bluuebunny/crossref_metadata_2025 huggingface dataset:
New Automated Chemiluminescence Immunoassay for Simultaneous but Separate Detection of Human Immunodeficiency Virus Antigens and Antibodies
Authors: Alonso Roberto , López Roa Paula , Suárez Marisol , Bouza Emilio
Published: February 2014

The recently launched Liaison XL Murex HIV Ab/Ag assay (DiaSorin S.p.A) uses chemiluminescence immunoassay technology for the combined qualitative determination of p24 antigen of HIV-1 and specific antibodies to both HIV-1 and HIV-2. We studied 571 serum samples from those submitted to our laboratory for HIV screening. The samples were divided into 3 subsets: subset A, 365 samples collected prospectively during 1 week; subset B, 158 samples from confirmed HIV-positive patients; and subset C, 48 samples with a positive screening result but a negative or indeterminate confirmatory test result. Our standard screening/confirmatory algorithm was used as a reference. In subset A (prospective), 5 samples were positive and 360 negative by the standard procedure. Liaison XL Murex HIV Ab/Ag correctly identified all 5 positive samples (100%) and 357 negative samples (99.2%). In subset B (confirmed positive), all 158 positive samples were in total agreement in both procedures. In subset C (screen positive only), Liaison XL Murex HIV Ab/Ag yielded accurate results in 42 out of 48 samples (87.5%). Global sensitivity and specificity for Liaison XL Murex HIV Ab/Ag (all subsets included) were 98.3% and 98.5%, respectively. Considering only nonselected prospective samples and confirmed positive samples (subsets A and B), the corresponding sensitivity and specificity values were 100% and 99.2%, respectively. The new fully automated HIV screening test showed high sensitivity and specificity compared to our standard algorithm. Its added advantage of being able to detect HIV-1 and HIV-2 antibodies and p24 antigen separately could prove useful in the diagnosis of early infections.
Rapid Detection of β-Lactamase-Hydrolyzing Extended-Spectrum Cephalosporins in Enterobacteriaceae by Use of the New Chromogenic βLacta Test
Authors: Morosini María Isabel , García-Castillo María , Tato Marta , Gijón Desirèe , Valverde Aránzazu , Ruiz-Garbajosa Patricia , Cantón Rafael
Published: February 2014

The chromogenic βLacta test developed for the rapid detection of β-lactamase-hydrolyzing extended-spectrum cephalosporins in
Enterobacteriaceae
revealed good performance with extended-spectrum β-lactamase (ESBL) producers (97.5% true-positive results). However, false-negative results occurred with chromosomal AmpC hyperproducers and plasmid AmpC producers, whereas uninterpretable results were mostly due to VIM-1 carbapenemase producers and possibly low levels of expressed ESBLs.
Dendritic Cell-Lymphocyte Cross Talk Downregulates Host Restriction Factor SAMHD1 and Stimulates HIV-1 Replication in Dendritic Cells
Authors: Su Bin , Biedma Marina Elizabeth , Lederle Alexandre , Peressin Maryse , Lambotin Mélanie , Proust Alizé , Decoville Thomas , Schmidt Sylvie , Laumond Géraldine , Moog Christiane
Published: February 2014

Human immunodeficiency virus type 1 (HIV-1) replication in dendritic cells (DCs) is restricted by SAMHD1. This factor is counteracted by the viral protein Vpx; Vpx is found in HIV-2 and simian immunodeficiency virus (SIV) from sooty mangabeys (SIVsm) or from macaques (SIVmac) but is absent from HIV-1. We previously observed that HIV-1 replication in immature DCs is stimulated by cocultivation with primary T and B lymphocytes, suggesting that HIV-1 restriction in DCs may be overcome under coculture conditions. Here, we aimed to decipher the mechanism of SAMHD1-mediated restriction in DC-lymphocyte coculture. We found that coculture with lymphocytes downregulated SAMHD1 expression and was associated with increased HIV-1 replication in DCs. Moreover, in infected DC-T lymphocyte cocultures, DCs acquired maturation status and secreted type 1 interferon (alpha interferon [IFN-α]). The blockade of DC-lymphocyte cross talk by anti-ICAM-1 antibody markedly inhibited the stimulation of HIV-1 replication and prevented the downregulation of SAMHD1 expression in cocultured DCs. These results demonstrate that, in contrast to purified DCs, cross talk with lymphocytes downregulates SAMHD1 expression in DCs, triggering HIV-1 replication and an antiviral immune response. Therefore, HIV-1 replication and immune sensing by DCs should be investigated in more physiologically relevant models of DC/lymphocyte coculture.

IMPORTANCE
SAMHD1 restricts HIV-1 replication in dendritic cells (DCs). Here, we demonstrate that, in a coculture model of DCs and lymphocytes mimicking early mucosal HIV-1 infection, stimulation of HIV-1 replication in DCs is associated with downregulation of SAMHD1 expression and activation of innate immune sensing by DCs. We propose that DC-lymphocyte cross talk occurring
in vivo
modulates host restriction factor SAMHD1, promoting HIV-1 replication in cellular reservoirs and stimulating immune sensing.
Mouse Dipeptidyl Peptidase 4 Is Not a Functional Receptor for Middle East Respiratory Syndrome Coronavirus Infection
Authors: Cockrell Adam S. , Peck Kayla M. , Yount Boyd L. , Agnihothram Sudhakar S. , Scobey Trevor , Curnes Nicole R. , Baric Ralph S. , Heise Mark T.
Published: February 2014

Human dipeptidyl peptidase 4 (hDPP4) was recently identified as the receptor for Middle East respiratory syndrome coronavirus (MERS-CoV) infection, suggesting that other mammalian DPP4 orthologs may also support infection. We demonstrate that mouse DPP4 cannot support MERS-CoV infection. However, employing mouse DPP4 as a scaffold, we identified two critical amino acids (A288L and T330R) that regulate species specificity in the mouse. This knowledge can support the rational design of a mouse-adapted MERS-CoV for rapid assessment of therapeutics.
Systemic lupus erythematosus mimicking lymphoma: the relevance of the clinical background in interpreting imaging studies
Authors: Gillmore Roopinder , Sin Wing Yee Chris
Published: February 2014

Systemic lupus erythematosus (SLE) is known as the ‘great imitator’ mimicking a myriad of conditions often resulting in a delayed diagnosis. We report a case with multisite adenopathy radiologically suggestive of lymphoma who initially was referred to the ‘Cancer of Unknown Primary’ team. Following a re-evaluation of the case the patient was diagnosed with SLE and was started on appropriate therapy. Many conditions presenting to oncology may mimic cancer which needs to be borne in mind when assessing referred cases.
Limiting progressive hippocampal metabolic abnormalities after smoke inhalation injury
Authors: Tobe Edward , Pradhan Basant K
Published: February 2014

A 46-year-old man had a smoke inhalation injury. Within 1 month, he developed neuropsychiatric problems including toxic encephalopathy, cognitive disorder, depression symptoms and personality change. From 3 to 14 years after the toxic inhalation injury, the patient received treatment with sertraline and methylphenidate. The18F-fluorodeoxyglucose positron emission tomography scan at 3 years after injury showed deterioration of glucose metabolism in the hippocampus and orbital frontal region; at 14 years after injury, the hippocampus had no significant change but the orbital frontal region had deterioration of glucose metabolism. It was hypothesised that sertraline may have provided selective hippocampal neuroprotection. Further study is justified to evaluate sertraline as a possible neuroprotective agent after smoke inhalation injury.
Primary tuberculosis of the thyroid gland: an unexpected cause of thyrotoxicosis
Authors: Raman Lavanya , Murray James , Banka Rajesh
Published: February 2014

We describe a 38-year-old Indian man who presented with a 2-week history of fever, night sweats and neck swelling who was found to be clinically thyrotoxic with a nodular goitre, tachycardia and high fever. Biochemical investigation revealed hyperthyroidism in association with deranged liver function tests and raised inflammatory markers. Ultrasound and CT scans of the neck revealed multinodular thyroid enlargement. He was considered most likely to have an acute infectious thyroiditis with a differential diagnosis of a toxic multinodular goitre and was started on carbimazole and antibiotics. He underwent fine needle aspiration of the thyroid which revealed necrotic cells and acid-fast bacilli, confirming a diagnosis of primary tuberculosis (TB) of the thyroid gland with no evidence of any other organ involvement on systemic imaging. He was started on TB therapy for 6 months and discharged with outpatient follow-up. Symptoms and biochemical markers subsequently resolved.
Interaction between body weight status and walking speed in steps monitoring by GT3X accelerometer
Authors: Bélanger Marie-Lyse , Kestens Yan , Gilbert Jo-Anne , Tremblay Angelo , Mathieu Marie-Eve
Published: February 2014

The measurement error of the step count function of the ActiGraph GT3X accelerometer was assessed at different walking speeds in 12 obese and 16 nonobese individuals. In comparison with visual verification, the accelerometer step count function measurement error was larger for obese individuals walking at low speeds (2.5 km·h−1). This error equated to an approximate 50% underestimation at these speeds.
ON CONTEXT-FREE LANGUAGES OF SCATTERED WORDS
Authors: ÉSIK ZOLTÁN , OKAWA SATOSHI
Published: February 2014

It is known that if a Büchi context-free language (BCFL) consists of scattered words, then there is an integer n, depending only on the language, such that the Hausdorff rank of each word in the language is bounded by n. Every BCFL is a Muller context-free language (MCFL). In the first part of the paper, we prove that an MCFL of scattered words is a BCFL iff the rank of every word in the language is bounded by an integer depending only on the language.

Then we establish operational characterizations of the BCFLs of well-ordered and scattered words. We prove that a language is a BCFL consisting of well-ordered words iff it can be generated from the singleton languages containing the letters of the alphabet by substitution into ordinary context-free languages and the ⍵-power operation. We also establish a corresponding result for BCFLs of scattered words and define expressions denoting BCFLs of well-ordered and scattered words. In the final part of the paper we give some applications.
HOMOMORPHISMS PRESERVING DETERMINISTIC CONTEXT-FREE LANGUAGES
Authors: LEHTINEN TOMMI , OKHOTIN ALEXANDER
Published: February 2014

The paper characterizes the family of homomorphisms, under which the deterministic context-free languages, the LL context-free languages and the unambiguous context-free languages are closed. The family of deterministic context-free languages is closed under a homomorphism h if and only if h is either a code of bounded deciphering delay, or the images of all symbols under h are powers of the same string. The same characterization holds for LL context-free languages. The unambiguous context-free languages are closed under h if and only if either h is a code, or the images of all symbols under h are powers of the same string.
THE EDIT-DISTANCE BETWEEN A REGULAR LANGUAGE AND A CONTEXT-FREE LANGUAGE
Authors: HAN YO-SUB , KO SANG-KI , SALOMAA KAI
Published: February 2014

The edit-distance between two strings is the smallest number of operations required to transform one string into the other. The distance between languages L1and L2is the smallest edit-distance between string wi∈ Li, i = 1, 2. We consider the problem of computing the edit-distance of a given regular language and a given context-free language. First, we present an algorithm that finds for the languages an optimal alignment, that is, a sequence of edit operations that transforms a string in one language to a string in the other. The length of the optimal alignment, in the worst case, is exponential in the size of the given grammar and finite automaton. Then, we investigate the problem of computing only the edit-distance of the languages without explicitly producing an optimal alignment. We design a polynomial time algorithm that calculates the edit-distance based on unary homomorphisms.
UNARY CODED NP-COMPLETE LANGUAGES IN ASPACE(log log n)
Authors: GEFFERT VILIAM , PARDUBSKÁ DANA
Published: February 2014

We shall show that (i) there exists a binary NP-complete language [Formula: see text] such that its unary coded version [Formula: see text] is in ASPACE( log log n), (ii) if P ≠ NP, there exists a binary language [Formula: see text] such that its unary version [Formula: see text] is in ASPACE( log log n), while the language [Formula: see text] itself is not in ASPACE( log n). As a consequence, under assumption that P ≠ NP, the standard space translation between unary and binary languages does not work for alternating machines with small space; the equivalence [Formula: see text] is valid only if s(n) ∈ Ω(n). This is quite different from deterministic and nondeterministic machines, for which the corresponding equivalence holds for each s(n) ∈ Ω( log n), and hence for s( log n) ∈ Ω( log log n). Under assumption that NP ≠ co-NP, we also show that binary versions of unary languages in ASPACE( log log n) form a complexity class not contained in NP.
Asymmetries in the angular distributions in the $t\bar t$ system
Authors: Demina Regina
Published: February 2014

We review the status of the forward–backward asymmetry measurements in the pair production of top and antitop in proton–antiproton collisions. We also comment on the charge asymmetry in the production of the [Formula: see text] system in the proton–proton collisions.
Composite leptons at the LHC
Authors: Hamber Herbert W. , Toriumi Reiko
Published: February 2014

In some models of electroweak interactions the W and Z bosons are considered composites, made up of spin-[Formula: see text] subconstituents. In these models a spin-0 counterpart of the W and Z boson naturally appears, whose higher mass can be attributed to a particular type of hyperfine spin interaction among the various subconstituents. Recently, it has been argued that the scalar state could be identified with the newly discovered Higgs (H) candidate. Here, we use the known spin splitting between the W/Z and H states to infer, within the framework of a purely phenomenological model, the relative strength of the spin–spin interactions. The results are then applied to the lepton sector, and used to crudely estimate the relevant spin splitting between the two lowest states. Our calculations in many ways parallels what is done in the SU(6) quark model, where most of the spin splittings between the lowest lying baryon and meson states are reasonably well-accounted for a simple color hyperfine interaction, with constituent (color-dressed) quark masses.
The Entrepreneur's Dilemma: Case of TMT Toughened Glass Pvt. Ltd.
Authors: Amitabh Manu
Published: February 2014

TMT Toughened Glass Company is in the glass processing industry. This industry requires a high level of innovation and expertise to process glass which is a very fragile and unworkable material. Customers typically want complete and technically sound solutions to their security, structural, design and architectural needs where glass is a material of choice. Shiv Prasad, the Managing Director of TMT Toughened Glass Company Pvt. Ltd., likes to call himself a “Glass Fabricator” and has been the pioneer in finding innovative solutions to glass processing needs in India.

Tempering is the core process in this. Manufacturers of float glass are the suppliers and real estate developers and builders, automobile manufacturers and industrial appliance manufacturers are its buyers. Growth in this industry has been fuelled by the economic boom in India. The industry is largely unregulated. The number of players in the industry has increased to 40 in the same period from a mere 10. While the demand in the glass processing industry is growing at a steady rate of 30%, the capacity is growing at a compound annual growth rate of almost 80%.

Prasad's competence is in engineering and design innovation. The dilemma he faces is whether to carry on with his time-tested strategy of innovation led growth or follow what other industry players are doing. Prasad has the option of concentrating his resources on doing what he does best — finding innovative solutions to the glass processing needs of his customers. The central question for Prasad is how to ensure that TMT Toughened Glass outperforms others on a sustained basis. Out of several options, this case explores the option of expanding the product line to include processed glass for the passenger car segment.
COSMOS Service Centre: Service Recovery Using Distribution Channels
Authors: Singh Ramendra , Jyothi Amer , Sinha Ashish , Agarwal Babita , Patro Arun
Published: February 2014

COSMOS is a technology solutions provider offering IT infrastructure, personal computing and access devices, global services, imaging, and printing for consumers and enterprises. The company uses a mix of distribution channels (both online and offline) to deliver its products and services. COSMOS uses authorized intermediaries to increase offline reach — both for sales and service.

To offer seamless customer service, COSMOS has a complaints website for customer logs. COSMOS service centres have well defined processes and policies to guide them in service delivery. However, this has not helped the case of Amer (the case protagonist), a business graduate student, who has faced multiple issues in service recovery after the purchase of his laptop from COSMOS.

Why is Amer facing this slew of problems because of the service failure from COSMOS? Is it because of the negligence of B'Devlop, the COSMOS Service Centre or are COSMOS's policies and processes flawed? Can COSMOS offer a permanent solution to Amer's problems? How can COSMOS rectify the situation and prevent it from recurring? What should be the service recovery strategies for the company, and its distribution channel members that have a direct interface with the customers? These are some of the key questions that the case highlights, and can bring up for discussion in the classroom.
Radioactive Ion Beams and Radiopharmaceuticals
Authors: Laxdal R. E. , Morton A. C. , Schaffer P.
Published: February 2014

Experiments performed at radioactive ion beam facilities shed new light on nuclear physics and nuclear structure, as well as nuclear astrophysics, materials science and medical science. The many existing facilities, as well as the new generation of facilities being built and those proposed for the future, are a testament to the high interest in this rapidly expanding field. The opportunities inherent in radioactive beam facilities have enabled the search for radioisotopes suitable for medical diagnosis or therapy. In this article, an overview of the production techniques and the current status of RIB facilities and proposals will be presented. In addition, accelerator-generated radiopharmaceuticals will be reviewed.
Accelerators for Inertial Fusion Energy Production
Authors: Bangerter R. O. , Faltens A. , Seidl P. A.
Published: February 2014

Since the 1970s, high energy heavy ion accelerators have been one of the leading options for imploding and igniting targets for inertial fusion energy production. Following the energy crisis of the early 1970s, a number of people in the international accelerator community enthusiastically began working on accelerators for this application. In the last decade, there has also been significant interest in using accelerators to study high energy density physics (HEDP). Nevertheless, research on heavy ion accelerators for fusion has proceeded slowly pending demonstration of target ignition using the National Ignition Facility (NIF), a laser-based facility at Lawrence Livermore National Laboratory. A recent report of the National Research Council recommends expansion of accelerator research in the US if and when the NIF achieves ignition.

Fusion target physics and the economics of commercial energy production place constraints on the design of accelerators for fusion applications. From a scientific standpoint, phase space and space charge considerations lead to the most stringent constraints. Meeting these constraints almost certainly requires the use of multiple beams of heavy ions with kinetic energies >1 GeV. These constraints also favor the use of singly charged ions. This article discusses the constraints for both fusion and HEDP, and explains how they lead to the requirements on beam parameters.

RF and induction linacs are currently the leading contenders for fusion applications. We discuss the advantages and disadvantages of both options. We also discuss the principal issues that must yet be resolved.
Targets and Secondary Beam Extraction
Authors: Noah Etam
Published: February 2014

Several applications make use of secondary beams of particles generated by the interaction of a primary beam of particles with a target. Spallation neutrons, bremsstrahlung photon-produced neutrons, radioactive ions and neutrinos are available to users at state-of-the-art facilities worldwide. Plans for even higher secondary beam intensities place severe constraints on the design of targets. This article reports on the main targetry challenges and highlights a variety of solutions for targetry and secondary beam extraction. Issues related to target station layout, instrumentation at the beam–target interface, safety and radioprotection are also discussed.
Middle Carboniferous intracontinental subduction in the Outer Zone of the Variscan Belt (Montagne Noire Axial Zone, French Massif Central): multimethod geochronological approach of polyphase metamorphism
Authors: Faure Michel , Cocherie Alain , Gaché Julien , Esnault Chloé , Guerrot Catherine , Rossi Philippe , Wei Lin , Qiuli Li
Published: February 2014

In the migmatitic dome of the Montagne Noire Axial Zone (Variscan French Massif Central), mafic eclogites yield zircon and rutile U–Pb SHRIMP and secondary-ion mass spectrometry (SIMS) ages of
c.
315–308 Ma. These ‘young’ dates, obtained in two different laboratories, do not comply with the geological constraints available for the study area that suggest an older age of the high-pressure–low-temperature (M
1
) metamorphism. Nevertheless, the Sm–Nd age of the same rock at
c.
358 Ma appears in better agreement with the geological constraints, and therefore might reflect the age of the high-pressure (HP) event. Similar 357–352 Ma monazite U–Th–Pb
tot
ages are obtained from relict grains in the Axial Zone kinzigites that represent restites enclosed in migmatites. Furthermore, monazite grains from biotite–garnet–staurolite micaschists from the dome envelope and Axial Zone kinzigites yield U–Th–Pb
tot
ages in the range 340–320 Ma. These dates are in good agreement with previously documented zircon and monazite ages from the migmatite and anatectic granites that represent a high-temperature–low-pressure (M
2
) event. The significance of the zircon and rutile ages in the eclogites is discussed in terms of hydrothermal circulations. A crustal-scale model considers: (1) a north-directed intracontinental subduction, responsible for the high-pressure–low-temperature (M
1
) metamorphism, coeval with kilometre-scale south-vergent recumbent folds in the Palaeozoic non-metamorphic cover, followed by (2) a high-temperature–low-pressure (M
2
) event, coeval with the development of the Axial Zone migmatitic dome, and upright folding in the Palaeozoic non-metamorphic series.
Timing of granite emplacement, crustal flow and gneiss dome formation in the Variscan segment of the Pyrenees
Authors: Denèle Yoann , Laumonier Bernard , Paquette Jean-Louis , Olivier Philippe , Gleizes Gérard , Barbey Pierre
Published: February 2014

The Variscan segment of the Pyrenees is well suited to study the timing of crustal-scale deformations as crustal flow and gneiss dome formation. This has been constrained from a synthesis of available structural and geochronological data of intrusive rocks, as well as new zircon U–Pb age determinations via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). After a stage of moderate thickening by fold–thrust belt development in the upper crust between 323 and 308 Ma, the Variscan segment of the Pyrenees experienced crustal flow at
c.
306 Ma and then gneiss dome formation at
c.
304 Ma. Localization of the deformation along reverse-dextral shear zones occurred at
c.
300 Ma. The Variscan segment of the Pyrenees recorded a high-temperature regime, which allowed crustal flow of the middle crust, but with limited amounts of heat which induced rapid cooling. The development of this enigmatic orogenic segment of the Variscan belt is closely contemporaneous with the formation of the Cantabrian Orocline and could correspond to a lithospheric-scale shear zone that accommodated buckling of the orocline. Late Variscan lithospheric delamination and asthenospheric upwelling associated with buckling in the core of the Cantabrian Orocline could explain the short-period high-temperature regime in the Variscan segment of the Pyrenees.

Supplementary material:

Review of published U–Th–Pb, Ar–Ar and K–Ar ages of granites from the Axial Zone of the Pyrenees; LA-ICP-MS U–Pb dating methodology (Clermont-Ferrand, France); and zircon LA-ICP-MS U–Pb data for Ax-les-Thermes, Carançà, Mont-Louis and Cauterets granites are available at
http://www.geolsoc.org.uk/SUP18729
.
Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury
Authors: Sörensen-Zender Inga , Rong Song , Susnik Nathan , Zender Steffen , Pennekamp Petra , Melk Anette , Haller Hermann , Schmitt Roland
Published: February 2014

The aging kidney has a diminished regenerative potential and an increased tendency to develop tubular atrophy and fibrosis after acute injury. In this study, we found that activation of tubular epithelial Notch1 signaling was prolonged in the aging kidney after ischemia/reperfusion (IR) damage. To analyze the consequences of sustained Notch activation, we generated mice with conditional inducible expression of Notch1 intracellular domain (NICD) in proximal tubules. NICD kidneys were analyzed 1 and 4 wk after renal IR. Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16INK4a. In wild-type mice pharmacological inhibition of Notch using the γ-secretase inhibitor N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT) improved tubulo-interstitial damage and antagonized the prosenescent pathway activation after IR. In vitro, activation of Notch signaling with delta-like-ligand-4 caused prosenescent changes in tubular cells while inhibition with DAPT attenuated these changes. In conclusion, our data suggest that sustained epithelial Notch activation after IR might contribute to the inferior outcome of old kidneys after injury. Sustained epithelial activation of Notch is associated with a prosenescent phenotype and maladaptive repair.
Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis
Authors: Cui Wenpeng , Maimaitiyiming Hasiyeti , Qi Xinyu , Norman Heather , Zhou Qi , Wang Xiaojun , Fu Jian , Wang Shuxia
Published: February 2014

Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-β signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-β levels. The interaction between macrophages and tubular cells contributes to TGF-β-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-β-induced fibrosis.
Repeatability of Quantitative FDG-PET/CT and Contrast-Enhanced CT in Recurrent Ovarian Carcinoma: Test–Retest Measurements for Tumor FDG Uptake, Diameter, and Volume
Authors: Rockall Andrea G. , Avril Norbert , Lam Raymond , Iannone Robert , Mozley P. David , Parkinson Christine , Bergstrom Donald , Sala Evis , Sarker Shah-Jalal , McNeish Iain A. , Brenton James D.
Published: February 2014

Purpose: Repeatability of baseline FDG-PET/CT measurements has not been tested in ovarian cancer. This dual-center, prospective study assessed variation in tumor 2[18F]fluoro-2-deoxy-D-glucose (FDG) uptake, tumor diameter, and tumor volume from sequential FDG-PET/CT and contrast-enhanced computed tomography (CECT) in patients with recurrent platinum-sensitive ovarian cancer.

Experimental Design: Patients underwent two pretreatment baseline FDG-PET/CT (n = 21) and CECT (n = 20) at two clinical sites with different PET/CT instruments. Patients were included if they had at least one target lesion in the abdomen with a standardized uptake value (SUV) maximum (SUVmax) of ≥2.5 and a long axis diameter of ≥15 mm. Two independent reading methods were used to evaluate repeatability of tumor diameter and SUV uptake: on site and at an imaging clinical research organization (CRO). Tumor volume reads were only performed by CRO. In each reading set, target lesions were independently measured on sequential imaging.

Results: Median time between FDG-PET/CT was two days (range 1–7). For site reads, concordance correlation coefficients (CCC) for SUVmean, SUVmax, and tumor diameter were 0.95, 0.94, and 0.99, respectively. Repeatability coefficients were 16.3%, 17.3%, and 8.8% for SUVmean, SUVmax, and tumor diameter, respectively. Similar results were observed for CRO reads. Tumor volume CCC was 0.99 with a repeatability coefficient of 28.1%.

Conclusions: There was excellent test–retest repeatability for FDG-PET/CT quantitative measurements across two sites and two independent reading methods. Cutoff values for determining change in SUVmean, SUVmax, and tumor volume establish limits to determine metabolic and/or volumetric response to treatment in platinum-sensitive relapsed ovarian cancer. Clin Cancer Res; 20(10); 2751–60. ©2014 AACR.
Rubbing salt into wounded endothelium: Sodium potentiates proatherogenic effects of TNF-α under non-uniform shear stress
Authors: Wild Johannes , Soehnlein Oliver , Dietel Barbara , Urschel Katharina , Garlichs Christoph D. , Cicha Iwona
Published: February 2014

Increased consumption of sodium is a risk factor for hypertension and cardiovascular diseases. In vivo studies indicated that high dietary sodium may have a direct negative influence on endothelium. We investigated the effects of high sodium on the endothelial activation during early steps of atherogenesis. Endothelial cells (HUVECs) grown in a model of arterial bifurcations were exposed to shear stress in the presence of normal or high (+ 30 mmol/l) sodium. Adherent THP-1 cells, and the adhesion molecule expression were quantified. Sodium channel blockers, pathways’ inhibitors, and siRNA against tonicity-responsive enhancer binding protein (TonEBP) were used to identify the mechanisms of sodium effects on endothelium. ApoE-deficient mice on low-fat diet received water containing normal or high salt (8% w/v) for four weeks, and the influence of dietary salt on inflammatory cell adhesion in the common carotid artery and carotid bifurcation was measured by intravital microscopy. In vitro, high sodium dramatically increased the endothelial responsiveness to tumour necrosis factor-α under non-uniform shear stress. Sodium-induced increase in monocytic cell adhesion was mediated by reactive oxygen species and the endothelial nitric oxygen synthase, and was sensitive to the knockdown of TonEBP. The results were subsequently confirmed in the ApoE-deficient mice. As compared with normal-salt group, high-salt intake significantly enhanced the adhesion of circulating CD11b+ cells to carotid bifurcations, but not to the straight segment of common carotid artery. In conclusion, elevated sodium has a direct effect on endothelial activation under atherogenic shear stress in vitro and in vivo, and promotes the endothelial-leukocyte interactions even in the absence of increased lipid concentrations.
Matrix as an Interstitial Transport System
Authors: Fan Dong , Creemers Esther E. , Kassiri Zamaneh
Published: February 2014

The extracellular matrix (ECM) is best known for its function as a structural scaffold for the tissue and more recently as a microenvironment to sequester growth factors and cytokines allowing for rapid and localized changes in their activity in the absence of new protein synthesis. In this review, we explore this and additional new aspects of ECM function in mediating cell-to-cell communications. Fibrillar and nonfibrillar components of ECM can limit and facilitate the transport of molecules through the extracellular space while also regulating interstitial hydrostatic pressure. In turn, transmembrane communications via molecules, such as ECM metalloproteinase inducer, thrombospondins, and integrins, can further mediate cell response to extracellular cues and affect ECM composition and tissue remodeling. Other means of cell-to-cell communication include extracellular microRNA transport and its contribution to gene expression in target cells and the nanotube formation between distant cells, which has recently emerged as a novel conduit for intercellular organelle sharing thereby influencing cell survival and function. The information summarized and discussed here are not limited to the cardiovascular ECM but encompass ECM in general with specific references to the cardiovascular system.
Myocardial Extracellular Matrix
Authors: Rienks Marieke , Papageorgiou Anna-Pia , Frangogiannis Nikolaos G. , Heymans Stephane
Published: February 2014

The cardiac extracellular matrix (ECM) is a complex architectural network consisting of structural and nonstructural proteins, creating strength and plasticity. The nonstructural compartment of the ECM houses a variety of proteins, which are vital for ECM plasticity, and can be divided into 3 major groups: glycoproteins, proteoglycans, and glycosaminoglycans. The common denominator for these groups is glycosylation, which refers to the decoration of proteins or lipids with sugars. This review will discuss the fundamental role of the matrix in cardiac development, homeostasis, and remodeling, from a glycobiology point of view. Glycoproteins (eg, thrombospondins, secreted protein acidic and rich in cysteine, tenascins), proteoglycans (eg, versican, syndecans, biglycan), and glycosaminoglycans (eg, hyaluronan, heparan sulfate) are upregulated on cardiac injury and regulate key processes in the remodeling myocardium such as inflammation, fibrosis, and angiogenesis. Albeit some parallels can be made regarding the processes these proteins are involved in, their specific functions are extremely diverse. In fact, under varying conditions, individual proteins can even have opposing functions, making spatiotemporal contribution of these proteins in the rearrangement of multifaceted ECM very hard to grasp. Alterations of protein characteristics by the addition of sugars may explain the immense, yet tightly regulated, variability of the remodeling cardiac matrix. Understanding the role of glycosylation in altering the ultimate function of glycoproteins, proteoglycans, and glycosaminoglycans in the myocardium may lead to the development of new biochemical structures or compounds with great therapeutic potential for patients with heart disease.
Cardiomyocyte-Specific Transforming Growth Factor β Suppression Blocks Neutrophil Infiltration, Augments Multiple Cytoprotective Cascades, and Reduces Early Mortality After Myocardial Infarction
Authors: Rainer Peter P. , Hao Scarlett , Vanhoutte Davy , Lee Dong Ik , Koitabashi Norimichi , Molkentin Jeffery D. , Kass David A.
Published: February 2014

Rationale:

Wound healing after myocardial infarction involves a highly regulated inflammatory response that is initiated by the appearance of neutrophils to clear out dead cells and matrix debris. Neutrophil infiltration is controlled by multiple secreted factors, including the master regulator transforming growth factor β (TGFβ). Broad inhibition of TGFβ early postinfarction has worsened post–myocardial infarction remodeling; however, this signaling displays potent cell specificity, and targeted suppression particularly in the myocyte could be beneficial.

Objective:

Our aims were to test the hypothesis that targeted suppression of myocyte TGFβ signaling ameliorates postinfarct remodeling and inflammatory modulation and to identify mechanisms by which this may be achieved.

Methods and Results:

Mice with TGFβ receptor–coupled signaling genetically suppressed only in cardiac myocytes (conditional TGFβ receptor 1 or 2 knockout) displayed marked declines in neutrophil recruitment and accompanying metalloproteinase 9 activation after infarction and were protected against early-onset mortality due to wall rupture. This is a cell-specific effect, because broader inhibition of TGFβ signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing the generation of proinflammatory cytokines/chemokines, myocyte-selective TGFβ inhibition augmented the synthesis of a constellation of highly protective cardiokines. These included thrombospondin 4 with associated endoplasmic reticulum stress responses, interleukin-33, follistatin-like 1, and growth and differentiation factor 15, which is an inhibitor of neutrophil integrin activation and tissue migration.

Conclusions:

These data reveal a novel role of myocyte TGFβ signaling as a potent regulator of protective cardiokine and neutrophil-mediated infarct remodeling.
Temporal Trends in Ischemic Heart Disease Mortality in 21 World Regions, 1980 to 2010
Authors: Moran Andrew E. , Forouzanfar Mohammad H. , Roth Gregory A. , Mensah George A. , Ezzati Majid , Murray Christopher J.L. , Naghavi Mohsen
Published: February 2014

Background—

Ischemic heart disease (IHD) is the leading cause of death worldwide. The Global Burden of Diseases, Risk Factors and Injuries 2010 Study estimated global and regional IHD mortality from 1980 to 2010.

Methods and Results—

Sources for IHD mortality estimates were country-level surveillance, verbal autopsy, and vital registration data. Regional income, metabolic and nutritional risk factors, and other covariates were estimated from surveys and a systematic review. An estimation and validation process led to an ensemble model of IHD mortality for 21 world regions. Globally, age-standardized IHD mortality has declined since the 1980s, and high-income regions (especially Australasia, Western Europe, and North America) experienced the most remarkable declines. Age-standardized IHD mortality increased in former Soviet Union countries and South Asia in the 1990s and attenuated after 2000. In 2010, Eastern Europe and Central Asia had the highest age-standardized IHD mortality rates. More IHD deaths occurred in South Asia in 2010 than in any other region. On average, IHD deaths in South Asia, North Africa and the Middle East, and sub-Saharan Africa occurred at younger ages in comparison with most other regions.

Conclusions—

In most world regions, particularly in high-income regions, age-standardized IHD mortality rates have declined significantly since 1980. High age-standardized IHD mortality in Eastern Europe, Central Asia, and South Asia point to the need to prevent and control established risk factors in those regions and to research the unique behavioral and environmental determinants of higher IHD mortality.
Clinical Usefulness, Angiographic Characteristics, and Safety Evaluation of Intracoronary Acetylcholine Provocation Testing Among 921 Consecutive White Patients With Unobstructed Coronary Arteries
Authors: Ong Peter , Athanasiadis Anastasios , Borgulya Gabor , Vokshi Ismail , Bastiaenen Rachel , Kubik Sebastian , Hill Stephan , Schäufele Tim , Mahrholdt Heiko , Kaski Juan Carlos , Sechtem Udo
Published: February 2014

Background—

Coronary spasm can cause myocardial ischemia and angina in patients with and those without obstructive coronary artery disease. However, provocation tests using intracoronary acetylcholine administration are rarely performed in clinical routine in the United States and Europe. Thus, we assessed the clinical usefulness, angiographic characteristics, and safety of intracoronary acetylcholine provocation testing in white patients with unobstructed coronary arteries.

Methods and Results—

From September 2007 to June 2010, a total of 921 consecutive patients (362 men, mean age 62±12years) who underwent diagnostic angiography for suspected myocardial ischemia and were found to have unobstructed coronary arteries (no stenosis ≥50%) were enrolled. The intracoronary acetylcholine provocation testing was performed directly after angiography according to a standardized protocol. Three hundred forty-six patients (35%) reported chest pain at rest, 222 (22%) reported chest pain on exertion, 238 (24%) reported a combination of effort and resting chest pain, and 41 (4%) presented with troponin-positive acute coronary syndrome. The overall frequency of epicardial spasm (>75% diameter reduction with angina and ischemic ECG shifts) was 33.4%, and the overall frequency of microvascular spasm (angina and ischemic ECG shifts without epicardial spasm) was 24.2%. Epicardial spasm was most often diffuse and located in the distal coronary segments (
P
<0.01). No fatal or irreversible nonfatal complications occurred. However, 9 patients (1%) had minor complications (nonsustained ventricular tachycardia [n=1], fast paroxysmal atrial fibrillation [n=1], symptomatic bradycardia [n=6], and catheter-induced spasm [n=1]).

Conclusions—

Epicardial and microvascular spasm are frequently found in white patients with unobstructed coronary arteries. Epicardial spasm is most often diffuse and located in the distal coronary segments. The intracoronary acetylcholine provocation test is a safe technique to assess coronary vasomotor function.
Thrombolysis Delivery by a Regional Telestroke Network—Experience From the UK National Health Service
Authors: Agarwal Smriti , Day Diana J. , Sibson Lynda , Barry Patrick J. , Collas David , Metcalf Kneale , Cotter Paul E. , Guyler Paul , O'Brien Eoin W. , O'Brien Anthony , O'Kane Declan , Owusu‐Agyei Peter , Phillips Peter , Shekhar Raj , Warburton Elizabeth A.
Published: February 2014

Background

The majority of established telestroke services are based on “hub‐and‐spoke” models for providing acute clinical assessment and thrombolysis. We report results from the first year of the successful implementation of a locally based telemedicine network, without the need of 1 or more hub hospitals, across a largely rural landscape.

Methods and Results

Following a successful pilot phase that demonstrated safety and feasibility, the East of England telestroke project was rolled out across 7 regional hospitals, covering an area of 7500 square miles and a population of 5.6 million to enable out‐of‐hours access to thrombolysis. Between November 2010 and November 2011, 142 telemedicine consultations were recorded out‐of‐hours. Seventy‐four (52.11%) cases received thrombolysis. Median (
IQR
) onset‐to‐needle and door‐to‐needle times were 169 (141.5 to 201.5) minutes and 94 (72 to 113.5) minutes, respectively. Symptomatic hemorrhage rate was 7.3% and stroke mimic rate was 10.6%.

Conclusions

We demonstrate the safety and effectiveness of a horizontal networking approach for stroke telemedicine, which may be applicable to areas where traditional “hub‐and‐spoke” models may not be geographically feasible.
Mechanism of the Susceptibility of Remodeled Pulmonary Vessels to Drug‐Induced Cell Killing
Authors: Ibrahim Yasmine F. , Wong Chi‐Ming , Pavlickova Ludmila , Liu Lingling , Trasar Lobsang , Bansal Geetanjali , Suzuki Yuichiro J.
Published: February 2014

Background

Pulmonary arterial hypertension remains a devastating disease without a cure. The major complication of this disease is the abnormal growth of vascular cells, resulting in pulmonary vascular remodeling. Thus, agents, which affect the remodeled vessels by killing unwanted cells, should improve treatment strategies. The present study reports that antitumor drugs selectively kill vascular cells in remodeled pulmonary vessels in rat models of pulmonary hypertension.

Methods and Results

After developing pulmonary vascular remodeling in chronic hypoxia or chronic hypoxia/SU‐5416 models, rats were injected with antitumor drugs including proteasome inhibitors (bortezomib and MG‐132) and daunorubicin. Within 1 to 3 days, these agents reduced the media and intima thickness of remodeled pulmonary vascular walls, but not the thickness of normal pulmonary vessels. These drugs also promoted apoptotic and autophagic death of vascular cells in the remodeled vessels, but not in normal vessels. We provide evidence that the upregulation of annexin A1, leading to GATA4‐dependent downregulation of Bcl‐

x
L

, is a mechanism for specific apoptotic killing, and for the role of parkin in defining specificity of autophagic killing of remodeled vascular cells. The reversal of pulmonary vascular remodeling increased the capacity of vasodilators to reduce pulmonary arterial pressure.

Conclusions

These results suggest that antitumor drugs can specifically kill cells in remodeled pulmonary vascular walls and may be useful for improving the efficacy of current therapeutic strategies to treat pulmonary arterial hypertension.