bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted versus Universal Neonatal Hearing Screening in a Single Egyptian Center
Authors: Imam Safaa S. , El-Farrash Rania A. , Taha Hesham M. , Bishoy Helbees E.
Published: September 2013

Aim. To compare targeted neonatal hearing screening (TNHS) and universal neonatal hearing screening (UNHS) since many developing countries, including Egypt, implement selective screening for high-risk neonates. Methods. 150 neonates were assessed; 50 full terms consecutively admitted to the well-baby nursery and 100 neonates consecutively admitted to neonatal intensive care unit (NICU), Ain Shams University. Patients were further subdivided into high-risk group which included 50 neonates with multiple risk factors for hearing loss and low risk group which included 50 neonates with only one risk factor. Transient evoked otoacoustic emissions (TEOAEs) were used for hearing screening. Auditory brain response (ABR) was performed 3 months later for failed TEOAEs. Results. The most frequent risk factor was consanguinity (46%). In the well-baby population, 16% failed TEOAEs. In the NICU, 30% of the low risk and 38% of the high risk groups failed TEOAEs. Regarding ABR, failed results were 12%, 10%, and 8% in the high-risk, low-risk, and healthy groups, respectively. Conclusion. The use of TNHS would have missed 8% of neonates from the well-baby group who actually had PCHL (permanent congenital hearing loss). The use of UNHS would identify all cases with PCHL, allowing for early intervention and follow-up.
Strain Distribution Measurement of a Shear Panel Damper Developed for Bridge Structure
Authors: Liu Y. , Aoki T. , Shimoda M.
Published: September 2013

A shear panel damper using low-yield steel is considered as one of cost-effective solutions to reduce earthquake damage to building structure. In this paper, we describe the development of a shear panel damper with high deformation capacity, which is a necessary condition for it to be a bridge bearing. The development is based on the measurement of strain distribution of the shear panels under cyclic loading test. For the measurement, an image processing technique is proposed to use with the two-dimensional finite element method, in which a constant stress triangular element is employed. The accuracy of the measurement is validated
by comparing with the results acquired by strain gauges. Various shapes of shear panels are tested in the experiment to obtain the relationship between the strain
distribution and the deformation capacity. Based on the results of the experiment, the shear panel damper is improved to achieve high seismic performance with
large deformation capacity.
Emission of Carbon Dioxide Influenced by Different Water Levels from Soil Incubated Organic Residues
Authors: Hossain M. B. , Puteh A. B.
Published: September 2013

We studied the influence of different organic residues and water levels on decomposition rate and carbon sequestration in soil. Organic residues (rice straw, rice root, cow dung, and poultry litter) including control were tested under moistened and flooding systems. An experiment was laid out as a complete randomized design at 25°C for 120 days. Higher CO2‐C (265.45 mg) emission was observed in moistened condition than in flooding condition from 7 to 120 days. Among the organic residues, poultry litter produced the highest CO2‐C emission. Poultry litter with soil mixture increased 121% cumulative CO2‐C compared to control. On average, about 38% of added poultry litter C was mineralized to CO2‐C. Maximum CO2‐C was found in 7 days after incubation and thereafter CO2‐C emission was decreased with the increase of time. Control produced the lowest CO2‐C (158.23 mg). Poultry litter produced maximum cumulative CO2‐C (349.91 mg). Maximum organic carbon was obtained in cow dung which followed by other organic residues. Organic residues along with flooding condition decreased cumulative CO2‐C, k value and increased organic C in soil. Maximum k value was found in poultry litter and control. Incorpored rice straw increased organic carbon and decreased k value (0.003 g d−1) in soil. In conclusion, rice straw and poultry litter were suitable for improving soil carbon.
Purification and Characterization of Phenylalanine Ammonia Lyase fromTrichosporon cutaneum
Authors: Goldson-Barnaby Andrea , Scaman Christine H.
Published: September 2013

Trichosporon cutaneumphenylalanine ammonia lyase was selected as a model to investigate the dual substrate activity of this family of enzymes. Sequencing of the PAL gene identified an extensive intron region at the N-terminus. Five amino acid residues differing from a prior report were identified. Highest Phe : Tyr activities (1.6 ±0.3 : 0.4±0.1 μmol/h g wet weight) were induced by Tyr. The enzyme has a temperature optimum of 32°C and a pH optimum of 8–8.5 and shows no metal cofactor dependence. Michaelis-Menten kinetics (Phe,Km  5.0 ± 1.1 mM) and positive allostery (Tyr,K′  2.4 ± 0.6 mM, Hill coefficient1.9±0.5) were observed. Anion exchange chromatography gave a purification fold of 50 with 20% yield. The His-Gln motif (substrate selectivity switch region) indicates the enzyme’s ability to act on both substrates.
Association between Angiotensin II Type 1 Receptor Polymorphism and Sudden Cardiac Death in Myocardial Infarction
Authors: Kruzliak Peter , Kovacova Gabriela , Pechanova Olga , Balogh Stefan
Published: September 2013

Objective. The renin-angiotensin system is involved in the pathogenesis of coronary artery disease and myocardial infarction (MI). Angiotensin II (Ang II) has many adverse effects such as vasoconstriction and vascular remodeling, and these actions are mediated by the angiotensin II type 1 receptor (AT1R).Patients and Methods. A total of 1376 patients were recruited from January 2010 to April 2012. The study group consisted of 749 patients with ACS (317 females and 432 males) and of 627 healthy controls.Results. The ACS patients demonstrated a lower proportion of AA genotypes and AC genotypes but higher proportions of CC genotypes than the control population. The AT1R CC genotype conferred a 2.76-fold higher risk of MI compared with the genotype AC and AA. In addition, the CC genotype was also associated with a 4.08 times higher risk of left anterior descending artery infarction and a 3.07 times higher risk of anterior wall infarction. We also found that the CC genotype was independently associated with sudden cardiac death.In Summary. This study demonstrated that the AT1R CC genotype is an independent risk factor for ACS incidence, and this genotype is associated with a greater ACS severity and greater risk of sudden cardiac death.
A Computational Determination of the Lowest Energy Electronic and Geometric States of First Row Transition Metal Dioxygen Dications
Authors: Lennartz Jillian , Dumas Eric , Ramirez Lennie , Galbraith John Morrison
Published: September 2013

The lowest energy geometric structures and electronic spin states of first row transition metal (TM) dioxygen dication molecules ([TM–O2]2+; TM = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) have been determined at the B3LYP/LANL2DZ level of theory (along with an extra d-type polarization function added to the O atoms). In order to further verify the spin states, CASSCF(6 + n, 9) energy points were determined (n = number of TM d electrons). It has been found that with the exception of [Sc–O2]2+, [V–O2]2+, [Co–O2]2+, and [Ni–O2]2+, all [TM–O2]2+ molecules take on a high-spin state. [Sc–O2]2+ adopts a trigonal structure, while [Ti–O2]2+-[Mn–O2]2+ are essentially linear and [Fe–O2]2+-[Zn–O2]2+ are bent. It is further noted that the O–O bond decreases from 130.0 pm to 118.1 pm as the TM changes from Sc to Zn. However, the TM–O2 bond lengths fluctuate between values of 182.2 pm for [Ni–O2]2+ and 232.2 pm for [Zn–O2]2+.
From Radical Mastectomy to Breast-Conserving Therapy and Oncoplastic Breast Surgery: A Narrative Review Comparing Oncological Result, Cosmetic Outcome, Quality of Life, and Health Economy
Authors: Kaviani Ahmad , Sodagari Nassim , Sheikhbahaei Sara , Eslami Vahid , Hafezi-Nejad Nima , Safavi Amin , Noparast Maryam , Fitoussi Alfred
Published: September 2013

Surgical management of breast cancer has evolved considerably over the last two decades. There has been a major shift toward less-invasive local treatments, from radical mastectomy to breast-conserving therapy (BCT) and oncoplastic breast surgery (OBS). In order to investigate the efficacy of each of the three abovementioned methods, a literature review was conducted for measurable outcomes including local recurrence, survival, cosmetic outcome, quality of life (QOL), and health economy. From the point of view of oncological result, there is no difference between mastectomy and BCT in local recurrence rate and survival. Long-term results for OBS are not available. The items assessed in the QOL sound a better score for OBS in comparison with mastectomy or BCT. OBS is also associated with a better cosmetic outcome. Although having low income seems to be associated with lower BCT and OBS utilization, prognosis of breast cancer is worse in these women as well. Thus, health economy is the matter that should be studied seriously. OBS is an innovative, progressive, and complicated subspeciality that lacks published randomized clinical trials comparing surgical techniques and objective measures of outcome, especially from oncologic and health economy points of view.
Recent Advances in NSAIDs-Induced Enteropathy Therapeutics: New Options, New Challenges
Authors: Lim Yun Jeong , Chun Hoon Jai
Published: September 2013

The injurious effects of NSAIDs on the small intestine were not fully appreciated until the widespread use of capsule endoscopy. It is estimated that over two-thirds of regular NSAID users develop injury in the small intestinal injuries and that these injuries are more common than gastroduodenal mucosal injuries. Recently, chronic low-dose aspirin consumption was found to be associated with injury to the lower gut and to be a significant contributing factor in small bowel ulceration, hemorrhage, and strictures. The ability of aspirin and NSAIDs to inhibit the activities of cyclooxygenase (COX) contributes to the cytotoxicity of these drugs in the gastrointestinal tract. However, many studies found that, in the small intestine, COX-independent mechanisms are the main contributors to NSAID cytotoxicity. Bile and Gram-negative bacteria are important factors in the pathogenesis of NSAID enteropathy. Here, we focus on a promising strategy to prevent NSAID-induced small intestine injury. Selective COX-2 inhibitors, prostaglandin derivatives, mucoprotective drugs, phosphatidylcholine-NSAIDs, and probiotics have potential protective effects on NSAID enteropathy.
A Meshless Method to Determine a Source Term in Heat Equation with Radial Basis Functions
Authors: Wang Baiyu , Liao Anping
Published: September 2013

This paper considers a numerical method based on the radial basis functions for the inverse problem of heat equation; the inverse problem is determining an unknown source term subject to the overdetermination along with the usual initial boundary conditions, and the unknown source term is only time-dependent. The radial basis functions method is a meshless method with high accuracy for the inverse problem. Some numerical experiments using this method are presented and discussed.
Efficacy of Ethanol Extract ofFructus lyciiand Its Constituents Lutein/Zeaxanthin in Protecting Retinal Pigment Epithelium Cells against Oxidative Stress:In VivoandIn VitroModels of Age-Related Macular Degeneration
Authors: Xu Xinrong , Hang Li , Huang Binglin , Wei Yuanhua , Zheng Shizhong , Li Wei
Published: September 2013

Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a large role in the pathogenesis of AMD. The present study was to evaluate the effects ofFructus lyciiethanol extract on AMD in mice and to investigate whether combination of lutein and zeaxanthin, two carotenoid pigments inFructus lycii, could protect human retinal pigment epithelial ARPE-19 cells treated with hydrogen peroxide (H2O2)in vitro. We found that severe sediment beneath retinal pigment epithelium and thickened Bruch membrane occurred in AMD mice. However,Fructus lyciiethanol extract improved the histopathologic changes and decreased the thickness of Bruch membrane. Furthermore, the gene and protein expression of cathepsin B and cystatin C was upregulated in AMD mice but was eliminated byFructus lyciiethanol extract. Investigationsin vitroshowed that ARPE-19 cell proliferation was suppressed by H2O2. However, lutein/zeaxanthin not only stimulated cell proliferation but also abrogated the enhanced expression of MMP-2 and TIMP-1 in H2O2-treated ARPE-19 cells. These data collectively suggested thatFructus lyciiethanol extract and its active components lutein/zeaxanthin had protective effects on AMDin vivoandin vitro, providing novel insights into the beneficial role ofFructus lyciifor AMD therapy.
SNiPloid: A Utility to Exploit High-Throughput SNP Data Derived from RNA-Seq in Allopolyploid Species
Authors: Peralta Marine , Combes Marie-Christine , Cenci Alberto , Lashermes Philippe , Dereeper Alexis
Published: September 2013

High-throughput sequencing is a common approach to discover SNP variants, especially in plant species. However, methods to analyze predicted SNPs are often optimized for diploid plant species whereas many crop species are allopolyploids and combine related but divergent subgenomes (homoeologous chromosome sets). We created a software tool, SNiPloid, that exploits and interprets putative SNPs in the context of allopolyploidy by comparing SNPs from an allopolyploid with those obtained in its modern-day diploid progenitors. SNiPloid can compare SNPs obtained from a sample to estimate the subgenome contribution to the transcriptome or SNPs obtained from two polyploid accessions to search for SNP divergence.
Arsenic, Zinc, and Aluminium Removal from Gold Mine Wastewater Effluents and Accumulation by Submerged Aquatic Plants (Cabomba piauhyensis,Egeria densa, andHydrilla verticillata)
Authors: Abu Bakar Ahmad Farid , Yusoff Ismail , Fatt Ng Tham , Othman Faridah , Ashraf Muhammad Aqeel
Published: September 2013

The potential of three submerged aquatic plant species (Cabomba piauhyensis, Egeria densa, andHydrilla verticillata) to be used for As, Al, and Zn phytoremediation was tested. The plants were exposed for 14 days under hydroponic conditions to mine waste water effluents in order to assess the suitability of the aquatic plants to remediate elevated multi-metals concentrations in mine waste water. The results show that theE. densaandH. verticillataare able to accumulate high amount of arsenic (95.2%) and zinc (93.7%) and resulted in a decrease of arsenic and zinc in the ambient water. On the other hand,C. piauhyensisshows remarkable aluminium accumulation in plant biomass (83.8%) compared to the other tested plants. The ability of these plants to accumulate the studied metals and survive throughout the experiment demonstrates the potential of these plants to remediate metal enriched water especially for mine drainage effluent. Among the three tested aquatic plants,H. verticillatawas found to be the most applicable (84.5%) and suitable plant species to phytoremediate elevated metals and metalloid in mine related waste water.
The Effect of External Magnetic Field on Microstructure and Magnetic Properties of Melt-Spun Nd-Fe-B/Fe-Co Nanocomposite Ribbons
Authors: Nguyen Xuan Truong , Vu Hong Ky , Do Hung Manh , Nguyen Van Khanh , Nguyen Van Vuong
Published: September 2013

The ribbons Nd2Fe14B/Fe-Co were prepared with the nominal composition Nd16Fe76B8/40% wt. Fe65Co35by the conventional and the developed magnetic field-assisted melt-spinning (MFMS) techniques. Both ribbons are nanocomposites with the smooth single-phase-like magnetization loops. The 0.32 T magnetic field perpendicular to the wheel surface and assisting the melt-spinning process reduces the grain size inside the ribbon, increases the texture of the ribbon, improves the exchange coupling, and, in sequence, increases the energy product(BH)maxof the isotropic powdered samples of MFMS ribbon in ~9% by comparison with that of the ribbon melt-spun conventionally. The grain size reduction effect caused by the assisted magnetic field has also been described quantitatively. The MFMS technique seems to be promising for producing high-performance nanocomposite ribbons.
Cutis Verticis Gyrata in Men Affected by HIV-Related Lipodystrophy
Authors: Khanijow Keshav , Unemori Patrick , Leslie Kieron S. , Mulligan Kathleen , Schambelan Morris , Maurer Toby
Published: September 2013

We report the occurrence of cutis verticis gyrata (CVG), a disfiguring dermatological condition, in four patients with HIV-related lipodystrophy (HIVLD). These four patients had abnormal metabolic and hormonal lab values which we compare with metabolic and hormonal perturbations cited in previous HIVLD cohorts. In addition, we describe the sole use of poly-L-lactic acid as a potential treatment for decreasing the appearance of CVG-associated ridges.
Semisupervised Kernel Marginal Fisher Analysis for Face Recognition
Authors: Wang Ziqiang , Sun Xia , Sun Lijun , Huang Yuchun
Published: September 2013

Dimensionality reduction is a key problem in face recognition due to the high‐dimensionality of face image. To effectively cope with this problem, a novel dimensionality reduction algorithm called semisupervised kernel marginal Fisher analysis (SKMFA) for face recognition is proposed in this paper. SKMFA can make use of both labelled and unlabeled samples to learn the projection matrix for nonlinear dimensionality reduction. Meanwhile, it can successfully avoid the singularity problem by not calculating the matrix inverse. In addition, in order to make the nonlinear structure captured by the data‐dependent kernel consistent with the intrinsic manifold structure, a manifold adaptive nonparameter kernel is incorporated into the learning process of SKMFA. Experimental results on three face image databases demonstrate the effectiveness of our proposed algorithm.
Proteome Profiling of Cancer-Associated Fibroblasts Identifies Novel Proinflammatory Signatures and Prognostic Markers for Colorectal Cancer
Authors: Torres Sofia , Bartolomé Rubén A. , Mendes Marta , Barderas Rodrigo , Fernandez-Aceñero M. Jesús , Peláez-García Alberto , Peña Cristina , Lopez-Lucendo María , Villar-Vázquez Roi , de Herreros Antonio García , Bonilla Felix , Casal J. Ignacio
Published: September 2013

Purpose: Cancer-associated fibroblasts (CAF) are essential components of the stroma that play a critical role in cancer progression. This study aimed to identify novel CAFs markers that might contribute to the invasion and the prognosis of colorectal cancer.

Experimental Design: The azoxymethane/dextran sodium sulfate mouse model of sporadic colon cancer represents an adequate source for the isolation of CAFs and normal fibroblasts. By using the explants technique, we purified CAFs and normal fibroblasts from colon tissues. Whole-cell extracts and supernatants were subjected to in-depth quantitative proteomic analysis by tandem mass spectrometry. Further validations of upregulated proteins in CAFs were carried out by chemokine microarray and immunohistochemical analyses of mouse and human tissues.

Results: Using a fold-change of 1.4 or more, we found 132 and 125 differentially expressed proteins in whole-cell extracts and supernatants, respectively. We found CAFs-associated proinflammatory and desmoplastic signatures. The proinflammatory signature was composed of several cytokines. Among them, CCL2 and CCL8 caused an increase in migration and invasion of colorectal cancer KM12 cells. The desmoplastic signature was composed of 30 secreted proteins. In mouse and human samples, expression of LTBP2, CDH11, OLFML3, and, particularly, FSTL1 was significantly increased in the tumoral stroma, without significant expression in the cancer epithelial cells. The combination of CALU and CDH11 stromal expression showed a significant association with disease-free survival and poor prognosis.

Conclusion: We have identified LTBP2, CDH11, OLFML3, and FSTL1 as selective biomarkers of cancer stroma, and CALU and CDH11 as candidate stromal biomarkers of prognostic significance in colon cancer. Clin Cancer Res; 19(21); 6006–19. ©2013 AACR.
Axl Mediates Acquired Resistance of Head and Neck Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Erlotinib
Authors: Giles Keith M. , Kalinowski Felicity C. , Candy Patrick A. , Epis Michael R. , Zhang Priscilla M. , Redfern Andrew D. , Stuart Lisa M. , Goodall Gregory J. , Leedman Peter J.
Published: September 2013

Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (e.g., erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed an HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial–mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated microRNAs (miRNA), and elevated vimentin expression. Phosphorylated receptor tyrosine kinase profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells were blocked with a specific Axl inhibitor, R428, and R428 resensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR = 1.66, P = 0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance. Mol Cancer Ther; 12(11); 2541–58. ©2013 AACR.
A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult
Authors: Goodwin Jonathan F. , Schiewer Matthew J. , Dean Jeffry L. , Schrecengost Randy S. , de Leeuw Renée , Han Sumin , Ma Teng , Den Robert B. , Dicker Adam P. , Feng Felix Y. , Knudsen Karen E.
Published: September 2013

Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA damage and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNA-dependent protein kinase catalytic subunit (DNAPKcs) was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR–DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance and establish a new node for therapeutic intervention in advanced disease.

Significance: The present study identifies for the first time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease. Cancer Discov; 3(11); 1254–71. ©2013 AACR.

See related commentary by Bartek et al., p. 1222

This article is highlighted in the In This Issue feature, p. 1207
Vascular Access Care and Treatment Practices Associated with Outcomes of Arteriovenous Fistula: International Comparisons from the Dialysis Outcomes and Practice Patterns Study
Authors: Asano Manabu , Thumma Jyothi , Oguchi Kenichi , Pisoni Ronald L. , Akizawa Tadao , Akiba Takashi , Fukuhara Shunichi , Kurokawa Kiyoshi , Ethier Jean , Saran Rajiv , Saito Akira ,   for the J-DOPPS Research Group
Published: September 2013

Background: Vascular access (VA) guidelines recommend the native arteriovenous fistula (AVF) as VA of first choice for chronic hemodialysis patients. AVF management is important in hemodialysis patient care. AVF survival is associated with various physical factors, but the effects of dialysis treatment factors upon AVF survival are still not clear. Methods: Study patients were treated at 498 dialysis facilities participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) 2 or 3 (2002-2007). Analyses included 1,183 incident hemodialysis patients (on dialysis ≤7 days and using an AVF at study entry) and 949 prevalent patients (on dialysis >7 days at DOPPS entry and using a new AVF created during study observation). AVF survival was modeled from the study entry date for incident patients and date of first AVF use for prevalent patients. Predictors of primary and final AVF survival were compared across Japan, North America and Europe/Australia/New Zealand (EUR/ANZ) with adjustments for patient characteristics. Results: No meaningful relationship was seen between AVF survival and various physician and staff practices. However, patients with prior catheter use displayed higher rates of primary and final AVF failure. Final AVF failure rates were higher in facilities with higher median blood flow rates (BFR). They were also greater in North America and EUR/ANZ than in Japan, but this difference was substantially attenuated after accounting for regional differences in facility median BFR. Conclusion: AVF longevity differed according to the DOPPS region, and was related to prior patient catheter use and facility BFR practice. Further longitudinal studies may help demonstrate meaningful associations between VA-handling skill and patency.
Trypsin causes platelet activation independently of known protease-activated receptors
Authors: Mao Yingying , Kunapuli Satya P.
Published: September 2013

To identify a physiological agonist of PAR3, we used PAR4 null murine platelets, which were known to express only PAR3. In this study, we tested several proteases and found that trypsin, but not heat-inactivated trypsin, activated PAR4 null murine platelets. Even at high concentrations, trypsin caused shape change without increasing intracellular calcium levels in PAR4 null murine platelets. Consistent with this result, the Gq inhibitor YM-254890 had no effect on trypsin-induced shape change. However, trypsin-induced platelet shape change was abolished by either p160ROCK inhibitor, Y27632 or H1152. Furthermore, trypsin caused phosphorylation of myosin light chain (Thr18), but not Akt or Erk. Surprisingly, trypsin caused a similar shape change in PAR4-desensitised PAR3 null murine platelets as in PAR4 null murine platelets, indicating that trypsin did not activate PAR3 to cause shape change. More interestingly, the Src family kinase (SFK) inhibitor PP2 abolished trypsin-induced, but not AYPGKF-induced, shape change. Hence, trypsin activated a novel signalling pathway through RhoA/p160ROCK and was regulated by SFKs. In conclusion, our study demonstrates a novel protease signalling pathway in platelets that is independent of PARs. This protease-induced novel signalling pathway regulates platelet shape change through SFKs and p160ROCK.
Questionable reversal of anticoagulation in the therapeutic management of cerebral haemorrhage associated with vitamin K antagonists
Authors: Huertas Nuria , Egido Jose A. , Muriel Alfonso , García Ana , Ruiz-Ares Gerardo , Díez-Tejedor Exuperio , Fuentes Blanca , de Leciñana Maria Alonso
Published: September 2013

Reversal of anticoagulation is recommended to correct the international normalised ratio (INR) for patients with intracranial haemorrhage (ICH) associated with vitamin K antagonists (VKA). However, the validity of such treatment is debated. We sought to identify, prospectively, the prognostic effect of VKA-ICH treatment in a cohort of patients (n=71; median age 78 years, range 20–89; 52% males). Data collated were: baseline characteristics, treatments, baseline and post-treatment INR, haematoma volume, and haematoma enlargement. Treatment effects and prognostic factor assessment were in relation to mortality and functional outcomes. On admission, the patients had a median score of 9 [p25; p75 of 5; 20] on the National Institute of Health Stroke Scale (NIHSS) and a mean INR of 2.7 (range: 0.9 – 10.8). Haematoma volume (34.6 cm3; SD: 24.9) correlated with NIHSS (r = 0.55; p<0.001) but not with INR. Anticoagulation reversal treatment was administered in 83% of patients. INR <1.5 was achieved in 60.7% of cases. Death or dependency at three months was 76%. Neither baseline INR, anticoagulation reversal nor haematoma enlargement were related to mortality or functional outcome. The only independent prognostic factor was clinical severity on admission. Baseline NIHSS predicted mortality (OR: 1.18; 95%CI: 1.09–1.27), independence (OR: 0.83; 95%CI: 0.74–0.94) and neurological recovery (NIHSS 0–1) (OR: 0.83; 95%CI: 0.73–0.95). The data indicate that VKA-ICH had a poor prognosis. Treatment and INR correction did not appear to affect outcomes.
Direct Cardiac Reprogramming
Authors: Qian Li , Srivastava Deepak
Published: September 2013

Heart disease affects millions worldwide and is a progressive condition involving loss of cardiomyocytes. The human heart has limited endogenous regenerative capacity and is thus an important target for novel regenerative medicine approaches. Although cell-based regenerative therapies hold promise, cellular reprogramming of endogenous cardiac fibroblasts, which represent more than half of the cells in the mammalian heart, may be an attractive alternative strategy for regenerating cardiac muscle. Recent advances leveraging years of developmental biology point to the feasibility of generating de novo cardiomyocyte-like cells from terminally differentiated nonmyocytes in the heart in situ after ischemic damage. Here, we review the progress in cardiac reprogramming methods and consider the opportunities and challenges that lie ahead in refining this technology for regenerative medicine.
Synaptojanin-2 Binding Protein Stabilizes the Notch Ligands DLL1 and DLL4 and Inhibits Sprouting Angiogenesis
Authors: Adam M. Gordian , Berger Caroline , Feldner Anja , Yang Wan-Jen , Wüstehube-Lausch Joycelyn , Herberich Stefanie E. , Pinder Marcel , Gesierich Sabine , Hammes Hans-Peter , Augustin Hellmut G. , Fischer Andreas
Published: September 2013

Rationale:

The formation of novel blood vessels is initiated by vascular endothelial growth factor. Subsequently, DLL4-Notch signaling controls the selection of tip cells, which guide new sprouts, and trailing stalk cells. Notch signaling in stalk cells is induced by DLL4 on the tip cells. Moreover, DLL4 and DLL1 are expressed in the stalk cell plexus to maintain Notch signaling. Notch loss-of-function causes formation of a hyperdense vascular network with disturbed blood flow.

Objective:

This study was aimed at identifying novel modifiers of Notch signaling that interact with the intracellular domains of DLL1 and DLL4.

Methods and Results:

Synaptojanin-2 binding protein (SYNJ2BP, also known as ARIP2) interacted with the PDZ binding motif of DLL1 and DLL4, but not with the Notch ligand Jagged-1. SYNJ2BP was preferentially expressed in stalk cells, enhanced DLL1 and DLL4 protein stability, and promoted Notch signaling in endothelial cells. SYNJ2BP induced expression of the Notch target genes HEY1, lunatic fringe (LFNG), and ephrin-B2, reduced phosphorylation of ERK1/2, and decreased expression of the angiogenic factor vascular endothelial growth factor (VEGF)-C. It inhibited the expression of genes enriched in tip cells, such as angiopoietin-2, ESM1, and Apelin, and impaired tip cell formation. SYNJ2BP inhibited endothelial cell migration, proliferation, and VEGF-induced angiogenesis. This could be rescued by blockade of Notch signaling or application of angiopoietin-2. SYNJ2BP-silenced human endothelial cells formed a functional vascular network in immunocompromised mice with significantly increased vascular density.

Conclusions:

These data identify SYNJ2BP as a novel inhibitor of tip cell formation, executing its functions predominately by promoting Delta-Notch signaling.
Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair
Authors: Ye Lei , Zhang Pengyuan , Duval Sue , Su Liping , Xiong Qiang , Zhang Jianyi
Published: September 2013

Background—

Thymosin β4 (Tβ4) has been shown to enhance the survival of cultured cardiomyocytes. Here, we investigated whether the cytoprotective effects of Tβ4 can increase the effectiveness of transplanted swine mesenchymal stem cells (sMSCs) for cardiac repair in a rat model of myocardial infarction (MI).

Methods and Results—

Under hypoxic conditions, cellular damage (lactate dehydrogenase leakage), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelingc cells), and caspase-8 activity were significantly lower, whereas B-cell lymphoma-extra large protein expression was significantly higher, in sMSCs cultured with Tβ4 (1 μg/mL) than in sMSCs cultured without Tβ4, and Tβ4 also increased sMSC proliferation. For in vivo experiments, animals were treated with basal medium (MI: n=6), a fibrin patch (Patch: n=6), a patch containing sMSCs (sMSC: n=9), or a patch containing sMSCs and Tβ4 (sMSC/Tβ4: n=11); Tβ4 was encapsulated in gelatin microspheres to extend Tβ4 delivery. Four weeks after treatment, echocardiographic assessments of left-ventricular ejection fraction and fractional shortening were significantly better (
P
<0.05) in sMSC/Tβ4 animals (left-ventricular ejection fraction=51.7±1.1%; fractional shortening=26.7±0.7%) than in animals from MI (39±3%; 19.5±1.7%) and Patch (43±1.4%; 21.6±0.9%) groups. Histological assessment of infarct wall thickness was significantly higher (
P
<0.05) in sMSC/Tβ4 animals (50%, [45%, 80%]) than in animals from MI (25%, [20%, 25%]) group. Measurements in sMSC (left-ventricular ejection fraction=45±2.6%; fractional shortening=22.9±1.6%; TH=43% [25%, 45%]), Patch, and MI animals were similar. Tβ4 administration also significantly increased vascular growth, the retention/survival of the transplanted sMSCs, and the recruitment of endogenous c-Kit
+
progenitor cells to the infarcted region.

Conclusions—

Extended-release Tβ4 administration improves the retention, survival, and regenerative potency of transplanted sMSCs after myocardial injury.
Mitral Valve Disease in Patients with Marfan Syndrome Undergoing Aortic Root Replacement
Authors: Kunkala Meghana R. , Schaff Hartzell V. , Li Zhuo , Volguina Irina , Dietz Harry C. , LeMaire Scott A. , Coselli Joseph S. , Connolly Heidi
Published: September 2013

Background—

Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP). Only scant data exist describing MVP in patients with Marfan syndrome undergoing aortic root replacement.

Methods and Results—

We retrospectively analyzed data from 166 MFS patients with MVP who were enrolled in a prospective multicenter registry of patients who underwent aortic root aneurysm repair. Of these 166 patients, 9% had mitral regurgitation (MR) grade >2, and 10% had MR grade 2. The severity of MVP and MR was evaluated by echocardiography preoperatively and ≤3 years postoperatively. Forty-one patients (25%) underwent composite graft aortic valve replacement, and 125 patients (75%) underwent aortic valve–sparing procedures; both groups had similar prevalences of MR grade >2 (
P
=0.7). Thirty-three patients (20%) underwent concomitant mitral valve (MV) intervention (repair, n=29; replacement, n=4), including all 15 patients with MR grade >2. Only 1 patient required MV reintervention during follow-up (mean clinical follow-up, 31±10 months). Echocardiography performed 21±13 months postoperatively revealed MR >2 in only 3 patients (2%). One early death and 2 late deaths occurred.

Conclusions—

Although the majority of patients with Marfan syndrome who undergo elective aortic root replacement have MVP, only 20% have concomitant MV procedures. These concomitant procedures do not seem to increase operative risk. In patients with MR grade ≤2 who do not undergo a concomitant MV procedure, the short-term incidence of progressive MR is low; however, more follow-up is needed to determine whether patients with MVP and MR grade ≤2 would benefit from prophylactic MV intervention.
Stroke and Outcomes in Patients With Acute Type A Aortic Dissection
Authors: Bossone Eduardo , Corteville David C. , Harris Kevin M. , Suzuki Toru , Fattori Rossella , Hutchison Stuart , Ehrlich Marek P. , Pyeritz Reed E. , Steg Philippe Gabriel , Greason Kevin , Evangelista Arturo , Kline-Rogers Eva , Montgomery Daniel G. , Isselbacher Eric M. , Nienaber Christoph A. , Eagle Kim A.
Published: September 2013

Background—

Stroke is a highly dreaded complication of type A acute aortic dissection (TAAAD). However, little data exist on its incidence and association with prognosis.

Methods and Results—

We evaluated 2202 patients with TAAAD (mean age 62±14 years, 1487 [67.5%] men) from the International Registry of Acute Aortic Dissection to determine the incidence and prognostic impact of stroke in TAAAD. Stroke was present at arrival in 132 (6.0%) patients with TAAAD. These patients were older (65±12 versus 62±15 years;
P
=0.002) and more likely to have hypertension (86% versus 71%;
P
=0.001) or atherosclerosis (29% versus 22%;
P
=0.04) than patients without stroke. Chest pain at arrival was less common in patients with stroke (70% versus 82%;
P
<0.001), and patients with stroke presented more often with syncope (44% versus 15%;
P
<0.001), shock (14% versus 7%;
P
=0.005), or pulse deficit (51% versus 29%;
P
≤0.001). Arch vessel involvement was more frequent among patients with stroke (68% versus 37%;
P
<0.001). They had less surgical management (74% versus 85%;
P
<0.001). Hospital stay was significantly longer in patients with stroke (median 17.9 versus 13.3 days;
P
<0.001). In-hospital complications, such as hypotension, coma, and malperfusion syndromes, and in-hospital mortality (adjusted odds ratio, 1.62; 95% confidence interval, 0.99–2.65) were higher among patients with stroke. Among hospital survivors, follow-up mortality was similar between groups (adjusted hazard ratio, 1.15; 95% confidence interval, 0.46–2.89).

Conclusions—

Stroke occurred in >1 of 20 patients with TAAAD and was associated with increased in-hospital morbidity but not long-term mortality. Whether aggressive early invasive interventions will reduce negative outcomes remains to be evaluated in future studies.
Sustained Release of Engineered Stromal Cell–Derived Factor 1-α From Injectable Hydrogels Effectively Recruits Endothelial Progenitor Cells and Preserves Ventricular Function After Myocardial Infarction
Authors: MacArthur John W. , Purcell Brendan P. , Shudo Yasuhiro , Cohen Jeffrey E. , Fairman Alex , Trubelja Alen , Patel Jay , Hsiao Philip , Yang Elaine , Lloyd Kelsey , Hiesinger William , Atluri Pavan , Burdick Jason A. , Woo Y. Joseph
Published: September 2013

Background—

Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell–derived factor 1-α (engineered stromal cell–derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.

Methods and Results—

Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical–initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.

Conclusions—

We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.
Impact of Expeditious Management of Perioperative Myocardial Ischemia in Patients Undergoing Isolated Coronary Artery Bypass Surgery
Authors: Davierwala Piroze M. , Verevkin Alexander , Leontyev Sergey , Misfeld Martin , Borger Michael A. , Mohr Friedrich W.
Published: September 2013

Background—

To analyze the effect of immediate treatment of perioperative myocardial ischemia (PMI) because of early graft failure or incomplete revascularization in patients undergoing coronary artery bypass grafting (CABG) surgery.

Methods and Results—

Between January 2004 and December 2010, 7461 patients underwent isolated CABG at our institution. All patients showing evidence of PMI (n=399; 5.3% of total) underwent emergent coronary angiography. A total of 900 grafts and 1061 distal anastomoses were examined. Two hundred fifty-five patients had 360 distal anastomoses compromised because of early graft failure or incomplete revascularization (ie, abnormal postoperative coronary angiogram). Revision CABG or percutaneous coronary intervention was performed in 130 (51.0%) and 34 (13.3%) patients with abnormal angiograms, respectively. Nonsurgical therapy was implemented in the remaining 91 patients (35.7%) with abnormal angiograms. One hundred forty-four patients had normal postoperative graft-related angiograms. In-hospital mortality was 7.3% and 2.9% in patients with and without PMI (
P
<0.001). In patients with PMI, in-hospital mortality was 9.4% and 3.5% in patients with abnormal and normal postoperative angiograms, respectively (
P
=0.03). Significant multivariable predictors of in-hospital mortality were hemodynamic deterioration, preangiography creatine kinase-MB isoenzyme rise >2× normal, and time interval between primary CABG and coronary angiography >30 hours. Five-year survival in patients without PMI (85.7±0.5%) was significantly better than those with PMI and abnormal angiograms (74.9±2.9%;
P
<0.001 log-rank). When in-hospital mortality was excluded, however, this difference in midterm survival disappeared (
P
=0.9).

Conclusions—

PMI is associated with increased in-hospital mortality in patients undergoing isolated CABG. Expeditious management of bypass graft failure results in similar midterm survival to nonischemic patients in hospital survivors.
Enhanced Survival of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes by the Combination of Cell Sheets With the Pedicled Omental Flap Technique in a Porcine Heart
Authors: Kawamura Masashi , Miyagawa Shigeru , Fukushima Satsuki , Saito Atsuhiro , Miki Kenji , Ito Emiko , Sougawa Nagako , Kawamura Takuji , Daimon Takashi , Shimizu Tatsuya , Okano Teruo , Toda Koichi , Sawa Yoshiki
Published: September 2013

Background—

Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply.

Methods and Results—

Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted to porcine hearts with or without the omentum flap (n=8 each). Two months after transplantation, the survival of superparamagnetic iron oxide–labeled hiPS-CMs, assessed by MRI, was significantly greater in mini-pigs with the omentum than in those without it; histologically, vascular density in the transplanted area was significantly greater in mini-pigs with the omentum than in those without it. The transplanted tissues contained abundant cardiac troponin T–positive cells surrounded by vascular-rich structures.

Conclusions—

The omentum flap enhanced the survival of hiPS-CMs after transplantation via increased angiogenesis, suggesting that this strategy is useful in clinical settings. The combination of hiPS-CMs and the omentum flap may be a promising technique for the development of tissue-engineered vascular-rich new myocardium in vivo.