bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of in vivo transfection with anti-miR-214 on gene expression in murine molar tooth germ
Authors: Sehic Amer , Risnes Steinar , Khuu Cuong , Khan Qalb-E-Saleem , Osmundsen Harald
Published: March 2011

MicroRNAs (miRNAs) are an abundant class of noncoding RNAs that are believed to be important in many biological processes through regulation of gene expression. Little is known of their function in tooth morphogenesis and differentiation. MicroRNA-214 (miR-214), encoded by the polycistronic Dnm30os gene, is highly expressed during development of molar tooth germ and was selected as a target for silencing with anti-miR-214. Mandibular injection of 1–100 pmol of anti-miR-214 close to the developing first molar in newborn mice resulted in significant decrease in expression of miR-214, miR-466h, and miR-574-5p in the tooth germ. Furthermore, levels of miR-199a-3p, miR-199a-5p, miR-690, miR-720, and miR-1224 were significantly increased. Additionally, the expression of 863 genes was significantly increased and the expression of 305 genes was significantly decreased. Among the genes with increased expression was Twist-1 and Ezh2, suggested to regulate expression of miR-214. Microarray results were validated using real-time RT-PCR and Western blotting. Among genes with decreased expression were Amelx, Calb1, Enam, and Prnp; these changes also being reflected in levels of corresponding encoded proteins in the tooth germ. In the anti-miR-214-treated molars the enamel exhibited evidence of hypomineralization with remnants of organic material and reduced surface roughness after acid etching, possibly due to the transiently decreased expression of Amelx and Enam. In contrast, several genes encoding contractile proteins exhibited significantly increased expression. mRNAs involved in amelogenesis ( Ambn, Amelx, Enam) were not found among targets of miRNAs that were differentially expressed following treatment with anti-miR-214. It is therefore suggested that effects of miR-214 on amelogenesis are indirect, perhaps mediated by the observed miR-214-dependent changes in levels of expression of numerous transcription factors.
Circulating Cytokine Profiles and Their Relationships with Autoantibodies, Acute Phase Reactants, and Disease Activity in Patients with Rheumatoid Arthritis
Authors: Meyer Pieter W. A. , Hodkinson Bridget , Ally Mahmood , Musenge Eustasius , Wadee Ahmed A. , Fickl Heidi , Tikly Mohammed , Anderson Ronald
Published: March 2011

Our objective was to analyse the relationship between circulating cytokines, autoantibodies, acute phase reactants, and disease activity in DMARDs-naïve rheumatoid arthritis (RA) patients (n=140). All cytokines were significantly higher in the RA cohort than in healthy controls. Moderate-to-strong positive intercorrelations were observed between Th1/Th2/macrophage/fibroblast-derived cytokines. RF correlated significantly with IL-1β, IL-2, IL-4, IL-10, IL-12, G-CSF, GM-CSF, IFN-γ, and TNF (P<.0001), and aCCP and aMCV with IL-1β, IL-2, IL-4, and IL-10 (P<.0002), while IL-6 correlated best with the acute phase reactants, CRP, and SAA (P<.0001). In patients with a DAS28 score of ≥5.1, IFN-γ, IL-1β, IL-1Ra, TNF, GM-CSF, and VEGF were significantly correlated (P<.04–.001) with high disease activity (HDA). Circulating cytokines in RA reflect a multifaceted increase in immune reactivity encompassing Th1 and Th2 cells, monocytes/macrophages, and synovial fibroblasts, underscored by strong correlations between these cytokines, as well as their relationships with RF, aCCP, and aMCV, with some cytokines showing promise as biomarkers of HDA.
Heat Shock Proteins in the Human Eye
Authors: Urbak Lærke , Vorum Henrik
Published: March 2011

Heat shock proteins (Hsps) are believed to primarily protect and maintain cell viability under stressful conditions such as those occurring during thermal and oxidative challenges chiefly by refolding and stabilizing proteins. Hsps are found throughout the various tissues of the eye where they are thought to confer protection from disease states such as cataract, glaucoma, and cancer. This minireview summarizes the placement, properties, and roles of Hsps in the eye and aims to provide a better comprehension of their function and involvement in ocular disease pathogenesis.
Measuring Distributional Inequality: Relative Body Mass Index Distributions by Gender, Race/Ethnicity, and Education, United States (1999–2006)
Authors: Houle Brian C.
Published: March 2011

Few studies consider obesity inequalities as a distributional property. This study uses relative distribution methods to explore inequalities in body mass index (BMI; kg/m2). Data from 1999–2006 from the National Health and Nutrition Examination Survey were used to compare BMI distributions by gender, Black/White race, and education subgroups in the United States. For men, comparisons between Whites and Blacks show a polarized relative distribution, with more Black men at increased risk of over or underweight. Comparisons by education (overall and within race/ethnic groups) effects also show a polarized relative distribution, with more cases of the least educated men at the upper and lower tails of the BMI distribution. For women, Blacks have a greater probability of high BMI values largely due to a right-shifted BMI distribution relative to White women. Women with less education also have a BMI distribution shifted to the right compared to the most educated women.
Comparison of Adjunctive Naoxintong versus Clopidogrel in Volunteers with the CYP2C19*2 Gene Mutation Accompanied with Qi Deficiency and Blood Stasis Constitution
Authors: Chen Hui , Yu Guangwei , Sun Hong , Wu Xiaoying , Wang Huan
Published: March 2011

This study was to determine the impact of adjunctive Buchang Naoxintong Jiaonang (BNJ) to clopidogrel on volunteers with the CYP2C19*2 gene mutation accompanied with qi deficiency and blood stasis (QDBS) constitution. Eighteen males with QDBS constitution were selected, who were 6 CYP2C19*1/*1, 6 CYP2C19*1/*2, and 6 CYP2C19*2/*2, and signed informed consent. Results showed that the maximal platelet aggregation (Aggmax) and 5 min aggregation (Agglate) with 5‐μmol/L ADP in three different CYP2C19*2 genotypes were significantly decreased after any drug therapy compared with corresponding baseline measurements (all values P < .05). But percent inhibitions of Aggmax and Agglate (IPAs) in CYP2C19*2/*2 genotype at 4 hours, 24 hours, 3 days, and 7 days after clopidogrel administration were all the lowest among three CYP2C19*2 genotypes (P < .01), and IPAs in CYP2C19*1/*2 genotype were between CYP2C19*1/*1 and CYP2C19*2/*2. IPAs had no significant difference among three different CYP2C19*2 genotypes after BNJ or adjunctive BNJ. In addition, changes of CD62P, PAC1, and sCD40L were similar to changes of ADP‐induced platelet aggregation in three different CYP2C19*2 genotypes. Conclusion was that adjunctive BNJ to clopidogrel can enhance the antiplatelet effect in volunteers with the CYP2C19*2 gene mutation.
Antitumour Effects of Isocurcumenol Isolated fromCurcuma zedoariaRhizomes on Human and Murine Cancer Cells
Authors: Lakshmi S. , Padmaja G. , Remani P.
Published: March 2011

Curcuma zedoariabelonging to the family Zingiberaceae has been used in the traditional system of medicine in India and Southwest Asia in treating many human ailments and is found to possess many biological activities. The rationale of the present study was to isolate, identify, and characterize antitumour principles from the rhizomes ofCurcuma zedoaria,to assess its cytotoxic effects on human and murine cancer cells, to determine its apoptosis inducing capacity in cancer cells, and to evaluate its tumour reducing properties inin vivomice models. Isocurcumenol was characterized as the active compound by spectroscopy and was found to inhibit the proliferation of cancer cells without inducing significant toxicity to the normal cells. Fluorescent staining exhibited the morphological features of apoptosis in the compound-treated cancer cells.In vivotumour reduction studies revealed that a dose of 35.7 mg/kg body weight significantly reduced the ascitic tumour in DLA-challenged mice and increased the lifespan with respect to untreated control mice.
Controlled Morphology of Porous Polyvinyl Butyral Nanofibers
Authors: Lubasova Daniela , Martinova Lenka
Published: March 2011

A simple and effective method for the fabrication of porous nanofibers based on the solvent evaporation methods in one-step electrospinning process from the commercial polyvinyl butyral (PVB) is presented. The obtained nanofibers are prevalently amorphous with diameters ranging from 150 to 4350 nm and specific surface area of approximately 2–20 m2/g. Pore size with irregular shape of the porous PVB fibers ranged approximately from 50 to 200 nm. The effects of polymer solution concentration, composition of the solvents mixture, and applied voltage on fiber diameter and morphology were investigated. The theoretical approach for the choice of poor and good solvents for PVB was explained by the application Hansen solubility parameter (HSP) and two-dimensional graph. Three basic conditions for the production of porous PVB nanofibers were defined: (i) application of good/poor solvent mixture for spinning solution, (ii) differences of the evaporation rate between good/poor solvent, and (iii) correct ratios of good/poor solvent (v/v). The diameter of prepared porous PVB fibers decreased as the polymer concentration was lowered and with higher applied voltage. These nanofiber sheets with porous PVB fibers could be a good candidate for high-efficiency filter materials in comparison to smooth fibers without pores.
Leea indica Ethyl Acetate Fraction Induces Growth‐Inhibitory Effect in Various Cancer Cell Lines and Apoptosis in Ca Ski Human Cervical Epidermoid Carcinoma Cells
Authors: Yau Hsiung Wong , Abdul Kadir Habsah
Published: March 2011

The anticancer potential of Leea indica, a Chinese medicinal plant was investigated for the first time. The crude ethanol extract and fractions (ethyl acetate, hexane, and water) of Leea indica were evaluated their cytotoxicity on various cell lines (Ca Ski, MCF 7, MDA‐MB‐435, KB, HEP G2, WRL 68, and Vero) by MTT assay. Leea indica ethyl acetate fraction (LIEAF) was found showing the greatest cytotoxic effect against Ca Ski cervical cancer cells. Typical apoptotic morphological changes such as DNA fragmentation and chromatin condensation were observed in LIEAF‐treated cells. Early signs of apoptosis such as externalization of phosphatidylserine and disruption of mitochondrial membrane potential indicated apoptosis induction. This was further substantiated by dose‐ and time‐dependent accumulation of sub‐G1 cells, depletion of intracellular glutathione, and activation of caspase‐3. In conclusion, these results suggested that LIEAF inhibited cervical cancer cells growth by inducing apoptosis and could be developed as potential anticancer drugs.
Bio Gas Oil Production from Waste Lard
Authors: Hancsók Jenő , Baladincz Péter , Kasza Tamás , Kovács Sándor , Tóth Csaba , Varga Zoltán
Published: March 2011

Besides the second generations bio fuels, one of the most promising products is the bio gas oil, which is a high iso‐paraffin containing fuel, which could be produced by the catalytic hydrogenation of different triglycerides. To broaden the feedstock of the bio gas oil the catalytic hydrogenation of waste lard over sulphided NiMo/Al2O3 catalyst, and as the second step, the isomerization of the produced normal paraffin rich mixture (intermediate product) over Pt/SAPO‐11 catalyst was investigated. It was found that both the hydrogenation and the decarboxylation/decarbonylation oxygen removing reactions took place but their ratio depended on the process parameters (T = 280–380∘C, P = 20–80 bar, LHSV = 0.75–3.0 h−1 and H2/lard ratio: 600 Nm3/m3). In case of the isomerization at the favourable process parameters (T = 360–370∘C, P = 40 –50 bar, LHSV = 1.0 h−1 and H2/hydrocarbon ratio: 400 Nm3/m3) mainly mono‐branching isoparaffins were obtained. The obtained products are excellent Diesel fuel blending components, which are practically free of heteroatoms.
Uncovering Relationships between Task Understanding and Monitoring Proficiencies in Postsecondary Learners: Comparing Work Task and Learner as Statistical Units of Analyses
Authors: Venkatesh Vivek , Shaikh Kamran
Published: March 2011

Educational psychologists have researched the generality and specificity of metacognitive monitoring in the context of college-level multiple-choice tests, but fairly little is known as to how learners monitor their performance on more complex academic tasks. Even lesser is known about how monitoring proficiencies such as discrimination and bias might be related to key self-regulatory processes associated with task understanding. This quantitative study explores the relationship between monitoring proficiencies and task understanding in 39 adult learners tackling ill-structured writing tasks for a graduate “theories of e-learning” course. Using learner as unit of analysis, the generality of monitoring is confirmed through intra-measure correlation analyses while facets of its specificity stand out due to the absence of inter-measure correlations. Unsurprisingly, learner-based correlational and repeated measures analyses did not reveal how monitoring proficiencies and task understanding might be related. However, using essay as unit of analysis, ordinal and multinomial regressions reveal how monitoring influences different levels of task understanding. Results are interpreted not only in light of novel procedures undertaken in calculating performance prediction capability but also in the application of essay-based, intra-sample statistical analysis that reveal heretofore unseen relationships between academic self-regulatory constructs.
Single-SectionFabry-Perot Mode-Locked Semiconductor Lasers
Authors: Yang Weiguo
Published: March 2011

We present a review of the theoretical models and experimental verification of the single-section Fabry-Perot mode-locked semiconductor lasers based on multiple-spatial-mode (MSM) coupling. The mode-locked operation at the repetition rates of 40 GHz and higher and the pulse width of a few picoseconds are confirmed by the intensity autocorrelation, the fast photo detection and RF spectrum, and the optical spectral interference measurement of ultrafast pulse. The spatial mode coupling theory of single-section Fabry-Perot mode-locked semiconductor lasers is also reviewed, and the results are compared with the experimental observations. The small signal modulation response of these lasers, which exhibits high-frequency responses well beyond the relaxation oscillation resonance limit, is also modeled theoretically, and the simulation is verified by the experimental measurements.
From Community Detection to Mentor Selection in Rating-Free Collaborative Filtering
Authors: Brun Armelle , Castagnos Sylvain , Boyer Anne
Published: March 2011

The number of items that users can now access when navigating on the Web is so huge that these might feel lost. Recommender systems are a way to cope with this profusion of data by suggesting items that fit the users needs. One of the most popular techniques for recommender systems is the collaborative filtering approach that relies on the preferences of items expressed by users, usually under the form of ratings. In the absence of ratings, classical collaborative filtering techniques cannot be applied. Fortunately, the behavior of users, such as their consultations, can be collected. In this paper, we present a new approach to perform collaborative filtering when no rating is available but when user consultations are known. We propose to take inspiration from local community detection algorithms to form communities of users and deduce the set of mentors of a given user. We adapt one state-of-the-art algorithm so as to fit the characteristics of collaborative filtering. Experiments conducted show that the precision achieved is higher then the baseline that does not perform any mentor selection. In addition, our model almost offsets the absence of ratings by exploiting a reduced set of mentors.
Community-Acquired MRSA Pyomyositis: Case Report and Review of the Literature
Authors: Olson Douglas P. , Soares Sarita , Kanade Sandhya V.
Published: March 2011

Community-acquired methicillin-resistantStaphylococcus aureus(CA-MRSA) is responsible for a broad range of infections. We report the case of a 46-year-old gentleman with a history of untreated, uncomplicated Hepatitis C who presented with a 2-month history of back pain and was found to have abscesses in his psoas and right paraspinal muscles with subsequent lumbar spine osteomyelitis. Despite drainage and appropriate antibiotic management the patient's clinical condition deteriorated and he developed new upper extremity weakness and sensory deficits on physical exam. Repeat imaging showed new, severe compression of the spinal cord and cauda equina from C1 to the sacrum by a spinal epidural abscess. After surgical intervention and continued medical therapy, the patient recovered completely. This case illustrates a case of CA-MRSA pyomyositis that progressed to lumbar osteomyelitis and a spinal epidural abscess extending the entire length of the spinal canal.
FKBPL and Peptide Derivatives: Novel Biological Agents That Inhibit Angiogenesis by a CD44-Dependent Mechanism
Authors: Valentine Andrea , O'Rourke Martin , Yakkundi Anita , Worthington Jenny , Hookham Michelle , Bicknell Roy , McCarthy Helen O. , McClelland Keeva , McCallum Lynn , Dyer Hayder , McKeen Hayley , Waugh David J. J. , Roberts Jennifer , McGregor Joanne , Cotton Graham , James Iain , Harrison Timothy , Hirst David G. , Robson Tracy
Published: March 2011

Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.

Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.

Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL's antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.

Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy. Clin Cancer Res; 17(5); 1044–56. ©2011 AACR.
In vivo Evaluation of Mucoadhesive Nanoparticulate Docetaxel for Intravesical Treatment of Non–Muscle-Invasive Bladder Cancer
Authors: Mugabe Clement , Matsui Yoshiyuki , So Alan I. , Gleave Martin E. , Baker Jennifer H. E. , Minchinton Andrew I. , Manisali Irina , Liggins Richard , Brooks Donald E. , Burt Helen M.
Published: March 2011

Purpose: The present work describes the development and in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy.

Experimental Design: Mucoadhesive formulations based on hyperbranched polyglycerols (HPG), hydrophobically derivatized with C8/C10 alkyl chains in the core and modified with methoxy-polyethylene glycol (MePEG) and amine groups in the shell (HPG-C8/10-MePEG-NH2) were synthesized and DTX was loaded into these by a solvent evaporation method. Both low-grade (RT4, MGHU3) and high-grade (UMUC3) human urothelial carcinoma cell lines were treated with various concentrations of DTX formulations in vitro. KU7 cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumors were given a single intravesical instillation with PBS, Taxotere (DTX from Sanofi-aventis), and DTX-loaded HPG-C8/10-MePEG and/or HPG-C8/10-MePEG-NH2. Drug uptake was conducted using LC/MS-MS (liquid chromatography/tandem mass spectrometry) and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed.

Results: In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX-loaded HPG-C8/10-MePEG-NH2 (mucoadhesive DTX) was the most effective formulation to inhibit tumor growth in an orthotopic model of bladder cancer. Furthermore, mucoadhesive DTX significantly increased drug uptake in mouse bladder tissues. In addition, rhodamine labeled HPG-C8/10-MePEG-NH2 showed enhanced uptake of these nanoparticles in bladder tumor tissues.

Conclusions: Our data show promising in vivo antitumor efficacy and provide preclinical proof of principle for the intravesical application of mucoadhesive nanoparticulate DTX formulation in the treatment of bladder cancer. Clin Cancer Res; 17(9); 2788–98. ©2011 AACR.
Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts
Authors: Takenouchi Makoto , Hirai Sachie , Sakuragi Naoya , Yagita Hideo , Hamada Hirofumi , Kato Kazunori
Published: March 2011

Purpose: The interleukin-13 receptor α2 (IL-13Rα2) is expressed by a variety of human malignant cells. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL-13Rα2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) and anti–IL-13Rα2 monoclonal antibody on mesothelioma xenografts.

Experimental Design: Cell surface expression of IL-13Rα2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti–IL-13Rα2 and 5-aza-dC were investigated using antibody-dependent cellular cytotoxicity and proliferation assays and by monitoring the survival of mesothelioma-bearing mice.

Results: We found that human malignant mesotheliomas expressed surface IL-13Rα2 on their surface and that it was upregulated by treatment with 5-aza-dC. This augmented expression of IL-13Rα2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13Rα2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by IFN-γ that was only detected in the supernatant when effector cells were exposed to 5-aza-dC–treated tumors in the presence of anti–IL-13Rα2. Compared with the control or either regimen alone, in vivo administration of anti-IL-13Rα2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts.

Conclusions: These observations indicate a promising role for IL-13Rα2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency. Clin Cancer Res; 17(9); 2819–29. ©2011 AACR.
D-dimer and residual vein obstruction as risk factors for recurrence during and after anticoagulation withdrawal in patients with a first episode of provoked deep-vein thrombosis
Authors: Legnani Cristina , Cini Michela , Guazzaloca Giuliana , Palareti Gualtiero , Cosmi Benilde
Published: March 2011

D-dimer and residual venous obstruction (RVO) have been separately shown to be risk factors for recurrent venous thromboembolism (VTE) after a first episode of unprovoked proximal deep-vein thrombosis (DVT). It was the objective of this study to assess the predictive value of D-dimer and residual vein obstruction (RVO), alone and in combination, for recurrence after provoked DVT of the lower limbs. A total of 296 consecutive patients with a first episode of symptomatic provoked proximal DVT were evaluated at a university hospital in Bologna, Italy. On the day of anticoagulation withdrawal (T0), RVO was determined by compression ultrasonography. D-dimer levels (cut-off: 500 ng/ml) were measured at T0 and after 30 ±10 days (T1). The main outcome was recurrent VTE during a two-year follow-up. D-dimer was abnormal in 11.6% (32/276) and 31% (85/276) of subjects at T0 and at T1, respectively. RVO was present in 44.8% (132/294) of patients. Recurrence rate was 5.1% (15/296; 95% confidence interval [CI]: 3–8%; 3% patient-years; 95% CI: 2–5 %). An abnormal D-dimer either at T0 or at T1 was associated with an adjusted hazard ratio (HR) for recurrence of 4.2 (95% CI:1.2–14.2; p=0.02) and 3.8 (95%CI: 1.2–12.1; p=0.02), respectively, when compared with normal D-dimer. The HR for recurrence associated with RVO was not significant, and RVO did not increase the recurrence risk associated with an abnormal D-dimer either at T0 or T1. In conclusion, an abnormal D-dimer during vitamin K antagonist (VKA) treatment or at one month after VKA withdrawal is a risk factor for recurrence in patients with provoked DVT, while RVO at the time of anticoagulation withdrawal is not.
High soluble Fas and soluble Fas Ligand serum levels before stent implantation are protective against restenosis
Authors: Speidl Walter , Kastl Stefan , Huber Kurt , Zorn Gerlinde , Niessner Alexander , Glogar Dietmar , Maurer Gerald , Katsaros Katharina , Wiesbauer Franz , Wojta Johann
Published: March 2011

Percutaneous coronary intervention (PCI) represents the most important treatment of coronary artery stenosis today. But instent restenosis (ISR) is a limitation for the outcome. Fas and Fas Ligand have been implicated in apoptosis and vessel wall inflammation. Their role in ISR is not known so far. In this prospective study we studied 137 patients with stable coronary artery disease who underwent elective PCI. Blood samples were taken directly before and 24 hours after PCI. Soluble (s)Fas and sFas Ligand serum levels were measured by ELISA. Restenosis was evaluated six to eight months later either by coronary angiography or by exercise testing. During the follow-up period, 18 patients (13%) developed ISR. At baseline, patients with ISR had significantly lower median sFas, as well as sFas Ligand levels compared to patients without ISR (sFAS: ISR 492 pg/ml, no ISR 967 pg/ml, p=0.014; sFAS Ligand: ISR: 26 pg/ml, no ISR: 42 pg/ml, p=0.001). After PCI median sFas levels significantly decreased in patients with ISR compared to patients without ISR [ISR: –152 pg/ml (IQR –36 to –227), no ISR: –38 pg/ml (IQR –173 to +150 pg/ml), p=0.03]. sFas Ligand levels after PCI significantly increased in ISR patients compared to patients without ISR [ISR: 14 pg/ ml (IQR –3 to +26 pg/ml), no ISR –6 pg/ml (IQR –22 to +21 pg/ml), p=0.014]. In conclusion, sFas and sFas Ligand seem to be associated with the development of ISR. Determination of serum levels before and after PCI might help identifying patients at higher risk of ISR.
Comparison of Zotarolimus-Eluting Stents With Sirolimus-Eluting and Paclitaxel-Eluting Stents
Authors: Kang Soo-Jin , Mintz Gary S. , Park Duk-Woo , Lee Seung-Whan , Kim Young-Hak , Lee Cheol Whan , Han Ki-Hoon , Kim Jae-Joong , Park Seong-Wook , Park Seung-Jung
Published: March 2011

Background—

As a substudy of the large, randomized ZEST (Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent with Sirolimus-Eluting and PacliTaxel-Eluting Stent for Coronary Lesions) trial comparing first- and second-generation drug-eluting stents, we evaluated intimal hyperplasia (IH) and vascular changes using volumetric intravascular ultrasound analysis.

Methods and Results—

Complete angiographic and volumetric intravascular ultrasound data immediately after stenting and at 9-month follow-up were available in 162 patients with 183 lesions: 61 sirolimus-eluting stents (SES), 64 paclitaxel-eluting stents (PES), and 58 zotarolimus-eluting stents (ZES). External elastic membrane, stent, lumen, and peristent plaque volumes (external elastic membrane minus stent) were normalized by stent length. Percent IH volumes were calculated as [IH volume/stent volume]×100, %. Reduction of minimal luminal area) was greater in PES than SES (−1.4±1.5 mm
2
versus −0.7±0.9 mm
2
,
P
=0.003), whereas minimal luminal area change in ZES was not significantly different from SES (−1.2±1.0 mm
2
versus −0.7±0.9 mm
2
,
P
=0.055). Percent IH volume was less in SES compared with PES (9.8±6.0% versus 17.5±11.2%,
P
=0.002) or with ZES (9.8±6.0% versus 18.2±7.6%,
P
=0.005). Comparing ZES versus PES, there were no significant differences in %IH volume (17.5±11.2% versus 18.2±7.6%,
P
=0.779) or changes in normalized lumen volume (−1.2±1.3 mm
2
versus −1.1±0.8 mm
2
,
P
=0.452). Late stent malapposition was identified in 8 (13%) SES and 2 (3%) PES but in no ZES (
P
=0.050). Angiographic restenosis was detected in 6 lesions (3 PES and 3 ZES).

Conclusions—

The degree of neointimal growth in ZES was similar to that in PES but less than that in SES. ZES had no late stent malappositions.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00418067.
Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)
Authors: Zareba Wojciech , Klein Helmut , Cygankiewicz Iwona , Hall W. Jackson , McNitt Scott , Brown Mary , Cannom David , Daubert James P. , Eldar Michael , Gold Michael R. , Goldberger Jeffrey J. , Goldenberg Ilan , Lichstein Edgar , Pitschner Heinz , Rashtian Mayer , Solomon Scott , Viskin Sami , Wang Paul , Moss Arthur J.
Published: March 2011

Background—

This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) trial.

Methods and Results—

Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (
P
<0.001) lower in LBBB patients (0.47;
P
<0.001) than in non-LBBB patients (1.24;
P
=0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (
P
<0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients.

Conclusions—

Heart failure patients with New York Heart Association class I or II and ejection fraction ≤30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances).

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00180271.
Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications
Authors: García Rodríguez Luis A. , Lin Kueiyu Joshua , Hernández-Díaz Sonia , Johansson Saga
Published: March 2011

Background—

This study evaluated the risk of upper gastrointestinal bleeding (UGIB) associated with use of low-dose acetylsalicylic acid (ASA) alone and in combination with other gastrotoxic medications.

Methods and Results—

The Health Improvement Network UK primary care database was used to identify individuals 40 to 84 years of age with a UGIB diagnosis in 2000 to 2007 (n=2049). An age-, sex-, and calendar year-matched control group (n=20 000) was identified from the same source population. The relative risk (RR) of UGIB associated with use of low-dose ASA (75 to 300 mg/d), clopidogrel, and other commonly coadministered medications was estimated by multivariate logistic regression. The risk of UGIB was increased in current users of low-dose ASA (RR, 1.80; 95% confidence interval [CI], 1.59 to 2.03) or clopidogrel (RR, 1.67; 95% CI, 1.24 to 2.24) compared with nonusers. Compared with low-dose ASA monotherapy, the risk of UGIB was significantly increased when low-dose ASA was coadministered with clopidogrel (RR, 2.08; 95% CI, 1.34 to 3.21), oral anticoagulants (RR, 2.00; 95% CI, 1.15 to 3.45), low-/medium-dose nonsteroidal antiinflammatory drugs (RR, 2.63; 95% CI, 1.93 to 3.60), high-dose nonsteroidal antiinflammatory drugs (RR, 2.66; 95% CI, 1.88 to 3.76), or high-dose oral corticosteroids (RR, 4.43; 95% CI, 2.10 to 9.34); this was not apparent with coadministration of statins (RR, 0.99; 95% CI, 0.81 to 1.21) or low-dose oral corticosteroids (RR, 1.01; 95% CI, 0.58 to 1.77).

Conclusions—

Use of low-dose ASA is associated with an almost 2-fold increase in the risk of UGIB compared with nonuse. This risk is increased further in individuals taking low-dose ASA along with clopidogrel, oral anticoagulants, nonsteroidal antiinflammatory drugs, or high-dose oral corticosteroids.
Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice
Authors: Shende Pankaj , Plaisance Isabelle , Morandi Christian , Pellieux Corinne , Berthonneche Corinne , Zorzato Francesco , Krishnan Jaya , Lerch René , Hall Michael N. , Rüegg Markus A. , Pedrazzini Thierry , Brink Marijke
Published: March 2011

Background—

Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown.

Methods and Results—

We generated mice with deficient myocardial mTORC1 activity by targeted ablation of
raptor
, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and β-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding–induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed.

Conclusions—

Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy.
Intracardiac Electrogram T-Wave Alternans/Variability Increases Before Spontaneous Ventricular Tachyarrhythmias in Implantable Cardioverter-Defibrillator Patients
Authors: Swerdlow Charles , Chow Theodore , Das Mithilesh , Gillis Anne M. , Zhou Xiaohong , Abeyratne Athula , Ghanem Raja N.
Published: March 2011

Background—

T-wave alternans (TWA) increases before ventricular tachycardia (VT) or fibrillation (VF), suggesting that it may warn of VT/VF in implantable cardioverter-defibrillator patients. Recently, we described a method for measuring alternans and nonalternans variability (TWA/V) from electrograms (EGMs) stored in implantable cardioverter-defibrillators before VT/VF. The goal of this prospective, multicenter study was to determine whether EGM TWA/V was greater before VT/VF than at baseline.

Methods and Results—

We enrolled 63 implantable cardioverter-defibrillator patients. TWA/V was computed from stored EGMs before spontaneous VT/VF and from sequential windows of 8 pairs of beats using 4 different control recordings: baseline rhythm, rapid pacing at 105 bpm, segments of ambulatory Holter EGMs matched to the time of VT/VF episodes, and EGMs before spontaneous supraventricular tachycardia. During follow-up, 28 patients had 166 episodes of VT/VF. TWA/V was greater before VT/VF (62.9±3.1 μV; n=28) than during baseline rhythm (12.8±1.8 μV;
P
<0.0001; n=62), during rapid pacing (14.5±2.0 μV;
P
<0.0001; n=52), before supraventricular tachycardia (27.5±6.1 μV;
P
<0.0001; n=9), or during time-matched ambulatory controls (12.3±3.5 μV;
P
<0.0001; n=16). By logistic regression, the odds of VT/VF increased by a factor of 2.2 for each 10-μV increment in TWA/V (
P
<0.0001).

Conclusions—

In implantable cardioverter-defibrillator patients, EGM TWA/V is greater before spontaneous VT/VF than in control recordings. Future implantable cardioverter-defibrillators that measure EGM TWA/V continuously may warn patients and initiate pacing therapies to prevent VT/VF.
Identification of Cathepsin L as a Potential Sex-Specific Biomarker for Renal Damage
Authors: Bauer Yasmina , Hess Patrick , Qiu Changbin , Klenk Axel , Renault Bérengère , Wanner Daniel , Studer Rolf , Killer Nina , Stalder Anna Katharina , Stritt Manuel , Strasser Daniel Stefan , Farine Hervé , Kauser Katalin , Clozel Martine , Fischli Walter , Nayler Oliver
Published: March 2011

The renin-angiotensin system is a well-known regulator of blood pressure and plays an important role in the pathogenesis of cardiovascular disease and renal damage. Genetic factors, including single nucleotide polymorphisms and sex, are increasingly recognized as potential risk factors for the development of cardiovascular disease. Double transgenic rats (dTGRs), harboring human renin and angiotensinogen genes, were used in this study to investigate potential sex differences influencing renal function and renal gene expression. dTGR males and females had comparable increases in blood pressure, whereas body weight, albuminuria/proteinuria, and urine flow rate were higher in males. At 8 weeks of age, renal plasma flow and glomerular filtration rate were proportionally lower in males, and renal vascular resistance tended to be higher. Males developed more severe tubulointerstitial and vascular lesions. By the end of week 8, 40%of the males but none of the females had died. Genome expression studies were performed with RNA from kidneys of 7-week–old male and female dTGRs and control rats to further investigate the sex-related differences on a molecular level. Forty-five genes showed sex-dependent expression patterns in dTGRs that were significantly different compared to controls. Cathepsin L, one of the genes differentially expressed between the sexes, was also shown to be strongly associated with the degree of renal injury. In dTGRs, urinary cathepsin L at week 7 was higher in males (nanograms per 24 hours: male, 512±163; female, 132±70). These results reveal a potential new biomarker for the personalized diagnosis and management of chronic kidney disease.
Intensive Blood Pressure Control Affects Cerebral Blood Flow in Type 2 Diabetes Mellitus Patients
Authors: Kim Yu-Sok , Davis Shyrin C.A.T. , Truijen Jasper , Stok Wim J. , Secher Niels H. , van Lieshout Johannes J.
Published: March 2011

Type 2 diabetes mellitus is associated with microvascular complications, hypertension, and impaired dynamic cerebral autoregulation. Intensive blood pressure (BP) control in hypertensive type 2 diabetic patients reduces their risk of stroke but may affect cerebral perfusion. Systemic hemodynamic variables and transcranial Doppler-determined cerebral blood flow velocity (CBFV), cerebral CO
2
responsiveness, and cognitive function were determined after 3 and 6 months of intensive BP control in 17 type 2 diabetic patients with microvascular complications (T2DM+), in 18 diabetic patients without (T2DM−) microvascular complications, and in 16 nondiabetic hypertensive patients. Cerebrovascular reserve capacity was lower in T2DM+ versus T2DM− and nondiabetic hypertensive patients (4.6±1.1 versus 6.0±1.6 [
P
<0.05] and 6.6±1.7 [
P
<0.01], Δ%mean CBFV/mm Hg). After 6 months, the attained BP was comparable among the 3 groups. However, in contrast to nondiabetic hypertensive patients, intensive BP control reduced CBFV in T2DM− (58±9 to 54±12 cm · s
−1
) and T2DM+ (57±13 to 52±11 cm · s
−1
) at 3 months, but CBFV returned to baseline at 6 months only in T2DM−, whereas the reduction in CBFV progressed in T2DM+ (to 48±8 cm · s
−1
). Cognitive function did not change during the 6 months. Static cerebrovascular autoregulation appears to be impaired in type 2 diabetes mellitus, with a transient reduction in CBFV in uncomplicated diabetic patients on tight BP control, but with a progressive reduction in CBFV in diabetic patients with microvascular complications, indicating that maintenance of cerebral perfusion during BP treatment depends on the progression of microvascular disease. We suggest that BP treatment should be individualized, aiming at a balance between BP reduction and maintenance of CBFV.
Effects of Human C-Reactive Protein on Pathogenesis of Features of the Metabolic Syndrome
Authors: Pravenec Michal , Kajiya Takashi , Zídek Václav , Landa Vladimír , Mlejnek Petr , Šimáková Miroslava , Šilhavý Jan , Malínská Hana , Oliyarnyk Olena , Kazdová Ludmila , Fan Jianglin , Wang Jiaming , Kurtz Theodore W.
Published: March 2011

Major controversy exists as to whether increased C-reactive protein (CRP) contributes to individual components of the metabolic syndrome or is just a secondary response to inflammatory disease processes. We measured blood pressure and metabolic phenotypes in spontaneously hypertensive rats (SHRs) in which we transgenically expressed human CRP in the liver under control of the apolipoprotein E promoter. In transgenic SHRs, serum levels of human CRP approximated the endogenous levels of CRP normally found in the rat. Systolic and diastolic blood pressures measured by telemetry were 10 to 15 mm Hg greater in transgenic SHRs expressing human CRP than in SHR controls (
P
<0.01). During oral glucose tolerance testing, transgenic SHRs exhibited hyperinsulinemia compared with controls (insulin area under the curve: 36±7 versus 8±2 nmol/L per 2 hours, respectively;
P
<0.05). Transgenic SHRs also exhibited resistance to insulin stimulated glycogenesis in skeletal muscle (174±18 versus 278±32 nmol of glucose per gram per 2 hours;
P
<0.05), hypertriglyceridemia (0.84±0.05 versus 0.64±0.03 mmol/L;
P
<0.05), reduced serum adiponectin (2.4±0.3 versus 4.3±0.6 mmol/L;
P
<0.05), and microalbuminuria (200±35 versus 26±5 mg of albumin per gram of creatinine, respectively;
P
<0.001). Transgenic SHRs had evidence of inflammation and oxidative tissue damage with increased serum levels of interleukin 6 (36.4±5.2 versus 18±1.7 pg/mL;
P
<0.005) and increased hepatic and renal thiobarbituric acid reactive substances (1.2±0.09 versus 0.8±0.07 and 1.5±0.1 versus 1.1±0.05 nmol/L per milligram of protein, respectively;
P
<0.01), suggesting that oxidative stress may be mediating adverse effects of increased human CRP. These findings are consistent with the hypothesis that increased CRP is more than just a marker of inflammation and can directly promote multiple features of the metabolic syndrome.
Sugar-Sweetened Beverage, Sugar Intake of Individuals, and Their Blood Pressure
Authors: Brown Ian J. , Stamler Jeremiah , Van Horn Linda , Robertson Claire E. , Chan Queenie , Dyer Alan R. , Huang Chiang-Ching , Rodriguez Beatriz L. , Zhao Liancheng , Daviglus Martha L. , Ueshima Hirotsugu , Elliott Paul
Published: March 2011

The obesity epidemic has focused attention on relationships of sugars and sugar-sweetened beverages (SSBs) to cardiovascular risk factors. Here we report cross-sectional associations of SSBs, diet beverages, and sugars with blood pressure (BP) for United Kingdom and US participants of the International Study of Macro/Micronutrients and Blood Pressure. Data collected include four 24-hour dietary recalls, two 24-hour urine collections, 8 BP readings, and questionnaire data for 2696 people ages 40 to 59 years of age from 10 US/United Kingdom population samples. Associations of SSBs, diet beverages, and sugars (fructose, glucose, and sucrose) with BP were assessed by multiple linear regression. SSB intake related directly to BP, with
P
values of 0.005 to <0.001 (systolic BP) and 0.14 to <0.001 (diastolic BP). SSB intake higher by 1 serving per day (355 mL/24 hours) was associated with systolic/diastolic BP differences of +1.6/+0.8 mm Hg (both
P
<0.001) and +1.1/+0.4 mm Hg (
P
<0.001/<0.05) with adjustment for weight and height. Diet beverage intake was inversely associated with BP (
P
0.41 to 0.003). Fructose- and glucose-BP associations were direct, with significant sugar-sodium interactions: for individuals with above-median 24-hour urinary sodium excretion, fructose intake higher by 2 SD (5.6% kcal) was associated with systolic/diastolic BP differences of +3.4/+2.2 mm Hg (both
P
<0.001) and +2.5/+1.7 mm Hg (both
P
=0.002) with adjustment for weight and height. Observed independent, direct associations of SSB intake and BP are consistent with recent trial data. These findings, plus adverse nutrient intakes among SSB consumers, and greater sugar-BP differences for persons with higher sodium excretion lend support to recommendations that intake of SSBs, sugars, and salt be substantially reduced.