The theory supporting strength training relied on the use of the ATP molecule and the creatine phosphate (ATP-phosphocreatine system) as energy sources for skeletal muscles. Here, we report two patients with McArdle disease who performed weight training at local gyms. A single set of repetitions lasted for maximum 10 seconds with minimum of 30 seconds of rest period in between sets of exercises. Benefits of this type of training included improvement in quality of life and amelioration of McArdle disease symptoms. We provide further safety evidence of this type of exercise in people with McArdle disease. We emphasise the importance of using a specific protocol developed for people affected by this condition.
Inguinal Bladder and Ureter Hernia Permagna: Definition of a Rare Clinical Entity and Case Report
Authors: De Angelis Michela , Mantovani Guido , Di Lecce Francesco , Boccia Luigi
Published: September 2018

Background. Inguinoscrotal herniation of the bladder is a rare clinical entity, with a frequency between 0.5% and 4% of all inguinal hernias. The bladder can partially or entirely herniate into the inguinal canal; when the whole bladder and ureters migrate into the scrotum, it may cause urinary disorders. Case Presentation. A 62-year-old male patient presented with urinary disorders and right-sided inguinoscrotal hernia. Under clinical suspicion of bladder involvement in the inguinal canal, abdominal and pelvic computed tomography (CT) scan with endovenous contrast was performed, revealing a right inguinoscrotal hernia, containing the whole urinary bladder and the right pelvic ureter. Without violating the urinary bladder wall integrity, the content of the hernial sac was reduced into the abdominal cavity. Hernioplasty was performed by means of Lichtenstein’s method. Conclusions. Ureteral involvement should be suspected when a clinical inguinal hernia is diagnosed concurrently with unexplained hydronephrosis, renal failure, or urinary tract infection, as in the case described. When suspected, the preoperative diagnosis, particularly with CT scan, is essential to avoid complications and to reduce risk of bladder and ureter injuries during hernia repair.
Classification of Gait Patterns in Patients with Neurodegenerative Disease Using Adaptive Neuro-Fuzzy Inference System
Authors: Ye Qiang , Xia Yi , Yao Zhiming
Published: September 2018

A common feature that is typical of the patients with neurodegenerative (ND) disease is the impairment of motor function, which can interrupt the pathway from cerebrum to the muscle and thus cause movement disorders. For patients with amyotrophic lateral sclerosis disease (ALS), the impairment is caused by the loss of motor neurons. While for patients with Parkinson’s disease (PD) and Huntington’s disease (HD), it is related to the basal ganglia dysfunction. Previously studies have demonstrated the usage of gait analysis in characterizing the ND patients for the purpose of disease management. However, most studies focus on extracting characteristic features that can differentiate ND gait from normal gait. Few studies have demonstrated the feasibility of modelling the nonlinear gait dynamics in characterizing the ND gait. Therefore, in this study, a novel approach based on an adaptive neuro-fuzzy inference system (ANFIS) is presented for identification of the gait of patients with ND disease. The proposed ANFIS model combines neural network adaptive capabilities and the fuzzy logic qualitative approach. Gait dynamics such as stride intervals, stance intervals, and double support intervals were used as the input variables to the model. The particle swarm optimization (PSO) algorithm was utilized to learn the parameters of the ANFIS model. The performance of the system was evaluated in terms of sensitivity, specificity, and accuracy using the leave-one-out cross-validation method. The competitive classification results on a dataset of 13 ALS patients, 15 PD patients, 20 HD patients, and 16 healthy control subjects indicated the effectiveness of our approach in representing the gait characteristics of ND patients.
Role of the Intrinsic Coagulation Pathway in Atherogenesis Assessed in Hemophilic Apolipoprotein E Knockout Mice
Authors: Khallou-Laschet J. , Caligiuri G. , Tupin E. , Gaston A.-T. , Poirier B. , Groyer E. , Urbain D. , Maisnier-Patin S. , Sarkar R. , Kaveri S.V. , Lacroix-Desmazes S. , Nicoletti A.
Published: September 2018

Objective—

The contribution of thrombosis and coagulation in atherogenesis is largely unknown. We investigated the contribution of the coagulation intrinsic factor VIII (FVIII)–dependent pathway in atherogenesis.

Methods and Results—

Apolipoprotein E and FVIII double–deficient mice (E°/FVIII°) were generated. Aortic root lesions were analyzed in 14-week-old and 22-week-old female mice maintained for 8 or 16 weeks, respectively, on a normal chow diet or a hypercholesterolemic diet.

Conclusion—

Despite a higher plasma total cholesterol concentration compared with E° mice, E°/FVIII° mice developed dramatically less early-stage atherosclerotic lesions. Whereas early lesions in E° mice contained abundant fibrin(ogen) deposits on which few platelets adhered, lesions in E°/FVIII° were almost devoid of fibrin(ogen), and no platelets could be detected. The genotype effect on development and composition of lesions tended to decrease with time. This study demonstrates that the activation of the intrinsic pathway of coagulation is potently proatherogenic at the early stage of atherogenesis.
Successful Treatment of Amiodarone-Induced Thyrotoxicosis
Authors: Osman Faizel , Franklyn Jayne A. , Sheppard Michael C. , Gammage Michael D.
Published: September 2018

Background

—

Amiodarone-induced thyrotoxicosis (AIT) is a difficult management problem about which there are little published data. We examined whether continuing amiodarone or differentiating AIT into 2 subtypes affected outcome.

Methods and Results

—

The type and duration of antithyroid treatment and response were recorded in a consecutive series of 28 cases. Comparisons were made between those in whom amiodarone either was continued or stopped and between those with either possible type 1 or type 2 AIT. Of the 28 cases, 5 had spontaneous resolution of AIT; 23 received carbimazole (CBZ) alone as first-line therapy. Eleven achieved long-term euthyroidism off CBZ or on a maintenance dose. Five became hypothyroid and required long-term thyroxine. Five relapsed after stopping CBZ treatment and were rendered euthyroid with either long-term CBZ (n=3) or radioiodine (n=2). Four were intolerant of CBZ and received propylthiouracil (PTU), with good effect in 3. One was resistant to thionamide alone (CBZ then PTU) and responded to adjunctive steroids. No difference in presentation or outcome was noted between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 AIT.

Conclusions

—

Continuing amiodarone has no adverse influence on response to treatment of AIT. First-line therapy with a thionamide alone is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. Differentiating between 2 possible types of AIT does not influence management or outcome.
Catheter-Based Endomyocardial Injection With Real-Time Magnetic Resonance Imaging
Authors: Lederman Robert J. , Guttman Michael A. , Peters Dana C. , Thompson Richard B. , Sorger Jonathan M. , Dick Alexander J. , Raman Venkatesh K. , McVeigh Elliot R.
Published: September 2018

Background

—

We tested the feasibility of targeted left ventricular (LV) mural injection using real-time MRI (rtMRI).

Methods and Results

—

A 1.5T MRI scanner was customized with a fast reconstruction engine, transfemoral guiding catheter–receiver coil (GCC), MRI-compatible needle, and tableside consoles. Commercial real-time imaging software was customized to facilitate catheter navigation and visualization of injections at 4 completely refreshed frames per second. The aorta was traversed and the left ventricular cavity was entered under direct rtMRI guidance. Pigs underwent multiple injections with dilute gadolinium-DTPA. All myocardial segments were readily accessed. The active GCC and the passive Stiletto needle injector were readily visualized. More than 50 endomyocardial injections were performed with the aid of rtMRI; 81% were successful with this first-generation prototype.

Conclusion

—

Percutaneous endomyocardial drug delivery is feasible with the aid of rtMRI, which permits precise 3-dimensional localization of injection within the LV wall.
Direct Comparison of Virtual-Histology Intravascular Ultrasound and Optical Coherence Tomography Imaging for Identification of Thin-Cap Fibroatheroma
Authors: Brown Adam J. , Obaid Daniel R. , Costopoulos Charis , Parker Richard A. , Calvert Patrick A. , Teng Zhongzhao , Hoole Stephen P. , West Nick E.J. , Goddard Martin , Bennett Martin R.
Published: September 2018

Background—

Although rupture of thin-cap fibroatheroma (TCFA) underlies most myocardial infarctions, reliable TCFA identification remains challenging. Virtual-histology intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT) can assess tissue composition and classify plaques. However, direct comparisons between VH-IVUS and OCT are lacking and it remains unknown whether combining these modalities improves TCFA identification.

Methods and Results—

Two hundred fifty-eight regions-of-interest were obtained from autopsied human hearts, with plaque composition and classification assessed by histology and compared with coregistered ex vivo VH-IVUS and OCT. Sixty-seven regions-of-interest were classified as fibroatheroma on histology, with 22 meeting criteria for TCFA. On VH-IVUS, plaque (10.91±4.82 versus 8.42±4.57 mm
2
;
P
=0.01) and necrotic core areas (1.59±0.99 versus 1.03±0.85 mm
2
;
P
=0.02) were increased in TCFA versus other fibroatheroma. On OCT, although minimal fibrous cap thickness was similar (71.8±44.1 μm versus 72.6±32.4;
P
=0.30), the number of continuous frames with fibrous cap thickness ≤85 μm was higher in TCFA (6.5 [1.75–11.0] versus 2.0 [0.0–7.0];
P
=0.03). Maximum lipid arc on OCT was an excellent discriminator of fibroatheroma (area under the curve, 0.92; 95% confidence interval, 0.87–0.97) and TCFA (area under the curve, 0.86; 95% confidence interval, 0.81–0.92), with lipid arc ≥80° the optimal cut-off value. Using existing criteria, the sensitivity, specificity, and diagnostic accuracy for TCFA identification was 63.6%, 78.1%, and 76.5% for VH-IVUS and 72.7%, 79.8%, and 79.0% for OCT. Combining VH-defined fibroatheroma and fibrous cap thickness ≤85 μm over 3 continuous frames improved TCFA identification, with diagnostic accuracy of 89.0%.

Conclusions—

Both VH-IVUS and OCT can reliably identify TCFA, although OCT accuracy may be improved using lipid arc ≥80° and fibrous cap thickness ≤85 μm over 3 continuous frames. Combined VH-IVUS/OCT imaging markedly improved TCFA identification.
Implementing a Continuous Quality Improvement Program in a High-Volume Clinical Echocardiography Laboratory
Authors: Samad Zainab , Minter Stephanie , Armour Alicia , Tinnemore Amanda , Sivak Joseph A. , Sedberry Brenda , Strub Karen , Horan Seanna M. , Harrison J. Kevin , Kisslo Joseph , Douglas Pamela S. , Velazquez Eric J.
Published: September 2018

Background—

The management of aortic stenosis rests on accurate echocardiographic diagnosis. Hence, it was chosen as a test case to examine the utility of continuous quality improvement (CQI) approaches to increase echocardiographic data accuracy and reliability. A novel, multistep CQI program was designed and prospectively used to investigate whether it could minimize the difference in aortic valve mean gradients reported by echocardiography when compared with cardiac catheterization.

Methods and Results—

The Duke Echo Laboratory compiled a multidisciplinary CQI team including 4 senior sonographers and MD faculty to develop a mapped CQI process that incorporated Intersocietal Accreditation Commission standards. Quarterly, the CQI team reviewed all moderate- or greater-severity aortic stenosis echocardiography studies with concomitant catheterization data, and deidentified individual and group results were shared at meetings attended by cardiologists and sonographers. After review of 2011 data, the CQI team proposed specific amendments implemented over 2012: the use of nontraditional imaging and Doppler windows as well as evaluation of aortic gradients by a second sonographer. The primary outcome measure was agreement between catheterization- and echocardiography-derived mean gradients calculated by using the coverage probability index with a prespecified acceptable echocardiography–catheterization difference of <10 mm Hg in mean gradient. Between January 2011 and January 2014, 2093 echocardiograms reported moderate or greater aortic stenosis. Among cases with available catheterization data pre- and post-CQI, the coverage probability index increased from 54% to 70% (
P
=0.03; 98 cases, year 2011; 70 cases, year 2013). The proportion of patients referred for invasive valve hemodynamics decreased from 47% pre-CQI to 19% post-CQI (
P
<0.001).

Conclusions—

A laboratory practice pattern that was amenable to reform was identified, and a multistep modification was designed and implemented that produced clinically valuable performance improvements. The new protocol improved aortic stenosis mean gradient agreement between echocardiography and catheterization and was associated with a measurable decrease in referrals of patients for invasive studies.
Prognostic Utility and Clinical Significance of Cardiac Mechanics in Heart Failure With Preserved Ejection Fraction
Authors: Freed Benjamin H. , Daruwalla Vistasp , Cheng Jeanette Y. , Aguilar Frank G. , Beussink Lauren , Choi Andrew , Klein David A. , Dixon Debra , Baldridge Abigail , Rasmussen-Torvik Laura J. , Maganti Kameswari , Shah Sanjiv J.
Published: September 2018

Background—

Left atrial (LA) enlargement is associated with adverse events in heart failure with preserved ejection fraction (HFpEF). However, the role of LA mechanics (ie, LA strain measures) in HFpEF has not been well studied. We hypothesized that in HFpEF, reduced (worse) LA strain is a key pathophysiologic abnormality and is a stronger correlate of adverse events than left ventricular or right ventricular longitudinal strain.

Methods and Results—

We evaluated baseline LA function in 308 patients with HFpEF who were followed up longitudinally for adverse outcomes. All patients underwent speckle-tracking echocardiography for measurement of left ventricular longitudinal strain, right ventricular free wall strain, and LA booster, conduit, and reservoir strains. The clinical and prognostic significance of left ventricular, right ventricular, and LA strain measures was assessed by regression analyses. The mean age was 65±13 years, 64% were women, 26% had atrial fibrillation, and LA enlargement was present in the majority of patients (67%). Decreased LA reservoir strain was associated with increased pulmonary vascular resistance (
P
<0.0001) and decreased peak oxygen consumption (
P
=0.0001). Of the left ventricular, right ventricular, and LA strain measures, LA reservoir strain was the strongest correlate of adverse events and was independently associated with the composite outcome of cardiovascular hospitalization or death (adjusted hazard ratio per 1-SD decrease in LA strain, 1.54; 95% CI, 1.15–2.07;
P
=0.006).

Conclusions—

Abnormal indices of LA mechanics (particularly LA reservoir strain) are powerful clinical and prognostic factors in HFpEF. Unloading the LA and augmentation of LA function may be important future therapeutic targets in HFpEF.

Registration Information—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01030991.
Evaluation of Aortic Blood Flow and Wall Shear Stress in Aortic Stenosis and Its Association With Left Ventricular Remodeling
Authors: von Knobelsdorff-Brenkenhoff Florian , Karunaharamoorthy Achudhan , Trauzeddel Ralf Felix , Barker Alex J. , Blaszczyk Edyta , Markl Michael , Schulz-Menger Jeanette
Published: September 2018

Background—

Aortic stenosis (AS) leads to variable stress for the left ventricle (LV) and consequently a broad range of LV remodeling. The aim of this study was to describe blood flow patterns in the ascending aorta of patients with AS and determine their association with remodeling.

Methods and Results—

Thirty-seven patients with AS (14 mild, 8 moderate, 15 severe; age, 63±13 years) and 37 healthy controls (age, 60±10 years) underwent 4-dimensional-flow magnetic resonance imaging. Helical and vortical flow formations and flow eccentricity were assessed in the ascending aorta. Normalized flow displacement from the vessel center and peak systolic wall shear stress in the ascending aorta were quantified. LV remodeling was assessed based on LV mass index and the ratio of LV mass:end-diastolic volume (relative wall mass). Marked helical and vortical flow formation and eccentricity were more prevalent in patients with AS than in healthy subjects, and patients with AS exhibited an asymmetrical and elevated distribution of peak systolic wall shear stress. In AS, aortic orifice area was strongly negatively associated with vortical flow formation (
P
=0.0274), eccentricity (
P
=0.0070), and flow displacement (
P
=0.0021). Bicuspid aortic valve was associated with more intense helical (
P
=0.0098) and vortical flow formation (
P
=0.0536), higher flow displacement (
P
=0.11), and higher peak systolic wall shear stress (
P
=0.0926). LV mass index and relative wall mass were significantly associated with aortic orifice area (
P
=0.0611,
P
=0.0058) and flow displacement (
P
=0.0058,
P
=0.0283).

Conclusions—

In this pilot study, AS leads to abnormal blood flow pattern and peak systolic wall shear stress in the ascending aorta. In addition to aortic orifice area, normalized flow displacement was significantly associated with LV remodeling.
Optical Coherence Tomography Findings in Bioresorbable Vascular Scaffolds Thrombosis
Authors: Cuculi Florim , Puricel Serban , Jamshidi Peiman , Valentin Jérémy , Kallinikou Zacharenia , Toggweiler Stefan , Weissner Melissa , Münzel Thomas , Cook Stéphane , Gori Tommaso
Published: September 2018

Background—

Everolimus-eluting bioresorbable vascular scaffolds have been developed to improve late outcomes after coronary interventions. However, recent registries raised concerns regarding an increased incidence of scaffold thrombosis (ScT). The mechanism of ScT remains unknown.

Methods and Results—

The present study investigated angiographic and optical coherence tomography findings in patients experiencing ScT. Fifteen ScT (14 patients, 79% male, age 59±10 years) occurred at a median of 16 days (25%–75% interquartile range: 1–263 days) after implantation. Early ScT (<30 days) occurred in 8 cases (53%). Possible causal factors in these patients included insufficient platelet inhibition in 2 cases and procedural factors (scaffold underexpansion, undersizing, or geographical miss) in 4 cases. No obvious cause could be found in 2 early ScT. In late (>1 month) and very late (>1 year) ScT (respectively, 5 and 2 cases), 5 scaffolds showed intimal neovessels or marked peristrut low-intensity areas. Scaffold fractures were additionally found in 2 patients, and scaffold collapse was found in 1 patient with very late ScT. Extensive strut malapposition was the presumed cause for ScT in 1 case. One scaffold did not show any morphological abnormality. Thrombectomy specimens were analyzed in 3 patients and did not demonstrate increased numbers of inflammatory cells.

Conclusions—

The mechanisms of early ScT seem to be similar to metallic stents (mechanical and inadequate antiplatelet therapy). The predominant finding in late and very late ScT is peristrut low-intensity area.
Comparison of Cardiovascular Risk Factors for Coronary Heart Disease and Stroke Type in Women
Authors: Leening Maarten J. G. , Cook Nancy R. , Franco Oscar H. , Manson JoAnn E. , Lakshminarayan Kamakshi , LaMonte Michael J. , Leira Enrique C. , Robinson Jennifer G. , Ridker Paul M , Paynter Nina P.
Published: September 2018

Background

Cardiovascular risk factors have differential effects on various manifestations of cardiovascular disease, but to date direct formal comparisons are scarce, have been conducted primarily in men, and include only traditional risk factors.

Methods and Results

Using data from the multi‐ethnic Women's Health Initiative Observational Study, we used a case–cohort design to compare 1731 women with incident cardiovascular disease during follow‐up to a cohort of 1914 women. The direction of effect of all 24 risk factors (including various apolipoproteins, hemoglobin A1
c
, high‐sensitivity C‐reactive protein, N‐terminal pro‐brain natriuretic peptide, and tissue plasminogen activator antigen) was concordant for coronary heart disease (CHD, defined as myocardial infarction and CHD death) and ischemic stroke; however, associations were generally stronger with CHD. Significant differences for multiple risk factors, including blood pressure, lipid levels, and measures of inflammation, were observed when comparing the effects on hemorrhagic stroke with those on ischemic outcomes. For instance, multivariable adjusted hazard ratios per standard deviation increase in non–high‐density lipoprotein cholesterol were 1.16 (95% confidence interval, 1.06–1.28) for CHD, 0.97 (0.88–1.07) for ischemic stroke, and 0.76 (0.63–0.91) for hemorrhagic stroke (
P
<0.05 for equal association). Model discrimination was better for models predicting CHD or ischemic stroke than for models predicting hemorrhagic stroke or a combined end point.

Conclusions

Cardiovascular risk factors have largely similar effects on incidence of CHD and ischemic stroke in women, although the magnitude of association varies. Determinants of ischemic and hemorrhagic stroke substantially differ, underscoring their distinct biology. Cardiovascular disease risk may be more accurately reflected when combined cardiovascular disease or cerebrovascular outcomes are broken down into different first manifestations, or when restricted to ischemic outcomes.
Genetic Variants Associated With Plasma Lipids Are Associated With the Lipid Response to Niacin
Authors: Tuteja Sony , Qu Liming , Vujkovic Marijana , Dunbar Richard L. , Chen Jinbo , DerOhannessian Stephanie , Rader Daniel J.
Published: September 2018

Background

Niacin is a broad‐spectrum lipid‐modulating drug, but its mechanism of action is unclear. Genome‐wide association studies have identified multiple loci associated with blood lipid levels and lipoprotein (a). It is unknown whether these loci modulate response to niacin.

Methods and Results

Using data from the
AIM
‐
HIGH
(Atherothrombosis Intervention in Metabolic Syndrome with Low
HDL
/High Triglycerides and Impact on Global Health Outcomes) trial (n=2054 genotyped participants), we determined whether genetic variations at validated loci were associated with a differential change in plasma lipids and lipoprotein (a) 1 year after randomization to either statin+placebo or statin+niacin in a variant‐treatment interaction model. Nominally significant interactions (
P
<0.05) were found for genetic variants in

MVK

,

LIPC
,
PABPC
4,
AMPD
3

with change in high‐density lipoprotein cholesterol;

SPTLC
3

with change in low‐density lipoprotein cholesterol;

TOM
1

with change in total cholesterol;

PDXDC
1

and

CYP
26A1

with change in triglycerides; and none for lipoprotein (a). We also investigated whether these loci were associated with cardiovascular events. The risk of coronary disease related death was higher in the minor allele carriers at the

LIPC

locus in the placebo group (odds ratio 2.08, 95% confidence interval 1.11‐3.90,
P
=0.02) but not observed in the niacin group (odds ratio 0.89, 95% confidence interval 0.48‐1.65,
P
=0.7);
P
‐interaction =0.02. There was a greater risk for acute coronary syndrome (odds ratio 1.85, 95% confidence interval 1.16‐2.77,
P
=0.02) and revascularization events (odds ratio 1.64, 95% confidence interval 1.2‐2.22,
P
=0.002) in major allele carriers at the

CYP
26A1

locus in the placebo group not seen in the niacin group.

Conclusions

Genetic variation at loci previously associated with steady‐state lipid levels displays evidence for lipid response to niacin treatment.

Clinical Trials Registration

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00120289.