bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood Vessel-Derived Acellular Matrix for Vascular Graft Application
Authors: Dall’Olmo Luigi , Zanusso Ilenia , Di Liddo Rosa , Chioato Tatiana , Bertalot Thomas , Guidi Enrica , Conconi Maria Teresa
Published: July 2014

To overcome the issues connected to the use of autologous vascular grafts and artificial materials for reconstruction of small diameter (<6 mm) blood vessels, this study aimed to develop acellular matrix- (AM-) based vascular grafts. Rat iliac arteries were decellularized by a detergent-enzymatic treatment, whereas endothelial cells (ECs) were obtained through enzymatic digestion of rat skin followed by immunomagnetic separation of CD31-positive cells. Sixteen female Lewis rats (8 weeks old) received only AM or previouslyin vitroreendothelialized AM as abdominal aorta interposition grafts (about 1 cm). The detergent-enzymatic treatment completely removed the cellular part of vessels and both MHC class I and class II antigens. One month after surgery, the luminal surface of implanted AMs was partially covered by ECs and several platelets adhered in the areas lacking cell coverage. Intimal hyperplasia, already detected after 1 month, increased at 3 months. On the contrary, all grafts composed by AM and ECs were completely covered at 1 month and their structure was similar to that of native vessels at 3 months. Taken together, our findings show that prostheses composed of AM preseeded with ECs could be a promising approach for the replacement of blood vessels.
The Alliance of Mesenchymal Stem Cells, Bone, and Diabetes
Authors: Napoli Nicola , Strollo Rocky , Paladini Angela , Briganti Silvia I. , Pozzilli Paolo , Epstein Sol
Published: July 2014

Bone fragility has emerged as a new complication of diabetes. Several mechanisms in diabetes may influence bone homeostasis by impairing the action between osteoblasts, osteoclasts, and osteocytes and/or changing the structural properties of the bone tissue. Some of these mechanisms can potentially alter the fate of mesenchymal stem cells, the initial precursor of the osteoblast. In this review, we describe the main factors that impair bone health in diabetic patients and their clinical impact.
Uncomplicated Diverticular Disease: Innate and Adaptive Immunity in Human Gut Mucosa before and after Rifaximin
Authors: Cianci Rossella , Frosali Simona , Pagliari Danilo , Cesaro Paola , Petruzziello Lucio , Casciano Fabio , Landolfi Raffaele , Costamagna Guido , Pandolfi Franco
Published: July 2014

Background/Aim. Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin.Methods. Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were enrolled. Among UDD patients, 20 were assigned to a 2-month course of treatment with Rifaximin 1.2 g/day for 15 days/month and 20 received placebo. Blood sample and colonic biopsies were obtained from patients and controls. The samples were collected and analyzed at baseline and at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD103, TCR-gamma/delta, CD14, TLR2, and TLR4).Results. In UDD, TLR2 and TLR4 expression on immune cell subpopulations from blood and mucosa of the affected colon are altered as compared with controls. Rifaximin treatment induced significant modifications of altered conditions.Conclusions. Our data show the role of TLRs in the development of inflammation in UDD. TLRs distribution is altered in UDD and these alterations are reversed after antibiotic treatment. This trial is registered with ClinicalTrials.gov:NCT02068482.
Modulation Instability of Ion-Acoustic Waves in Plasma with Nonthermal Electrons
Authors: Ghosh Basudev , Banerjee Sreyasi
Published: July 2014

Modulational instability of ion-acoustic waves has been theoretically investigated in an unmagnetized collisionless plasma with nonthermal electrons, Boltzmann positrons, and warm positive ions. To describe the nonlinear evolution of the wave amplitude a nonlinear Schrödinger (NLS) equation has been derived by using multiple scale perturbation technique. The nonthermal parameter, positron concentration, and ion temperature are shown to play significant role in the modulational instability of ion-acoustic waves and the formation of envelope solitons.
Trabecular Bone Image Segmentation Using Wavelet and Marker-Controlled Watershed Transformation
Authors: Abid Fourati Wafa , Bouhlel Mohamed Salim
Published: July 2014

This paper presents a new strategy for the segmentation of trabecular bone image. This kind of image is acquired with microcomputed tomography (micro-CT) to assess bone microarchitecture based chiefly on bone mineral density (BMD) measurements to improve fracture risk prediction. Disease osteoporosis can be predicted from features of CT image where a bone region may consist of several disjoint pieces. It relies on a multiresolution representation of the image by the wavelet transform to compute the multiscale morphological gradient. The coefficients of detail found at the different scales are used to determine the markers and homogeneous regions that are extracted with the watershed algorithm. The method reduces the tendency of the watershed algorithm to oversegment and results in closed homogeneous regions. The performance of the proposed segmentation scheme is presented via experimental results obtained with a broad series of images.
Intestinal Mucosal Barrier Is Injured by BMP2/4 via Activation of NF-κB Signals after Ischemic Reperfusion
Authors: Chen Kang , Xie Wei , Luo Binyu , Xiao Weidong , Teitelbaum Daniel H. , Yang Hua , Zhang Kebin , Zhang Chaojun
Published: July 2014

Intestinal ischemic reperfusion (I/R) can cause dysfunction of the intestinal mucosal barrier; however, the mechanism of the intestinal mucosal barrier dysfunction caused by I/R remains unclear. In this study, using intestinal epithelial cells under anaerobic cultivation and an in vivo rat intestinal I/R model, we found that hypoxia and I/R increased the expression of BMP2/4 and upregulated BMP type Ia receptor and BMP type II receptor expression. We also found that exogenous BMP2/4 can activate the ERK and AKT signaling pathways in rat small intestine (IEC-6) cells, thereby activating NF-κB signaling, which leads to increased levels of inflammatory factors, such as TNF-αand IL-6. Furthermore, recombinant BMP2/4 decreased the expression of the tight junction protein occludin via the activation of the NF-κB pathway; these effects were abolished by treatment with the BMP-specific antagonist noggin or the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). All these factors can destroy the intestinal mucosal barrier, thereby leading to weaker barrier function. On the basis of these data, we conclude that BMP2/4 may act as the pathogenic basis for intestinal mucosal barrier dysfunction when the intestines suffer an I/R injury. Our results provide background for the development pharmacologic interventions in the management of I/R injury.
Influence of Al and Ti Additions on Microstructure and Mechanical Properties of Leaded Brass Alloys
Authors: Hussein Rajab Mohammed , Abd Osama Ibrahim
Published: July 2014

Brass has an attractive combination of properties, namely, good corrosion resistance, good wear properties, and high thermal and electrical conductivity. In this study, influence of selected alloy additions (Al and Ti) on performance of leaded brass alloys (CuZn39pb3) was investigated. The observation of microstructures, compression tests, and hardness tests were performed. The results of metallographic and mechanical tests indicate some influence of small amount additives of Al and Ti. Optical emission spectrometer (OES), light optical microscope (LOM), micro-Vickers hardness tester, and compression testing machine were used in this investigation. Consequently, Al had a significant effect on microstructure and mechanical properties of CuZn39Pb3 alloy. A larger compression strength at 0.31% wt of Al was obtained, as compared with the other alloys. Adding of Al and Ti led to the modification of the microstructure; thus, the compression strength was increased.
IL-6 as a Druggable Target in Psoriasis: Focus on Pustular Variants
Authors: Saggini Andrea , Chimenti Sergio , Chiricozzi Andrea
Published: July 2014

Psoriasis vulgaris (PV) is a cutaneous inflammatory disorder stemming from abnormal, persistent activation of the interleukin- (IL-)23/Th17 axis. Pustular psoriasis (PP) is a clinicopathological variant of psoriasis, histopathologically defined by the predominance of intraepidermal collections of neutrophils. Although PP pathogenesis is thought to largely follow that of (PV), recent evidences point to a more central role for IL-1, IL-36, and IL-6 in the development of PP. We review the role of IL-6 in the pathogenesis of PV and PP, focusing on its cross-talk with cytokines of the IL-23/Th17 axis. Clinical inhibitors of IL-6 signaling, including tocilizumab, have shown significant effectiveness in the treatment of several inflammatory rheumatic diseases, including rheumatoid arthritis and juvenile idiopathic arthritis; accordingly, anti-IL-6 agents may potentially represent future promising therapies for the treatment of PP.
Strengthening Reinforced Concrete Beams with CFRP and GFRP
Authors: Önal Mehmet Mustafa
Published: July 2014

Concrete beams were strengthened by wrapping the shear edges of the beams twice at 45° in opposite directions by either carbon fiber reinforced polymer (CFRP) or glass fiber reinforced polymer (GFRP). The study included 3 CFRP wrapped beams, 3 GFRP wrapped beams, and 3 control beams, all of which were 150×250×2200 mm and manufactured with C20 concrete and S420a structural steel at the Gazi University Technical Education Faculty labs, Turkey. Samples in molds were cured by watering in the open air for 21 days. Four-point bending tests were made on the beam test specimens and the data were collected. Data were evaluated in terms of load displacement, bearing strength, ductility, and energy consumption. In the CFRP and GFRP reinforced beams, compared to controls, 38% and 42%, respectively, strength increase was observed. In all beams, failure-flexural stress occurred in the center as expected. Most cracking was observed in the flexural region 4. A comparison of CFRP and GFRP materials reveals that GFRP enforced parts absorb more energy. Both materials yielded successful results. Thicker epoxy application in both CFRP and GFRP beams was considered to be effective in preventing break-ups.
Building a Smooth Medical Service for Operating Room Using RFID Technologies
Authors: Hung Lun-Ping , Lu Hsin-Ke , Wang Ching-Sheng , Chiang Ding-Jung
Published: July 2014

Due to the information technology advancement, the feasibility for the establishment of mobile medical environments has been strengthened. Using RFID to facilitate the tracing of patients’ mobile position in hospital has attracted more attentions from researchers due to the demand on advanced features. Traditionally, the management of surgical treatment is generally manually operated and there is no consistent operating procedure for patients transferring among wards, surgery waiting rooms, operating rooms, and recovery rooms, resulting in panicky and urgent transferring work among departments and, thus, leading to delays and errors. In this paper, we propose a new framework using radio frequency identification (RFID) technology for a mobilized surgical process monitoring system. Through the active tag, an application management system used before, during, and after the surgical processes has been proposed. The concept of signal level matrix, SLM, was proposed to accurately identify patients and dynamically track patients’ location. By updating patient’s information real-time, the preprocessing time needed for various tasks and incomplete transfers among departments can be reduced, the medical resources can be effectively used, unnecessary medical disputes can be reduced, and more comprehensive health care environment can be provided. The feasibility and effectiveness of our proposed system are demonstrated with a number of experimental results.
Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward?
Authors: Hatzis Christos , Bedard Philippe L. , Birkbak Nicolai J. , Beck Andrew H. , Aerts Hugo J.W.L. , Stern David F. , Shi Leming , Clarke Robert , Quackenbush John , Haibe-Kains Benjamin
Published: July 2014

Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers. Subsequent evaluation, however, found only moderate interlaboratory concordance in the drug response phenotypes, possibly due to differences in the experimental protocols used in the two studies. This highlights the need for community-wide implementation of standardized assays for measuring drug response phenotypes so that the full potential of HTS is realized. We suggest that the path forward is to establish best practices and standardization of the critical steps in these assays through a collective effort to ensure that the data produced from large-scale screens would not only be of high intrastudy consistency, so that they could be replicated and compared successfully across multiple laboratories. Cancer Res; 74(15); 4016–23. ©2014 AACR.
A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors That Repress FGFR Signaling
Authors: Lin Ling , Chamberlain Lynn , Pak Magnolia L. , Nagarajan Arvindhan , Gupta Romi , Zhu Lihua J. , Wright Casey M. , Fong Kwun M. , Wajapeyee Narendra , Green Michael R.
Published: July 2014

To discover new tumor-suppressor genes (TSG), we developed a functional genomics approach in which immortalized but nontumorigenic cells were stably transduced with large-scale shRNA pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly downregulated in human lung squamous cell carcinomas (hLSCC). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 amplification or activating mutations.

Significance: A functional genomics approach identifies new lung TSGs whose loss aberrantly increases FGFR signaling to promote tumorigenesis. These TSGs are frequently downregulated in hLSCCs, indicating that increased FGFR signaling promotes tumorigenesis in many hLSCCs lacking FGFR1 amplification or activating mutations. Cancer Discov; 4(10); 1168–81. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1103
Electrocardiographic Features and Prevalence of Bilateral Bundle-Branch Delay
Authors: Tzogias Leonidas , Steinberg Leonard A. , Williams Andrew J. , Morris Kent E. , Mahlow William J. , Fogel Richard I. , Olson Jeff A. , Prystowsky Eric N. , Padanilam Benzy J.
Published: July 2014

Background—

Definitive diagnosis of bilateral bundle-branch delay/block may be made when catheter-induced right bundle-branch block (RBBB) develops in patients with baseline left bundle-branch (LBB) block. We hypothesized that a RBBB pattern with absent S waves in leads I and aVL will identify bilateral bundle-branch delay/block.

Methods and Results—

Fifty patients developing transient RBBB pattern in lead V1 during right heart catheterization were studied. Patients were grouped according to whether the baseline ECG demonstrated a normal QRS, left fascicular blocks, or LBB block pattern. The RBBB morphologies in each group were compared. The prevalence of bilateral bundle-branch delay/block pattern was examined in our hospital ECG database. All patients with baseline normal QRS complexes (n=30) or left fascicular blocks (4 anterior, 5 posterior) developed a typical RBBB pattern. Among the 11 patients with a baseline LBB block pattern, 7 developed an atypical RBBB pattern with absent S waves in leads I and aVL and the remaining 4 demonstrated a typical RBBB. The absence of S waves in leads I and aVL during RBBB was 100% specific and 64% sensitive for the presence of pre-existing LBB block. Among the consecutive 2253 hospitalized patients with RBBB, 34 (1.5%) had the bilateral bundle-branch delay/block pattern.

Conclusions—

An ECG pattern of RBBB in lead V1 with absent S wave in leads I and aVL indicates concomitant LBB delay. Pure RBBB and bifascicular blocks are associated with S waves in leads I and aVL.
Current Management of Focal Atrial Tachycardia in Children
Authors: Kang Kristopher T. , Etheridge Susan P. , Kantoch Michal J. , Tisma-Dupanovic Svjetlana , Bradley David J. , Balaji Seshadri , Hamilton Robert M. , Singh Anoop K. , Cannon Bryan C. , Schaffer Michael S. , Potts James E. , Sanatani Shubhayan
Published: July 2014

Background—

Focal atrial tachycardia (FAT) is an uncommon cause of supraventricular tachycardia in children. Incessant FAT can lead to tachycardia-induced cardiomyopathy. There is limited information regarding the clinical course and management of FAT. This study characterizes current management strategies for FAT in children including the prevalence of spontaneous resolution and the role of catheter ablation.

Methods and Results—

This is a retrospective chart review of pediatric patients with FAT managed between January 2000 and November 2010 at 10 pediatric centers. There were 249 patients with a median age at diagnosis of 7.2 (95% confidence interval, 5.8–10.4) years. Cardiomyopathy was observed in 28%. Resolution of FAT occurred in 89%, including spontaneous resolution without catheter ablation in 34%. Antiarrhythmic medications were used for initial therapy in 154 patients with control of FAT in 72%. Among first-line medications, β-blockers were the most common (53%) and effective (42%). Catheter ablation was successful in 80% of patients. FAT recurrence was less common with electroanatomic mapping compared with conventional mapping techniques (16% versus 35%;
P
=0.02). Patients were followed for a median of 2.1 (95% confidence interval, 1.8–2.6) years.

Conclusions—

FAT is managed successfully in most children. Current approaches are variable. Many patients have control of FAT with medications; however, catheter ablation is used for most patients. Spontaneous resolution is common for young children, emphasizing the role for delayed ablation in this group. Ablation is successful for all ages. Lower recurrence occurs when electroanatomic mapping techniques are used.
Resumption of Chest Compressions After Successful Defibrillation and Risk for Recurrence of Ventricular Fibrillation in Out-of-Hospital Cardiac Arrest
Authors: Conover Zacherie , Kern Karl B. , Silver Annemarie E. , Bobrow Bentley J. , Spaite Daniel W. , Indik Julia H.
Published: July 2014

Background—

Prior investigation of out-of-hospital cardiac arrest has raised the concern that ventricular fibrillation (VF) recurrence may be triggered by chest compression (CC) resumption. We investigated predictors of VF recurrence after defibrillation, including timing of CC resumption.

Methods and Results—

Patients with witnessed out-of-hospital cardiac arrest and initial rhythm of VF from an Utstein-style database were analyzed. For each shock that defibrillated VF, CC resumption and VF recurrence times were determined. Shocks were classified according to postshock rhythm. Factors (age, sex, time from dispatch to monitor/defibrillator application, and CC resumption) that could predict VF recurrence were analyzed. CC resumption was categorized into groups: CC1, 1 to 5 seconds; CC2, 6 to 10 seconds; CC3, 11 to 30 seconds; and CC4, >30 seconds. Eighty-eight subjects were analyzed, with a total of 285 shocks, with 226 shocks that achieved asystole (n=102), organized rhythm (n=120), or monomorphic ventricular tachycardia (n=4). After a successful shock, CC resumption occurred at a median (interquartile range) of 8 (5–18) seconds. VF recurred after 166 shocks (74%) and recurred within 30 seconds in 69 shocks. There was no significant relationship between VF recurrence and factors analyzed including CC resumption time, nor stratified by postshock rhythm. The hazard ratios (HRs) for VF recurrence within 30 seconds for later CC groups (CC2, CC3, and CC4) relative to early CC resumption (CC1) were as follows: HR(CC2)=1.05 (
P
=0.9); HR(CC3)=1.75 (
P
=0.1); and HR(CC4)=0.67 (
P
=0.4).

Conclusions—

VF recurrence within 30 seconds of a defibrillatory shock was not dependent on timing of CC resumption in patients with witnessed arrest and initial rhythm of VF.
Myocardial Lesion Size After Epicardial Electroporation Catheter Ablation After Subxiphoid Puncture
Authors: Neven Kars , van Driel Vincent , van Wessel Harry , van Es René , Doevendans Pieter A. , Wittkampf Fred
Published: July 2014

Background—

Irreversible electroporation is a promising nonthermal ablation modality able to create deep myocardial lesions. We investigated lesion size after epicardial electroporation catheter ablation with various energy levels after subxiphoid pericardial puncture.

Methods and Results—

In six 6-month-old pigs (60–75 kg), a custom deflectable octopolar 12-mm circular catheter with 2-mm ring electrodes was introduced via a deflectable sheath after pericardial access by subxiphoid puncture. Nonarcing, nonbarotraumatic, cathodal 50, 100, and 200 J electroporation applications were delivered randomly on the basal, mid and lateral left ventricle. After 3-month survival, myocardial lesion size and degree of intimal hyperplasia of the coronary arteries were analyzed histologically. Five animals survived the follow-up without complications and 1 animal died of shock after the subxiphoid puncture. At autopsy, whitish circular scars with indentation of the epicardium could be identified. Average lesion depths of the 50-, 100-, and 200-J lesions were 5.0±2.1, 7.0±2.0, and 11.9±1.5 mm, respectively. Average lesion widths of the 50-, 100-, and 200-J lesions were 16.6±1.1, 16.2±4.3, and 19.8±1.8 mm, respectively. In the 100- and 200-J cross sections, transmural left ventricular lesions and significant tissue shrinkage were observed. No intimal hyperplasia of the coronary arteries was observed.

Conclusions—

Epicardial electroporation ablation after subxiphoid pericardial puncture can create deep, wide, and transmural ventricular myocardial lesions. There is a significant relationship between the amounts of electroporation energy delivered epicardially and lesion size in the absence of major adverse events.
Renal Function–Adjusted Contrast Volume Redefines the Baseline Estimation of Contrast-Induced Acute Kidney Injury Risk in Patients Undergoing Primary Percutaneous Coronary Intervention
Authors: Andò Giuseppe , de Gregorio Cesare , Morabito Gaetano , Trio Olimpia , Saporito Francesco , Oreto Giuseppe
Published: July 2014

Background—

Age, estimated glomerular renal function (eGFR), and ejection fraction are preprocedural predictors of contrast-induced acute kidney injury (CI-AKI) after primary percutaneous coronary intervention. The effect of renal function–adjusted contrast volume (CV) remains not totally explored, and a threshold has not yet been established.

Methods and Results—

Logistic regression and receiver-operating characteristic curve analyses were used to assess whether CV/eGFR was an independent predictor of CI-AKI. The increased discriminative value of CV/eGFR over the preprocedural model based on age, eGFR, and ejection fraction was examined using the net reclassification improvement analysis. Of 470 patients enrolled, we observed 25 (5.3%) cases of CI-AKI. Patients with CI-AKI had received a higher renal function–adjusted CV (CV/eGFR 3.62 versus 1.96;
P
<0.001), and CI-AKI incidence was higher (15%;
P
<0.001) in patients in the highest quartile of CV/eGFR, corresponding to the cutoff indicated by the receiver-operating characteristic curve (>2.5; area under the curve, 0.77). At multivariable analysis, CV/eGFR above the cutoff (odds ratio, 5.57;
P
=0.002) remained an independent predictor of CI-AKI. The model with CV/eGFR demonstrated a statistically significantly net reclassification improvement of 0.23 (
P
=0.021) over the baseline preprocedural model, largely driven by a correct decrease in risk estimates for patients not experiencing CI-AKI, with a likelihood ratio χ
2
of 5.973 (
P
=0.029).

Conclusions—

CV remains a key risk factor for CI-AKI after primary percutaneous coronary intervention and our study supports the need for minimizing CV, independently from baseline preprocedural risk. A CV restricted to no more than twice and a half the baseline eGFR might be valuable in reducing the risk of CI-AKI.
Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as an In Vitro Model for Coxsackievirus B3–Induced Myocarditis and Antiviral Drug Screening Platform
Authors: Sharma Arun , Marceau Caleb , Hamaguchi Ryoko , Burridge Paul W. , Rajarajan Kuppusamy , Churko Jared M. , Wu Haodi , Sallam Karim I. , Matsa Elena , Sturzu Anthony C. , Che Yonglu , Ebert Antje , Diecke Sebastian , Liang Ping , Red-Horse Kristy , Carette Jan E. , Wu Sean M. , Wu Joseph C.
Published: July 2014

Rationale:

Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. However, human cardiac tissues are difficult to procure in sufficient enough quantities for studying the mechanisms of cardiac-specific viral infection.

Objective:

This study examined whether human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy.

Methods and Results:

hiPSC-CMs were infected with a luciferase-expressing coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs for alterations in cellular morphology and calcium handling. Viral proliferation in hiPSC-CMs was quantified using bioluminescence imaging. Antiviral compounds including interferonβ1, ribavirin, pyrrolidine dithiocarbamate, and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with reported drug effects in previous studies. Mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways after interferonβ1 treatment.

Conclusions:

This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to predict antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that can screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion.
Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling
Authors: Nam Yoon Seok , Kim Yoojung , Joung Hosouk , Kwon Duk-Hwa , Choe Nakwon , Min Hyun-Ki , Kim Yong Sook , Kim Hyung-Seok , Kim Don-Kyu , Cho Young Kuk , Kim Yong-Hoon , Nam Kwang-Il , Choi Hyoung Chul , Park Dong Ho , Suk Kyoungho , Lee In-Kyu , Ahn Youngkeun , Lee Chul-Ho , Choi Hueng-Sik , Eom Gwang Hyeon , Kook Hyun
Published: July 2014

Rationale
:

Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated.

Objective
:

We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy.

Methods and Results
:

The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP-null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and, by direct physical interaction with Gata6, interfered with the binding of Gata6 to GATA-binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an antidiabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced antihypertrophic effect was attenuated either by SHP small interfering RNA in cardiomyocytes or in SHP-null mice.

Conclusions
:

These results establish SHP as a novel antihypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced antihypertrophic response.
Cost-Effectiveness of Follow-Up of Pulmonary Nodules Incidentally Detected on Cardiac Computed Tomographic Angiography in Patients With Suspected Coronary Artery Disease
Authors: Goehler Alexander , McMahon Pamela M. , Lumish Heidi S. , Wu Carol C. , Munshi Vidit , Gilmore Michael , Chung Jonathan H. , Ghoshhajra Brian B. , Mark Daniel , Truong Quynh A. , Gazelle G. Scott , Hoffmann Udo
Published: July 2014

Background—

Pulmonary nodules (PNs) are often detected incidentally during coronary computed tomographic (CT) angiography, which is increasingly being used to evaluate patients with chest pain symptoms. However, the efficiency of following up on incidentally detected PN is unknown.

Methods and Results—

We determined demographic and clinical characteristics of stable symptomatic patients referred for coronary CT angiography in whom incidentally detected PNs warranted follow-up. A validated lung cancer simulation model was populated with data from these patients, and clinical and economic consequences of follow-up per Fleischner guidelines versus no follow-up were simulated. Of the 3665 patients referred for coronary CT angiography, 591 (16%) had PNs requiring follow-up. The mean age of patients with PNs was 59±10 years; 66% were male; 67% had ever smoked; and 21% had obstructive coronary artery disease. The projected overall lung cancer incidence was 5.8% in these patients, but the majority died of coronary artery disease (38%) and other causes (57%). Follow-up of PNs was associated with a 4.6% relative reduction in cumulative lung cancer mortality (absolute mortality: follow-up, 4.33% versus non–follow-up, 4.54%), more downstream testing (follow-up, 2.34 CTs per patient versus non–follow-up, 1.01 CTs per patient), and an average increase in quality-adjusted life of 7 days. Costs per quality-adjusted life-year gained were $154 700 to follow up the entire cohort and $129 800 per quality-adjusted life-year when only smokers were included.

Conclusions—

Follow-up of PNs incidentally detected in patients undergoing coronary CT angiography for chest pain evaluation is associated with a small reduction in lung cancer mortality. However, significant downstream testing contributes to limited efficiency, as demonstrated by a high cost per quality-adjusted life-year, especially in nonsmokers.
Prognostic Value of Fasting Versus Nonfasting Low-Density Lipoprotein Cholesterol Levels on Long-Term Mortality
Authors: Doran Bethany , Guo Yu , Xu Jinfeng , Weintraub Howard , Mora Samia , Maron David J. , Bangalore Sripal
Published: July 2014

Background—

National and international guidelines recommend fasting lipid panel measurement for risk stratification of patients for prevention of cardiovascular events. However, the prognostic value of fasting versus nonfasting low-density lipoprotein cholesterol (LDL-C) is uncertain.

Methods and Results—

Patients enrolled in the National Health and Nutrition Examination Survey III (NHANES-III), a nationally representative cross-sectional survey performed from 1988 to 1994, were stratified on the basis of fasting status (≥8 or <8 hours) and followed for a mean of 14.0 (±0.22) years. Propensity score matching was used to assemble fasting and nonfasting cohorts with similar baseline characteristics. The risk of outcomes as a function of LDL-C and fasting status was assessed with the use of receiver operating characteristic curves and bootstrapping methods. The interaction between fasting status and LDL-C was assessed with Cox proportional hazards modeling. Primary outcome was all-cause mortality. Secondary outcome was cardiovascular mortality. One-to-one matching based on propensity score yielded 4299 pairs of fasting and nonfasting individuals. For the primary outcome, fasting LDL-C yielded prognostic value similar to that for nonfasting LDL-C (C statistic=0.59 [95% confidence interval, 0.57–0.61] versus 0.58 [95% confidence interval, 0.56–0.60];
P
=0.73), and LDL-C by fasting status interaction term in the Cox proportional hazards model was not significant (
P
interaction
=0.11). Similar results were seen for the secondary outcome (fasting versus nonfasting C statistic=0.62 [95% confidence interval, 0.60–0.66] versus 0.62 [95% confidence interval, 0.60–0.66];
P
=0.96;
P
interaction
=0.34).

Conclusions—

Nonfasting LDL-C has prognostic value similar to that of fasting LDL-C. National and international agencies should consider reevaluating the recommendation that patients fast before obtaining a lipid panel.
Vitamin D Promotes Vascular Regeneration
Authors: Wong Michael Sze Ka , Leisegang Matthias S. , Kruse Christoph , Vogel Juri , Schürmann Christoph , Dehne Nathalie , Weigert Andreas , Herrmann Eva , Brüne Bernhard , Shah Ajay M. , Steinhilber Dieter , Offermanns Stefan , Carmeliet Geert , Badenhoop Klaus , Schröder Katrin , Brandes Ralf P.
Published: July 2014

Background—

Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone 1,25-dihydroxycholecalciferol (1,25-dihydroxy-vitamin D
3
; 1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D
3
deficiency, however, has been linked to cardiovascular disease because the hormone has anti-inflammatory properties. We therefore hypothesized that 1,25-VitD3 promotes regeneration after vascular injury.

Methods and Results—

In healthy volunteers, supplementation of vitamin D
3
(4000 IU cholecalciferol per day) increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells, which are thought to promote vascular regeneration. Similarly, in mice, 1,25-VitD3 (100 ng/kg per day) increased the number of angiogenic myeloid cells and promoted reendothelialization in the carotid artery injury model. In streptozotocin-induced diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the impaired angiogenesis in the femoral artery ligation model. Angiogenic myeloid cells home through the stromal cell–derived factor 1 (SDF1) receptor CXCR4. Inhibition of CXCR4 blocked 1,25-VitD3–stimulated healing, pointing to a role of SDF1. The combination of injury and 1,25-VitD3 increased SDF1 in vessels. Conditioned medium from injured, 1,25-VitD3–treated arteries elicited a chemotactic effect on angiogenic myeloid cells, which was blocked by SDF1-neutralizing antibodies. Conditional knockout of the vitamin D receptor in myeloid cells but not the endothelium or smooth muscle cells blocked the effects of 1,25-VitD3 on healing and prevented SDF1 formation. Mechanistically, 1,25-VitD3 increased hypoxia-inducible factor 1-α through binding to its promoter. Increased hypoxia-inducible factor signaling subsequently promoted SDF1 expression, as revealed by reporter assays and knockout and inhibitory strategies of hypoxia-inducible factor 1-α.

Conclusions—

By inducing SDF1, vitamin D
3
is a novel approach to promote vascular repair.
Reducing Endoglin Activity Limits Calcineurin and TRPC‐6 Expression and Improves Survival in a Mouse Model of Right Ventricular Pressure Overload
Authors: Kapur Navin K. , Qiao Xiaoying , Paruchuri Vikram , Mackey Emily E. , Daly Gerard H. , Ughreja Kishan , Morine Kevin J. , Levine Jonathan , Aronovitz Mark J. , Hill Nicholas S. , Jaffe Iris Z. , Letarte Michelle , Karas Richard H.
Published: July 2014

Background

Right ventricular (
RV
) failure is a major cause of mortality worldwide and is often a consequence of
RV
pressure overload (
RVPO
). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (
TGF
‐β1).
TGF
‐β1 signaling by the canonical transient receptor protein channel 6 (
TRPC
‐6) was recently reported to stimulate calcineurin‐mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the
TGF
‐β1 coreceptor, endoglin, limits
RV
calcineurin expression and improves survival in
RVPO
.

Methods and Results

We first demonstrate that endoglin is required for
TGF
‐β1‐mediated calcineurin/
TRPC
‐6 expression and up‐regulation of alpha‐smooth muscle antigen (α‐
SMA
), a marker of myofibroblast transformation, in human
RV
fibroblasts. Using endoglin haploinsufficient mice (Eng
+/−
) we show that reduced endoglin activity preserves
RV
function, limits
RV
fibrosis, and attenuates activation of the calcineurin/
TRPC
‐6/α‐
SMA
pathway in a model of angio‐obliterative pulmonary hypertension. Next, using Eng
+/−
mice or a neutralizing antibody (Ab) against endoglin (N‐Eng) in wild‐type mice, we show that reduced endoglin activity improves survival and attenuates
RV
fibrosis in models of
RVPO
induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of
RV
fibrosis and calcineurin levels in wild‐type mice treated with a N‐Eng Ab, compared to an immunoglobulin G control.

Conclusion

These data establish endoglin as a regulator of
TGF
‐β1 signaling by calcineurin and
TRPC
‐6 in the
RV
and identify it as a potential therapeutic target to limit
RV
fibrosis and improve survival in
RVPO
, a common cause of death in cardiac and pulmonary disease.
In‐Hospital Worsening Heart Failure and Associations With Mortality, Readmission, and Healthcare Utilization
Authors: DeVore Adam D. , Hammill Bradley G. , Sharma Puza P. , Qualls Laura G. , Mentz Robert J. , Waltman Johnson Katherine , Fonarow Gregg C. , Curtis Lesley H. , Hernandez Adrian F.
Published: July 2014

Background

A subset of patients hospitalized with acute heart failure experiences worsening clinical status and requires escalation of therapy. Worsening heart failure is an end point in many clinical trials, but little is known about its prevalence in clinical practice and its associated outcomes.

Methods and Results

We analyzed inpatient data from the Acute Decompensated Heart Failure National Registry linked to Medicare claims to examine the prevalence and outcomes of patients with worsening heart failure, defined as the need for escalation of therapy at least 12 hours after hospital presentation. We compared patients with worsening heart failure to patients with an uncomplicated hospital course and patients with a complicated presentation. Of 63 727 patients hospitalized with acute heart failure, 11% developed worsening heart failure. These patients had the highest observed rates of mortality, all‐cause readmission, and Medicare payments at 30 days and 1 year after hospitalization (
P
 < 0.001 for all comparisons). The adjusted hazards of 30‐day mortality were 2.56 (99%
CI
, 2.34 to 2.80) compared with an uncomplicated course and 1.29 (99%
CI
, 1.17 to 1.42) compared with a complicated presentation. The adjusted cost ratios for postdischarge Medicare payments at 30 days were 1.35 (99%
CI
, 1.24 to 1.46) compared with an uncomplicated course and 1.11 (99%
CI
, 1.02 to 1.22) compared with a complicated presentation.

Conclusions

In‐hospital worsening heart failure was common and was associated with higher rates of mortality, all‐cause readmission, and postdischarge Medicare payments. Prevention and treatment of in‐hospital worsening heart failure represents an important goal for patients hospitalized with acute heart failure.
Von Willebrand Factor Drives the Association Between Elevated Factor VIII and Poor Outcomes in Patients With Ischemic Stroke
Authors: Samai Alyana , Monlezun Dominique , Shaban Amir , George Alexander , Dowell Lauren , Kruse-Jarres Rebecca , Schluter Laurie , El Khoury Ramy , Martin-Schild Sheryl
Published: July 2014

Background and Purpose—

Despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few studies have examined the relationship of these factors with acute ischemic stroke (AIS). We sought to determine whether concurrent elevation in FVIII and vWF was associated with adverse events and outcomes.

Methods—

From our prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October 2013 were included if both FVIII and vWF were measured during admission. The primary outcome was the modified Rankin Scale score on discharge.

Results—

Among 1453 cases in our stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9%) had FVIII−/vWF−, 16 patients (10.8%) had FVIII+/vWF−, and 51 patients (34.5%) had FVIII+/vWF+. In the fully adjusted model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio, 8.6; 95% confidence interval, 1.58–46.85;
P
=0.013) and neuroworsening (odds ratio, 3.2; 95% confidence interval, 1.18–8.73;
P
=0.022) than patients with FVIII−/vWF−. Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had increased odds of poor functional outcome (modified Rankin Scale>2; odds ratio, 2.87; 95% confidence interval, 1.16–7.06;
P
=0.021) than patients with FVIII−/vWF−.

Conclusions—

Concurrent FVIII/vWF elevation predicts higher odds of inpatient complications, neuroworsening, and worse functional outcomes for patients with AIS compared with patients with normal levels. Our findings suggest that FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS.
Mind the Gaps: The ilc Guide to Practice on Reservations to Human Rights Treaties
Authors: McCall-Smith Kasey L.
Published: July 2014

At the best of times the rules on reservations to treaties baffle many international law practitioners and the states that must navigate them. The persisting confusion from the application of the default reservations regime codified by the 1969 Vienna Convention is exacerbated when these rules are used to interpret reservations to human rights treaties. Great hope for clarity in the reservations rules was focused on the outcome of the ilc’s Guide to Practice on Reservations. However, following the 2011 publication of the Guide it is apparent that despite several progressive guidelines, little has changed in the context of reservations to human rights treaties. This article examines the practice of making reservations to human rights treaties. Specifically it will address the problems perpetuated by the object and purpose test, the lack of clarity of the legal effect and consequence of invalid reservations as well as the question of who decides invalidity.
The “Reservations Dialogue” as a Constitution-Making Process
Authors: Krivenko Ekaterina Yahyaoui
Published: July 2014

The article proposes a new reading of the reservations regime to human rights treaties. The practice developed by states in relation to the reservations regime is analysed and presented as a constitution-making process. This new vision is based on the notion of the reservations dialogue as presented and developed by the Special Rapporteur of the International Law Commission on reservations to treaties. However, the article also proposes a wide reading of the practice of the reservations dialogue using examples from the Convention on the Elimination of All Forms of Discrimination against Women. Based on this analysis, the author formulates some proposals as to a more adequate development of the reservations dialogue and the reservations regime. A development which will favour the formation of inclusive international human rights as a basis for a future international constitution accepted as legitimate by all members of the international community.
Classifications of Objections Based on the Legal Assessment of a Reservation by Objecting States
Authors: Girshovich Marina
Published: July 2014

Current doctrine assumes that the “Vienna regime” delinked objections from the criterion of object and purpose (op) compatibility of reservations. Shifting the focus from reservations to objections, this article finds implicit continuity between the Genocide Advisory Opinion and the Vienna regime: in both cases the op criterion enables a distinction between objections on the grounds of incompatibility of reservations (op objections) and all others. Embracing this distinction, a new theoretical interpretation of the Vienna regime safeguards against the adverse effects of objections, namely a “reinforced two-tier test” is suggested, whereby any reservation may be subject to an assessment of opposability (non-op objections) and a double assessment of permissibility. Adopting a functional approach, the article suggests a classification of international obligations based on the applicability of the Vienna regime’s various safeguard mechanisms, locating the roles of objections to reservations to human rights treaties in context.
Reservations to Human Rights Treaties: A Case Study on the Practice of Czechoslovakia and Its Successor States
Authors: Týč Vladimír , Janků Linda , Šipulová Katarína
Published: July 2014

Conformity with human rights norms is currently a standard component of democratic states’ policies. However, this conformity is reflected not only in domestic binding catalogues of human rights embodied in constitutions, but also in the continuous rise of international control and treaty commitments. States are widely expected to commit to and ratify international human rights documents. Nevertheless, a great deal of the research on state commitments disregards the effects and changes which might be brought upon these ratifications by the submission of reservations. This article proposes an in-depth analysis of state commitments and the practice of submitting reservations in two case studies: the Czech Republic and Slovakia, together with their common predecessor, communist (and, briefly, democratic) Czechoslovakia, and maps the way these regimes, in their different stages of transitional development, worked with reservations.

This contribution has been elaborated within the framework of the project „International Human Rights Obligations of the Czech Republic: Trends, Practice, Causes and Consequences“, GA13-27956S, supported by the Czech Science Foundation GAČR.