bluuebunny/crossref_metadata_2025 huggingface dataset:
IAGC and IAEA Interlaboratory Comparisons of Geothermal Water Chemistry: The Propagation of Uncertainty in the Reservoir pH Calculation
Authors: Verma Mahendra P.
Published: September 2008

A statistical evaluation of the results of geochemical analyses of geothermal waters during interlaboratory comparison programmes of the International Association of Geochemistry and Cosmochemistry (IAGC) and International Atomic Energy Agency (IAEA) was performed to estimate the uncertainty of measurement of pH, electrical conductivity, Na+, K+, Ca2+, Mg2+, Li+, Cl−, HCO3−, SO42−, SiO2 and B. The uncertainty of measurement was found to increase exponentially with decrease in value (concentration) for all the parameters except for pH, electrical conductivity and SiO2 and was of the same order of magnitude as the concentrations for values of less than 1 μ ml−1. There was an overall uncertainty of ± 2.5% in the measurement of pH and ± 30% in SiO2. For all the other chemical species the uncertainty data were modelled by exponential curves. The sample IAEA14 was prepared by dissolving commercial reagents (i.e., represents a solution of known composition). Thus, the calculated values are considered to be the conventional true values for each chemical parameter. The difference between the measured mean of the data submitted by participating laboratories and the conventional true value for each parameter (i.e., bias of submitted measurements) for the species Na+, K+, Ca2+, Mg2+, Cl− and SO42− was ‐3.5, ‐1.1, ‐13.3, ‐53.6, ‐12.6 and ‐86.6%, respectively. The observed bias was of the same order of magnitude as statistical fluctuations (1s) for Na+ and K+, but significantly higher for Ca2+, Mg2+, Cl− and SO42−. Two methods, uncertainty interval and GUM (“guide to the expression of uncertainty of measurement”) were used to propagate uncertainty in the pH calculation of geothermal reservoir fluid. The application of the methods is illustrated by considering the IAEA10 and IAEA11 samples analysed in the interlaboratory comparisons as separated geothermal waters at atmospheric pressure.
Refinement of Phosphorus Determination in Quartz by LA‐ICP‐MS through Defining New Reference Material Values
Authors: Müller Axel , Wiedenbeck Michael , Flem Belinda , Schiellerup Henrik
Published: September 2008

The aim of this study was to improve the quality of laser ablation inductively coupled plasma‐mass spectrometry (LA‐ICP‐MS) determination of phosphorus in crystalline quartz. Over the last decade, the Geological Survey of Norway has routinely performed trace element determinations on quartz from both operating and potential quartz deposits by LA‐ICP‐MS. The determined phosphorus concentrations were, with but few exceptions, consistently within the range of 10 to 30 μg g−1, results that seemed to be both too high and too consistent. The multi‐material calibration curve obtained from a suite of reference materials (NIST SRM 610, 612, 614, 1830, BAM No. 1 amorphous SiO2 glass) did not define a precise regression line. Published phosphorus concentrations for the reference materials are poorly constrained and the observed dispersions along the multi‐material calibration curve suggest that some of the reference values may be inaccurate. Furthermore, the calibration curve did not pass through the origin of the [(cps 31P/cps 30Si) · cone. Si] vs. P concentration diagram; thus, in addition to the uncertainties of the literature values of phosphorus, it is difficult to define the calibration curve. Three reference materials (NIST SRM 614, 1830, synthetic quartz KORTH) were sent for phosphorus accelerator implantation, providing an independent and accurate (± 3%) approach for determining phosphorus concentrations in crystalline quartz. The intrinsic phosphorus concentrations of the three implanted samples plus those for NIST SRM 610 and 612 were determined by secondary ion mass spectrometry (SIMS), yielding new phosphorus values for NIST SRM 610, 612, 614 and 1830. Using these new values resulted in a better defined LA‐ICP‐MS calibration curve. However, the source of the ICP‐MS related background could not be defined, such that it must still be empirically corrected for.
Complex Ciprofloxacin Resistome Revealed by Screening a
Pseudomonas aeruginosa
Mutant Library for Altered Susceptibility
Authors: Breidenstein Elena B. M. , Khaira Bhavjinder K. , Wiegand Irith , Overhage Joerg , Hancock Robert E. W.
Published: September 2008

Pseudomonas aeruginosa
offers substantial therapeutic challenges due to its high intrinsic resistance to many antibiotics and its propensity to develop mutational and/or adaptive resistance. The PA14 comprehensive mutant library was screened for mutants exhibiting either two- to eightfold increased susceptibilities (revealing genes involved in intrinsic resistance) or decreased susceptibilities (mutational resistance) to the fluoroquinolone ciprofloxacin. Thirty-five and 79 mutants with increased and decreased susceptibilities, respectively, were identified, as confirmed by broth dilution.
Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
Authors: Seiwert Scott D. , Andrews Steven W. , Jiang Yutong , Serebryany Vladimir , Tan Hua , Kossen Karl , Rajagopalan P. T. Ravi , Misialek Shawn , Stevens Sarah K. , Stoycheva Antitsa , Hong Jin , Lim Sharlene R. , Qin Xiaoli , Rieger Robert , Condroski Kevin R. , Zhang Hailong , Do Mary Geck , Lemieux Christine , Hingorani Gary P. , Hartley Dylan P. , Josey John A. , Pan Lin , Beigelman Leonid , Blatt Lawrence M.
Published: September 2008

Future treatments for chronic hepatitis C virus (HCV) infection are likely to include agents that target viral components directly. Here, the preclinical characteristics of ITMN-191, a peptidomimetic inhibitor of the NS3/4A protease of HCV, are described. ITMN-191 inhibited a reference genotype 1 NS3/4A protein in a time-dependent fashion, a hallmark of an inhibitor with a two-step binding mechanism and a low dissociation rate. Under preequilibrium conditions, 290 pM ITMN-191 half-maximally inhibited the reference NS3/4A protease, but a 35,000-fold-higher concentration did not appreciably inhibit a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Subnanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 4, 5, and 6, while single-digit nanomolar potency was observed against NS3/4A from genotypes 2b and 3a. Dilution of a preformed enzyme inhibitor complex indicated ITMN-191 remained bound to and inhibited NS3/4A for more than 5 h after its initial association. In cell-based potency assays, half-maximal reduction of genotype 1b HCV replicon RNA was afforded by 1.8 nM; 45 nM eliminated the HCV replicon from cells. Peginterferon alfa-2a displayed a significant degree of antiviral synergy with ITMN-191 and reduced the concentration of ITMN-191 required for HCV replicon elimination. A 30-mg/kg of body weight oral dose administered to rats or monkeys yielded liver concentrations 12 h after dosing that exceeded the ITMN-191 concentration required to eliminate replicon RNA from cells. These preclinical characteristics compare favorably to those of other inhibitors of NS3/4A in clinical development and therefore support the clinical investigation of ITMN-191 for the treatment of chronic hepatitis C.
Antimony Resistance and Trypanothione in Experimentally Selected and Clinical Strains of
Leishmania panamensis
Authors: Goyeneche-Patino Diego A. , Valderrama Liliana , Walker John , Saravia Nancy G.
Published: September 2008

The participation of trypanothione in clinical and experimental antimony (Sb) resistance in
Leishmania panamensis
was examined by using specific inhibitors. Buthionine sulfoximine (BSO) significantly reversed the resistance to trivalent Sb (Sb
III
) of promastigotes of experimentally derived Sb-resistant lines, supporting the participation of a trypanothione-mediated mechanism of resistance. In contrast, promastigotes of strains isolated at the time of clinical treatment failure and resistant to pentavalent Sb (Sb
V
) as intracellular amastigotes were not cross resistant to Sb
III
, and BSO had little or no effect on susceptibility. Difluoromethylornithine did not alter the Sb
III
susceptibilities of experimentally selected lines or clinical strains. The mechanisms of acquired resistance emerging in clinical settings may differ from those selected by in vitro exposure to Sb.
A Type IV Secretion System Contributes to Intracellular Survival and Replication of
Burkholderia cenocepacia
Authors: Sajjan S. Umadevi , Carmody Lisa A. , Gonzalez Carlos F. , LiPuma John J.
Published: September 2008

Burkholderia cenocepacia
is an important respiratory pathogen in persons with cystic fibrosis (CF). Recent studies indicate that
B. cenocepacia
survives within macrophages and airway epithelial cells in vitro by evading endosome-lysosome fusion. We investigated the role of a plasmid-encoded type IV secretion system in the intracellular survival, replication, and processing of
B. cenocepacia
. Both a wild-type strain (K56-2) and its type IV secretion system mutant (designated LC101) entered and replicated in CF airway epithelial cells and monocyte-derived macrophages. However, significantly more intracellular K56-2 than LC101 bacteria were found in both cell types at 24 h postinfection. Colocalization of bacteria with markers of the classical endocytic pathway indicated that although both K56-2 and LC101 reside transiently in early endosomes, a greater proportion of the mutant bacteria are targeted to lysosomal degradation. In contrast, wild-type bacteria escape from the classical endocytic pathway and traffic to the endoplasmic reticulum, where they replicate. Our results show that the intracellular processing of
B. cenocepacia
is similar in both professional and nonprofessional phagocytes and that a functional plasmid-encoded type IV secretion system contributes to the survival and replication of
B. cenocepacia
in eukaryotic cells.
Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease
Authors: Brown Charles R. , Lai Annie Y.-C. , Callen Steven T. , Blaho Victoria A. , Hughes Jennifer M. , Mitchell William J.
Published: September 2008

Production of interleukin-10 (IL-10) by C57BL/6 mice following infection withBorrelia burgdorferihas been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis- and carditis-susceptible C3H mice. Infection of C3H IL-10−/−mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement ofB. burgdorferinumbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10−/−mice. However, in contrast to previous in vitro work, infection of C3H IL-10−/−mice led to decreased in vivo expression of the cytokines KC, IL-1β, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance orBorrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected withB. burgdorferiand that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.
An AraC-Type Transcriptional Regulator Encoded on the
Enterococcus faecalis
Pathogenicity Island Contributes to Pathogenesis and Intracellular Macrophage Survival
Authors: Coburn Phillip S. , Baghdayan Arto S. , Dolan GT , Shankar Nathan
Published: September 2008

A gene encoding a putative AraC-type transcriptional regulator was identified on the 153-kb pathogenicity island (PAI) found among virulent
Enterococcus faecalis
strains. In an effort to understand the function of this regulator, designated PerA (for pathogenicity island-encoded regulator), we first examined the expression of the
perA
gene in the original PAI strain MMH594 and in an unrelated clinical isolate E99 by reverse transcription-PCR. Interestingly, expression analysis revealed no detectable
perA
transcript in MMH594, whereas a transcript was observed in strain E99. Nucleotide sequence analysis revealed that this altered expression between the two strains was attributable to the differential location of an IS
1191
element within the putative promoter region upstream of the
perA
gene. In order to determine the role of this putative regulator in
E. faecalis
pathogenesis, a
perA
-deficient mutant was created in strain E99, and the wild-type and mutant pair were compared for phenotypic differences. In in vitro biofilm assays, the mutant strain showed a significantly higher level of growth medium-specific biofilm formation compared to the wild type. However, in a murine intraperitoneal infection model, the mutant strain was significantly less pathogenic. The mutant was also attenuated for survival within macrophages in vitro. These findings highlight the importance of PerA as a regulator of biofilm formation and survival within macrophages and is likely a regulator controlling determinants important to pathogenesis.
Platelet Antistaphylococcal Responses Occur through P2X1and P2Y12Receptor-Induced Activation and Kinocidin Release
Authors: Trier Darin A. , Gank Kimberly D. , Kupferwasser Deborah , Yount Nannette Y. , French William J. , Michelson Alan D. , Kupferwasser Leon I. , Xiong Yan Q. , Bayer Arnold S. , Yeaman Michael R.
Published: September 2008

Platelets (PLTs) act in antimicrobial host defense by releasing PLT microbicidal proteins (PMPs) or PLT kinocidins (PKs). Receptors mediating staphylocidal efficacy and PMP or PK release versus isogenic PMP-susceptible (ISP479C) and -resistant (ISP479R)Staphylococcus aureusstrains were examined in vitro. Isolated PLTs were incubated with ISP479C or ISP479R (PLT/S. aureusratio range, 1:1 to 10,000:1) in the presence or absence of a panel of PLT inhibitors, including P2X and P2Y receptor antagonists of increasingly narrow specificity, and PLT adhesion receptors (CD41, CD42b, and CD62P). PLT-to-S. aureusexposure ratios of ≥10:1 yielded significant reductions in the viability of both strains. Results from reversed-phase high-performance liquid chromatography indicated that staphylocidal PLT releasates contained PMPs and PKs. At ratios below 10:1, the PLT antistaphylococcal efficacy relative to the intrinsicS. aureusPMP-susceptible or -resistant phenotype diminished. Apyrase (an agent of ADP degradation), suramin (a general P2 receptor antagonist), pyridoxal 5′-phosphonucleotide derivative (a specific P2X1antagonist), and cangrelor (a specific P2Y12antagonist) mitigated the PLT staphylocidal response against both strains, correlating with reduced levels of PMP and PK release. Specific inhibition occurred in the presence and absence of homologous plasma. The antagonism of the thromboxane A2, cyclooxygenase-1/cyclooxygenase-2, or phospholipase C pathway or the hindrance of surface adhesion receptors failed to impede PLT anti-S. aureusresponses. These results suggest a multifactorial PLT anti-S. aureusresponse mechanism involving (i) a PLT-to-S. aureusratio sufficient for activation; (ii) the ensuing degranulation of PMPs, PKs, ADP, and/or ATP; (iii) the activation of P2X1/P2Y12receptors on adjacent PLTs; and (iv) the recursive amplification of PMP and PK release from these PLTs.
Preimplantation genetic diagnosis: a step by step guide to recent Italian ethical and legislative troubles
Authors: Turillazzi E , Fineschi V
Published: September 2008

Objective:

To analyse legislation and medical professionals’ position concerning the doctor’s role in assisted reproduction techniques in Italy, and to discuss the implications for physicians of preimplantation genetic diagnosis (PGD).

Background:

Until recently a strict interpretation of the assisted reproduction law (40/2004) and the guidelines subsequently issued, lead to denying infertile couples affected by genetic diseases the right to resort to PGD. In October 2006 the Constitutional Court ruled regarding the question of the constitutional legitimacy of the prohibition of PGD.

Discussion:

The Constitutional Court declared the manifest inadmissibility of the question of the constitutional legitimacy of article 13 of law 40/2004. The debate has become very animated since the ruling. After the negative sentence of the Constitutional Court, three further sentences recognised the right of couples to obtain PGD, representing a hard blow to law 40/2004 and to the ministerial guidelines; a further confirmation of the untenability of a law that violates fundamental principles such as the right to healthcare for women and the unborn child, the right to responsible motherhood and to informed consent.

Conclusion:

It seems that in Italy the legislative inadequacy for medically assisted procreation is reprieved by the courageous decisions of the judges, which refer to the values of the Italian Constitution, in defence of the fundamental rights of the citizens.
A critique of “the best secular argument against abortion”
Authors: Strong C
Published: September 2008

Don Marquis has put forward a non-religious argument against abortion based on what he claims is a morally relevant similarity between killing adult human beings and killing fetuses. He asserts that killing adults is wrong because it deprives them of their valuable futures. He points out that a fetus’s future includes everything that is in an adult’s future, given that fetuses naturally develop into adults. Thus, according to Marquis, killing a fetus deprives it of the same sort of valuable future that an adult is deprived of in being killed and this makes abortion seriously wrong. Commentators have raised a number of objections to Marquis’s argument, to which he has satisfactorily responded. In this paper, difficulties with Marquis’s argument that have not been considered by previous commentators are pointed out. A main thesis of this paper is that Marquis does not adequately defend his argument against several important objections that he himself has raised. These new considerations support the view that Marquis’s argument is unsuccessful.
ON ITERATED TWISTED TENSOR PRODUCTS OF ALGEBRAS
Authors: JARA MARTÍNEZ PASCUAL , PEÑA JAVIER LÓPEZ , PANAITE FLORIN , VAN OYSTAEYEN FREDDY
Published: September 2008

We introduce and study the definition, main properties and applications of iterated twisted tensor products of algebras, motivated by the problem of defining a suitable representative for the product of spaces in noncommutative geometry. We find conditions for constructing an iterated product of three factors and prove that they are enough for building an iterated product of any number of factors. As an example of the geometrical aspects of our construction, we show how to construct differential forms and involutions on iterated products starting from the corresponding structures on the factors and give some examples of algebras that can be described within our theory. We prove a certain result (called "invariance under twisting") for a twisted tensor product of two algebras, stating that the twisted tensor product does not change when we apply certain kind of deformation. Under certain conditions, this invariance can be iterated, containing as particular cases a number of independent and previously unrelated results from Hopf algebra theory.
COHERENT SYSTEMS OF GENUS 0 III: COMPUTATION OF FLIPS FOR k = 1
Authors: LANGE H. , NEWSTEAD P. E.
Published: September 2008

In this paper, we continue the investigation of coherent systems of type (n, d, k) on the projective line which are stable with respect to some value of a parameter α. We consider the case k = 1 and study the variation of the moduli spaces with α. We determine inductively the first and last moduli spaces and the flip loci, and give an explicit description for ranks 2 and 3. We also determine the Hodge polynomials explicitly for ranks 2 and 3 and in certain cases for arbitrary rank.
NONSINGULAR COMPLEX INSTANTONS ON EUCLIDEAN SPACETIME
Authors: DALLAGNOL LLOHANN , JARDIM MARCOS
Published: September 2008

Building on a variation of 't Hooft's harmonic function ansatz for SU(2) instantons on ℝ4, we provide new explicit nonsingular solutions of the Yang–Mills anti-self-duality equations on Euclidean spacetime with gauge group SL(2, ℂ) and SL(3, ℝ).
Sizing Your System
Authors: Neville-Neil George
Published: September 2008

Dear KV, I’m working on a network server that gets into the situation you called livelock in a previous response to a letter (Queue May/June 2008). Our problem is that our system has only a fixed amount of memory to receive network data, but the system is frequently overwhelmed and can’t make progress. When I ask our application engineers about how much data they expect, the only answer I get is "a lot," which isn’t much help. How can I figure out how to size our systems appropriately?
A Pioneer’s Flash of Insight
Authors: Cantrill Bryan
Published: September 2008

In the May/June issue of Queue, Eric Allman wrote a tribute to Jim Gray, mentioning that Queue would be running some of Jim’s best works in the months to come. I’m embarrassed to confess that when this idea was first discussed, I assumed these papers would consist largely of Jim’s seminal work on databases showing only that I (unlike everyone else on the Queue editorial board) never knew Jim. In an attempt to learn more about both his work and Jim himself, I attended the tribute held for him at UC Berkeley in May.
Enterprise SSDs
Authors: Moshayedi Mark , Wilkison Patrick
Published: September 2008

For designers of enterprise systems, ensuring that hardware performance keeps pace with application demands is a mind-boggling exercise. The most troubling performance challenge is storage I/O. Spinning media, while exceptional in scaling areal density, will unfortunately never keep pace with I/O requirements. The most cost-effective way to break through these storage I/O limitations is by incorporating high-performance SSDs (solid-state drives) into the systems.
Calendar
Authors: Stanik John
Published: September 2008

IT Roadmap Conference and Expo
Interview with Herman Tavani, winner of the 2008 SIGCAS Service Award
Authors: Henderson Kathrine Andrews
Published: September 2008

I sat down with SIGCAS 2008 Outstanding Service Award recipient, Dr. Herman Tavani a few weeks ago to chat about his long-standing relationship with SIGCAS. Our conversation started out with a simple question, how long have you been a member? Answer, 14 years. And with that, the stories, the friendships, and his hopes for SIGCAS started flowing. --- KAH
The irrelevance of the machine
Authors: Fee Samuel
Published: September 2008

We've all heard the expression "can't see the forest for the trees." But when considering the role of technology in education, it seems that many of us suffer from this obscured view. Of course, it's easy to understand why: new tools are sometimes fascinating, and new technologies often enjoy a certain coolness quotient. But ultimately, it is the way in which these technologies are incorporated into the classroom -- and their underlying pedagogy -- that is the foremost determiner of whether the educational treatment will facilitate learning. The hardware and software are largely irrelevant. The truly important issue here is what the student needs to learn, and how the tools support that learning.
Effect of Hydrogen Content and Dilution on Laminar Burning Velocity and Stability Characteristics of Producer Gas-Air Mixtures
Authors: Ratna Kishore V. , Ravi M. R. , Ray Anjan
Published: September 2008

Producer gas is one of the promising alternative fuels with typical constituents of H2, CO, CH4, N2, and CO2. The laminar burning velocity of producer gas was computed for a wide range of operating conditions. Flame stability due to preferential diffusional effects was also investigated. Computations were carried out for spherical outwardly propagating flames and planar flames. Different reaction mechanisms were assessed for the prediction of laminar burning velocities of CH4, H2, H2-CO, and CO-CH4and results showed that the Warnatz reaction mechanism with C1 chemistry was the smallest among the tested mechanisms with reasonably accurate predictions for all fuels at 1 bar, 300 K. To study the effect of variation in the producer gas composition, each of the fuel constituents in ternary CH4-H2-CO mixtures was varied between 0 to 48%, while keeping diluents fixed at 10% CO2and 42% N2by volume. Peak burning velocity shifted fromϕ=1.6to 1.1 as the combined volumetric percentage of hydrogen and CO varied from 48% to 0%. Unstable flames due to preferential diffusion effects were observed for lean mixtures of fuel with high hydrogen content. The present results indicate that H2has a strong influence on the combustion of producer gas.
Miniaturised Optical Fibre Sensor for Dew Detection Inside Organ Pipes
Authors: Baldini Francesco , Falciai Riccardo , Mencaglia Andrea Azelio , Senesi Folco , Camuffo Dario , della Valle Antonio , Bergsten Carl Johan
Published: September 2008

A new optical sensor for the continuous monitoring of the dew formation inside organ pipes was designed. This aspect is particularly critical for the conservation of organs in unheated churches since the dew formation or the condensation on the pipe surfaces can contribute to many kinds of physical and chemical disruptive mechanisms. The working principle is based on the change in the reflectivity which is observed on the surface of the fibre tip, when a water layer is formed on its distal end. Intensity changes of the order of 35% were measured, following the formation of the water layer on the distal end of a 400/430 μm optical fibre. Long‐term tests carried out placing the fibre tip inside the base of an in‐house‐made metallic foot of an organ pipe located in an external environment revealed the consistency of the proposed system.
Saddle-Shaped Mitral Valve Annuloplasty Rings Experience Lower Forces Compared With Flat Rings
Authors: Jensen Morten O. , Jensen Henrik , Smerup Morten , Levine Robert A. , Yoganathan Ajit P. , Nygaard Hans , Hasenkam J. Michael , Nielsen Sten L.
Published: September 2008

Background—

New insight into the 3D dynamic behavior of the mitral valve has prompted a reevaluation of annuloplasty ring designs. Force balance analysis indicates correlation between annulus forces and stresses in leaflets and chords. Improving this stress distribution can intuitively enhance the durability of mitral valve repair. We tested the hypothesis that saddle-shaped annuloplasty rings have superior uniform systolic force distribution compared with a nonuniform force distribution in flat annuloplasty rings.

Methods and Results—

Sixteen 80-kg pigs had a flat (n=8) or saddle-shaped (n=8) mitral annuloplasty ring implanted. Mitral annulus 3D dynamic geometry was obtained with sonomicrometry before ring insertion. Strain gauges mounted on dedicated D-shaped rigid flat and saddle-shaped annuloplasty rings provided the intraoperative force distribution perpendicular to the annular plane. Average systolic annular height to commissural width ratio before ring implantation was 14.0%±1.6%. After flat and saddle shaped ring implantation, the annulus was fixed in the diastolic (9.0%±1.0%) and systolic (14.3%±1.3%) configuration, respectively (
P
<0.01). Force accumulation was seen from the anterior (0.72N±0.14N) and commissural annular segments (average 1.38N±0.27N) of the flat rings. In these segments, the difference between the 2 types of rings was statistically significant (
P
<0.05). The saddle-shaped annuloplasty rings did not experience forces statistically significantly larger than zero in any annular segments.

Conclusions—

Saddle-shaped annuloplasty rings provide superior uniform annular force distribution compared to flat rings and appear to represent a configuration that minimizes out-of-plane forces that could potentially be transmitted to leaflets and chords. This may have important implications for annuloplasty ring selections.
Performance of Cavopulmonary Palliation at Elevated Altitude
Authors: Malhotra Sunil P. , Ivy D. Dunbar , Mitchell Max B. , Campbell David N. , Dines Marshall L. , Miyamoto Shelley , Kay Joseph , Clarke David R. , Lacour-Gayet Francois
Published: September 2008

Background—

Outcomes of patients undergoing cavopulmonary palliation for single ventricle physiology may be impacted by living at altitude, as the passive pulmonary circulation is dependent on the resistance of the pulmonary vascular bed. The objective of this study is to identify risk factors for failure of cavopulmonary palliation at elevated altitude.

Methods and Results—

Between January 1995 and March 2007, 122 consecutive patients living at a mean altitude of 1600 m (range 305 to 2570) underwent a bidirectional Glenn (BDG). There was one in-hospital mortality and 7 late deaths. 52 have proceeded to the Fontan procedure. Survival after BDG was 92.4% at 5 years. Freedom from palliation failure, defined as death, transplant, BDG/Fontan takedown, or revision was 81% at 5 years. At a mean follow-up of 39.8 months, 90 patients (75%) were in New York Heart Association class I. Patients with failing cavopulmonary circulation had higher pre-BDG pulmonary artery pressure (PAP) (18.3±6.1 mm Hg versus 14.8±5.1 mm Hg,
P
=0.016) and higher pre-BDG transpulmonary gradient (TPG) (11.2±6.2 mm Hg versus 7.7±4.3 mm Hg,
P
=0.014). Post-BDG, patients with palliation failure had increased PAP (15.0±5.7 mm Hg versus 10.8±2.8 mm Hg,
P
=0.008) and indexed pulmonary vascular resistance (PVRI) (2.43±1.0 Wood U · m
2
versus 1.52±0.9 Wood U · m
2
,
P
=0.007).

Conclusions—

The majority of patients at moderate altitude have favorable outcomes after BDG or Fontan palliation. Risk factors for palliation failure at elevated altitude include PAP >15 mm Hg, TPG >8 mm Hg, and PVRI >2.5 Wood U · m
2
.
Loss of Myocardial Ischemic Postconditioning in Adenosine A
1
and Bradykinin B
2
Receptors Gene Knockout Mice
Authors: Xi Lei , Das Anindita , Zhao Zhi-Qing , Merino Vanessa F. , Bader Michael , Kukreja Rakesh C.
Published: September 2008

Background—

Ischemic postconditioning (PostC) is a recently described cardioprotective modality against reperfusion injury, through series of brief reflow interruptions applied at the very onset of reperfusion. It is proposed that PostC can activate a complex cellular signaling cascade, in which cell membrane receptors could serve as the upstream triggers of PostC. However, the exact subtypes of such receptors remain controversial or uninvestigated. To this context, the purpose of present study was to determine the definitive role of adenosine A
1
and bradykinin B
1
and B
2
receptors in PostC.

Methods and Results—

The hearts isolated from adult male C57BL/6J wild-type mice or the mice lacking adenosine A
1
, or bradykinin B
1
or B
2
receptors subjected to zero-flow global ischemia and reperfusion in a Langendorff model. PostC, consisting of 6 cycles of 10 seconds of reperfusion and 10 seconds of ischemia, demonstrated significantly reduced myocardial infarct size (22.8±3.1%, mean±SEM) as compared with the non-PostC wild-type controls (35.1±2.8%,
P
<0.05). The infarct-limiting protection of PostC was absent in adenosine A
1
receptor knockout mice (34.9±2.7%) or bradykinin B
2
receptor knockout mice (33.3±1.7%) and was partially attenuated in bradykinin B
1
receptor-deficient mice (25.6±2.9%;
P
>0.05). On the other hand, PostC did not significantly alter postischemic cardiac contractile function and coronary flow.

Conclusions—

With the use of three distinctive strains of gene knockout mice, the current study has provided the first conclusive evidence showing PostC-induced infarct-limiting cardioprotection could be triggered by activation of multiple types of cell membrane receptors, which include adenosine A
1
and bradykinin B
2
receptors.
Biventricular Assist Devices as a Bridge to Heart Transplantation in Small Children
Authors: Gandhi Sanjiv K. , Huddleston Charles B. , Balzer David T. , Epstein Deirdre J. , Boschert Traci A. , Canter Charles E.
Published: September 2008

Background—

Experience with the use of biventricular assist device (BiVAD) support to bridge small children to heart transplantation is limited.

Methods and Results—

We used BIVAD support (Berlin EXCOR) in 9 pediatric heart transplant candidates from 4/05 to 7/07. The median patient age was 1.7 years (12 days to 17 years). The median patient weight was 9.4 kg (3 to 38 kg). All children were supported with multiple intravenous inotropes±mechanical ventilation (6) or ECMO (3) before BiVAD implantation. All had significant right ventricular dysfunction. The median pulmonary vascular resistance index (Rpi) was 6.0 WU/m
2
. Eight patients were successfully bridged to heart transplantation after a median duration of BiVAD support of 35 days (1 to 77 days). One death occurred after 10 days of support from perioperative renal failure in a 3 kg infant. Five patients required at least 1 blood pump change. One patient had a driveline infection requiring treatment. There were no acute neurological complications, no thromboembolic events, and no bleeding complications. In 2 patients with Rpi >10 WU/m
2
unresponsive to pulmonary vasodilator therapy, Rpi dropped to 1.4 and 4.6 WU/m
2
, after 33 and 41 days of support, respectively. All 8 survivors underwent successful heart transplantation. Of 5 patients supported >30 days, 3 developed an extremely elevated (>90%) panel reactive antibody by ELISA that was not confirmed by other methods; none had a positive donor-specific retrospective crossmatch. There was 1 episode of rejection (with hemodynamic compromise) in the 8 transplanted patients. Rpi was normal (<3 WU/m
2
) without pulmonary vasodilators in all patients within 3 months after transplant. There have been no deaths after transplant with a median follow-up of 19 months.

Conclusions—

BiVAD support can effectively be used in small children as a bridge to heart transplantation and can be accomplished with low mortality and morbidity. BiVAD support may offer an additional means to reverse extremely elevated pulmonary vascular resistance. Surveillance for HLA antibody sensitization during BiVAD support may be complicated by the development of non-HLA antibodies which may not reflect true HLA presensitization.
Impact of Donor-to-Recipient Weight Ratio on Survival After Heart Transplantation
Authors: Patel Nishant D. , Weiss Eric S. , Nwakanma Lois U. , Russell Stuart D. , Baumgartner William A. , Shah Ashish S. , Conte John V.
Published: September 2008

Background—

Generally accepted donor criteria for heart transplantation limit allografts from donors within approximately 20% to 30% of the recipient’s weight. We analyzed the impact of donor-to-recipient weight ratio on survival after heart transplantation.

Methods and Results—

Adult heart transplant recipients reported to the United Network for Organ Sharing from 1999 to 2007 were divided into 3 groups based on donor-to-recipient weight ratio: <0.8, 0.8 to 1.2, and >1.2. Kaplan-Meier methodology was used to estimate survival. Propensity-adjusted Cox regression modeling was used to analyze predictors of mortality. A total of 15 284 heart transplant recipients were analyzed; 2078 had weight ratio of <0.8, 9684 had 0.8 to 1.2, and 3522 had >1.2. Kaplan-Meier survival was not statistically different between groups at 5 years (
P
=0.26). Among patients with weight ratio <0.8, 5-year survival was lower for recipients with high pulmonary vascular resistance (>4 Woods units;
P
=0.02). Among recipients with high pulmonary vascular resistance, 5-year survival was similar for those with weight ratio 0.8 to 1.2 and >1.2 (
P
=0.44)
.
Furthermore, male recipients with elevated pulmonary vascular resistance who received hearts from female donors had a significantly worse survival than males who received hearts from male donors (
P
=0.01). Propensity-adjusted multivariable analysis demonstrated that weight ratio <0.8 did not predict mortality (hazard ratio, 1.09; 95% CI, 0.94 to 1.27;
P
=0.21). Five-year survival after propensity matching was not statistically different between those with weight ratio <0.8 versus ≥0.8 (
P
=0.37).

Conclusions—

Weight ratio did not predict mortality after heart transplantation. However, recipients with elevated pulmonary vascular resistance who received undersized hearts had poor survival. Furthermore, in the setting of high pulmonary vascular resistance, male recipients who received hearts from female donors had worse survival than those who received hearts from male donors. Extending donor criteria to include undersized hearts in select recipients should be considered.
Ascending and Transverse Aortic Arch Repair
Authors: Estrera Anthony L. , Miller Charles C. , Lee Taek-Yeon , Shah Pallav , Safi Hazim J.
Published: September 2008

Background—

The benefit of retrograde cerebral perfusion (RCP) with profound hypothermic circulatory arrest has been subject to much debate. We examined our experience with ascending and transverse arch repairs to determine the impact of retrograde cerebral perfusion on stroke and mortality.

Methods and Results—

Between August 1991 and June 2007, we performed 1107 repairs of the ascending and transverse aortic arch. RCP was used in 82% of cases (907 of 1107). Sixty-two percent were men (682 of 1107); median age was 64 years (range, 16 to 93 years). Perioperative variables were evaluated using univariate and multivariable analysis for mortality and stroke. Thiry-day mortality was 10.4% (115 of 1107). Stroke occurred in 2.8% (31 of 1107) of patients. Univariate risk factors for mortality were increasing age (
P
<0.0001), history of coronary artery disease (
P
=0.02), previous coronary artery bypass (
P
=0.02), emergency status (
P
<0.0001), acute dissection (
P
=0.02), rupture (
P
=0.0001), preoperative glomerular filtration rate, bypass time (
P
<0.0001), crossclamp time (
P
<0.007), RCP time (
P
<0.0001), and packed red blood cell transfusions (
P
=0.0001). Univariate risk factors for stroke included emergency status (
P
<0.02), cerebrovascular disease (
P
<0.02), and crossclamp time (
P
<0.04). Independent risk factors for mortality were glomerular filtration rate <90 mL/min (
P
=0.0004), emergency status (
P
=0.006), rupture (
P
=0.004), cardiopulmonary bypass time >120 minutes (
P
<0.04), and packed red blood cell transfusions (
P
=0.0002). Risk factors for stroke were emergency status (
P
<0.009) and hypertension (
P
<0.05). RCP was protective against mortality and stroke.

Conclusions—

The use of RCP with profound hypothermic circulatory arrest was associated with a reduction in mortality and stroke. The use of RCP remains warranted during repairs of the ascending and transverse aortic arch.
Predictors of Outcomes in Low-Flow, Low-Gradient Aortic Stenosis
Authors: Clavel Marie-Annick , Fuchs Christina , Burwash Ian G. , Mundigler Gerald , Dumesnil Jean G. , Baumgartner Helmut , Bergler-Klein Jutta , Beanlands Rob S. , Mathieu Patrick , Magne Julien , Pibarot Philippe
Published: September 2008

Background—

Patients with low-flow, low-gradient aortic stenosis have a poor prognosis with conservative therapy but a high operative mortality if treated surgically. Recently, we proposed a new index of aortic stenosis severity derived from dobutamine stress echocardiography, the projected aortic valve area at a normal transvalvular flow rate, as superior to other conventional indices to differentiate true-severe from pseudosevere aortic stenosis. The objective of this study was to identify the determinants of survival, functional status, and change in left ventricular ejection fraction during follow-up of patients with low-flow, low-gradient aortic stenosis.

Methods and Results—

One hundred one patients with low-flow, low-gradient aortic stenosis (aortic valve area ≤1.2 cm
2
, left ventricular ejection fraction ≤40%, and mean gradient ≤40 mm Hg) underwent dobutamine stress echocardiography and an assessment of functional capacity using the Duke Activity Status Index. A subset of 72 patients also underwent a 6-minute walk test. Overall survival was 70±5% at 1 year and 57±6% at 3 years. After adjusting for age, gender, and the type of treatment (aortic valve replacement versus no aortic valve replacement), significant predictors of mortality during follow-up were a Duke Activity Status Index ≤20 (
P
=0.0005) or 6-minute walk test distance ≤320 m (
P
<0.0001, in the subset of 72 patients), projected aortic valve area at a normal transvalvular flow rate ≤1.2 cm
2
(
P
=0.03), and peak dobutamine stress echocardiography left ventricular ejection fraction ≤35% (
P
=0.03). More severe stenosis, defined as projected aortic valve area ≤1.2 cm
2
, was a predictor of mortality only in the no aortic valve replacement group. The Duke Activity Status Index, 6-minute walk test, and left ventricular ejection fraction improved significantly during follow-up in the aortic valve replacement group, but remained unchanged or decreased in the no aortic valve replacement group.

Conclusion—

In patients with low-flow, low-gradient aortic stenosis, the most significant risk factors for poor outcome were (1) impaired functional capacity as measured by Duke Activity Status Index or 6-minute walk test distance; (2) more severe valve stenosis as measured by projected aortic valve area at a normal transvalvular flow rate; and (3) reduced peak stress left ventricular ejection fraction, a composite measure accounting for both resting left ventricular function and contractile reserve.
Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility
Authors: Szokodi István , Kerkelä Risto , Kubin Anna-Maria , Sármán Balázs , Pikkarainen Sampsa , Kónyi Attila , Horváth Iván G. , Papp Lajos , Tóth Miklós , Skoumal Réka , Ruskoaho Heikki
Published: September 2008

Background—Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38-MAPK) have been shown to regulate various cellular processes, including cell growth, proliferation, and apoptosis in the heart. However, the function of these signaling pathways in the control of cardiac contractility is unclear. Here, we characterized the contribution of ERK1/2 and p38-MAPK to the inotropic effect of endothelin-1 (ET-1).

Methods and Results—In isolated perfused rat hearts, infusion of ET-1 (1 nmol/L) for 10 minutes increased contractility and phosphorylation of ERK1/2 and their downstream target p90 ribosomal S6 kinase (p90RSK). Suppression of ERK1/2 activation prevented p90RSK phosphorylation and attenuated the inotropic effect of ET-1. Pharmacological inhibition of epidermal growth factor receptor kinase activity abolished ET-1–induced epidermal growth factor receptor transactivation and ERK1/2 and p90RSK phosphorylation and reduced ET-1–mediated inotropic response. Moreover, inhibition of the p90RSK target Na+-H+exchanger 1 attenuated the inotropic effect of ET-1. In contrast to ERK1/2 signaling, suppression of p38-MAPK activity further augmented ET-1–enhanced contractility, which was accompanied by increased phosphorylation of phospholamban at Ser-16.

Conclusions—MAPKs play opposing roles in the regulation of cardiac contractility in that the ERK1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. Hence, selective activation of ERK1/2 signaling and inhibition of p38-MAPK signaling may represent novel means to support cardiac function in disease.
Short Hairpin RNA Interference Therapy for Ischemic Heart Disease
Authors: Huang Mei , Chan Denise A. , Jia Fangjun , Xie Xiaoyan , Li Zongjin , Hoyt Grant , Robbins Robert C. , Chen Xiaoyuan , Giaccia Amato J. , Wu Joseph C.
Published: September 2008

Background—

During hypoxia, upregulation of hypoxia inducible factor-1 alpha transcriptional factor can activate several downstream angiogenic genes. However, hypoxia inducible factor-1 alpha is naturally degraded by prolyl hydroxylase-2 (PHD2) protein. Here we hypothesize that short hairpin RNA (shRNA) interference therapy targeting PHD2 can be used for treatment of myocardial ischemia and this process can be followed noninvasively by molecular imaging.

Methods and Results—

PHD2 was cloned from mouse embryonic stem cells by comparing the homolog gene in human and rat. The best candidate shRNA sequence for inhibiting PHD2 was inserted into the pSuper vector driven by the H1 promoter followed by a separate hypoxia response element-incorporated promoter driving a firefly luciferase reporter gene. This construct was used to transfect mouse C2C12 myoblast cell line for in vitro confirmation. Compared with the control short hairpin scramble (shScramble) as control, inhibition of PHD2 increased levels of hypoxia inducible factor-1 alpha protein and several downstream angiogenic genes by >30% (
P
<0.01). Afterward, shRNA targeting PHD2 (shPHD2) plasmid was injected intramyocardially following ligation of left anterior descending artery in mice. Animals were randomized into shPHD2 experimental group (n=25) versus shScramble control group (n=20). Bioluminescence imaging detected plasmid-mediated transgene expression for 4 to 5 weeks. Echocardiography showed the shPHD2 group had improved fractional shortening compared with the shScramble group at Week 4 (33.7%±1.9% versus 28.4%±2.8%;
P
<0.05). Postmortem analysis showed increased presence of small capillaries and venules in the infarcted zones by CD31 staining. Finally, Western blot analysis of explanted hearts also confirmed that animals treated with shPHD2 had significantly higher levels of hypoxia inducible factor-1 alpha protein.

Conclusions—

This is the first study to image the biological role of shRNA therapy for improving cardiac function. Inhibition of PHD2 by shRNA led to significant improvement in angiogenesis and contractility by in vitro and in vivo experiments. With further validation, the combination of shRNA therapy and molecular imaging can be used to track novel cardiovascular gene therapy applications in the future.
Pilot Proteomic Profile of Differentially Regulated Proteins in Right Atrial Appendage Before and After Cardiac Surgery Using Cardioplegia and Cardiopulmonary Bypass
Authors: Clements Richard T. , Smejkal Gary , Sodha Neel R. , Ivanov Alexander R. , Asara John M. , Feng Jun , Lazarev Alexander , Gautam Shiva , Senthilnathan Venkatachalam , Khabbaz Kamal R. , Bianchi Cesario , Sellke Frank W.
Published: September 2008

Background—

Although highly protective, cardiac surgery using cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function which results in a greatly enhanced risk of mortality. Acute changes in myocardial contractile activity are likely regulated via protein modifications. We performed the following study to determine changes in the protein profile of human myocardium following CP/CPB.

Methods and Results—

Right atrial appendage was collected from 8 male patients pre and post-CP/CPB. Atrial tissue lysates were subjected to 2-dimensional electrophoresis, total protein staining, gel averaging, and quantitative densitometry. Ten prominent spots regulated in response to CP/CPB were identified using mass spectrometry. Two hundred twenty-five and 256 protein spots were reliably detected in 2D-gels from pre- and post-CP/CPB patients, respectively. Five unique (ie, not detected post-CP/CPB) and 17 significantly increased spots were detected pre-CP/CPB. Thirty-four unique and 25 significantly increased spots were detected in the post-CP/CPB group. Identified proteins that changed after CP/CPB included: MLC-2a, ATP-synthase delta chain and Enoyl-CoenzymeA hydratase, glutathione-s-transferase omega, α-1-acid-glycoprotein, and phosphatidylethanolamine-binding protein.

Conclusions—

Cardiac surgery results in multiple consistent changes in the human myocardial protein profile. CP/CPB modifies specific cytoskeletal, metabolic, and inflammatory proteins potentially involved in deleterious effects of CP/CPB.