bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Innate Immune Receptors in Paradoxical Caspofungin ActivityIn Vivoin Preclinical Aspergillosis
Authors: Moretti Silvia , Bozza Silvia , D'Angelo Carmen , Casagrande Andrea , Della Fazia Maria Agnese , Pitzurra Lucia , Romani Luigina , Aversa Franco
Published: May 2012

This study investigated the possible mechanisms underlying the paradoxical caspofungin activityin vivoin preclinical aspergillosis. We evaluated the activity of escalating doses of caspofunginin vivoin different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors. The therapeutic efficacy of caspofungin in experimental invasive aspergillosis was strictly dose dependent, being observed at doses of 0.1 and 1 mg/kg of body weight depending on the experimental models. Paradoxical increase in pulmonary fungal burden as well as inflammatory pathology was observed at the highest dose of caspofungin (5 mg/kg), occurred independently of the so-called Eagle effect and susceptibility to caspofunginin vitro, and was contingent upon the presence of TLR2, Dectin-1, and TLR9. Increased expression of Dectin-1 and TLR9 were observed upon exposure to caspofunginin vitroandin vivo. Together, these findings suggest that the net activity of caspofunginin vivois orchestrated by the activation, directly or indirectly, of multiple innate immune receptors.
Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects
Authors: Vourvahis Manoli , Davis John , Wang Rong , Layton Gary , Choo Heng Wee , Chong Chew-Lan , Tawadrous Margaret
Published: May 2012

Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile exhibiting potent antiviral activity against wild-type HIV and several clinically relevant NNRTI-resistant strains. Lersivirine, a weak inducer of the cytochrome P450 (CYP) enzyme CYP3A4, is metabolized by CYP3A4 and UDP glucuronosyltransferase 2B7 (UGT2B7). Two open, randomized, two-way (study 1; study A5271008) or three-way (study 2; study A5271043) crossover phase I studies were carried out under steady-state conditions in healthy subjects. Study 1 (n= 17) investigated the effect of oral rifampin on the pharmacokinetics (PKs) of lersivirine. Study 2 (n= 18) investigated the effect of oral rifabutin on the PKs of lersivirine and the effect of lersivirine on the PKs of rifabutin and its active metabolite, 25-O-desacetyl-rifabutin. Coadministration with rifampin decreased the profile of the lersivirine area under the plasma concentration-time curve from time zero to 24 h postdose (AUC24), maximum plasma concentration (Cmax), and plasma concentration observed at 24 h postdose (C24) by 85% (90% confidence interval [CI], 83, 87), 83% (90% CI, 79, 85), and 92% (90% CI, 89, 94), respectively, versus the values for lersivirine alone. Coadministration with rifabutin decreased the lersivirine AUC24,Cmax, andC24by 34% (90% CI, 29, 39), 25% (90% CI, 16, 33), and 58% (90% CI, 52, 64), respectively, compared with the values for lersivirine alone. Neither the rifabutin concentration profile nor overall exposure was affected following coadministration with lersivirine. Lersivirine and rifabutin reduced the 25-O-desacetyl-rifabutin AUC24by 27% (90% CI, 21, 32) andCmaxby 27% (90% CI, 19, 34). Lersivirine should not be coadministered with rifampin, which is a potent inducer of CYP3A4, UGT2B7, and P-glycoprotein activity and thus substantially lowers lersivirine exposure. No dose adjustment of rifabutin is necessary in the presence of lersivirine; an upward dose adjustment of lersivirine may be warranted when it is coadministered with rifabutin.
Efficacy of LFF571 in a Hamster Model of Clostridium difficile Infection
Authors: Trzasko Anna , Leeds Jennifer A. , Praestgaard Jens , LaMarche Matthew J. , McKenney David
Published: May 2012

LFF571 is a novel semisynthetic thiopeptide antibiotic with potent activity against a variety of Gram-positive pathogens, including
Clostridium difficile
.
In vivo
efficacy of LFF571 was compared to vancomycin in a hamster model of
C. difficile
infection (CDI). Infection was induced in Golden Syrian hamsters using a toxigenic strain of
C. difficile
. Treatment started 24 h postinfection and consisted of saline, vancomycin, or LFF571. Cox regression was used to analyze survival data from a cohort of animals evaluated across seven serial experimental groups treated with vancomycin at 20 mg/kg, LFF571 at 5 mg/kg, or vehicle alone. Survival was right censored; animals were not observed beyond day 21. At death or end of study, cecal contents were tested for
C. difficile
toxins A and B. In summary, the data showed that 5 mg/kg LFF571 decreased the risk of death by 79% (
P
< 0.0001) and 69% (
P
= 0.0022) compared with saline and 20 mg/kg vancomycin, respectively. Further analysis of the pooled data indicated that the survival benefit of LFF571 treatment at 5 mg/kg compared to vancomycin at 20 mg/kg was due primarily to a decrease in the risk of recurrence after end of treatment. Animals successfully treated with LFF571 or vancomycin had no detectable
C. difficile
toxin. Overall, LFF571 was more efficacious at the end of the study, at a lower dose, and with fewer recurrences, than vancomycin in the hamster model of CDI. LFF571 is being assessed in humans for safety and efficacy in the treatment of
C. difficile
infections.
High-Dose Daptomycin plus Fosfomycin Is Safe and Effective in Treating Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Endocarditis
Authors: Miró José M. , Entenza José M. , del Río Ana , Velasco Maria , Castañeda Ximena , Garcia de la Mària Cristina , Giddey Marlyse , Armero Yolanda , Pericàs Juan M. , Cervera Carlos , Mestres Carlos A. , Almela Manuel , Falces Carlos , Marco Francesc , Moreillon Philippe , Moreno Asuncion
Published: May 2012

We describe 3 patients with left-sided staphylococcal endocarditis (1 with methicillin-susceptible
Staphylococcus aureus
[MSSA] prosthetic aortic valve endocarditis and 2 with methicillin-resistant
S. aureus
[MRSA] native-valve endocarditis) who were successfully treated with high-dose intravenous daptomycin (10 mg/kg/day) plus fosfomycin (2 g every 6 h) for 6 weeks. This combination was tested
in vitro
against 7 MSSA, 5 MRSA, and 2 intermediately glycopeptide-resistant
S. aureus
isolates and proved to be synergistic against 11 (79%) strains and bactericidal against 8 (57%) strains. This combination deserves further clinical study.
Antibody Pressure by a Human Monoclonal Antibody Targeting the 2009 Pandemic H1N1 Virus Hemagglutinin Drives the Emergence of a Virus with Increased Virulence in Mice
Authors: O’Donnell Christopher D. , Vogel Leatrice , Wright Amber , Das Suman R. , Wrammert Jens , Li Gui-Mei , McCausland Megan , Zheng Nai-Ying , Yewdell Jonathan W. , Ahmed Rafi , Wilson Patrick C. , Subbarao Kanta
Published: May 2012

In 2009, a novel H1N1 influenza A virus (2009 pH1N1) emerged and caused a pandemic. A human monoclonal antibody (hMAb; EM4C04), highly specific for the 2009 pH1N1 virus hemagglutinin (HA), was isolated from a severely ill 2009 pH1N1 virus-infected patient. We postulated that under immune pressure with EM4C04, the 2009 pH1N1 virus would undergo antigenic drift and mutate at sites that would identify the antibody binding site. To do so, we infected MDCK cells in the presence of EM4C04 and generated 11 escape mutants, displaying 7 distinct amino acid substitutions in the HA. Six substitutions greatly reduced MAb binding (K123N, D131E, K133T, G134S, K157N, and G158E). Residues 131, 133, and 134 are contiguous with residues 157 and 158 in the globular domain structure and contribute to a novel pH1N1 antibody epitope. One mutation near the receptor binding site, S186P, increased the binding affinity of the HA to the receptor. 186P and 131E are present in the highly virulent 1918 virus HA and were recently identified as virulence determinants in a mouse-passaged pH1N1 virus. We found that pH1N1 escape variants expressing these substitutions enhanced replication and lethality in mice compared to wild-type 2009 pH1N1 virus. The increased virulence of these viruses was associated with an increased affinity for α2,3 sialic acid receptors. Our study demonstrates that antibody pressure by an hMAb targeting a novel epitope in the Sa region of 2009 pH1N1 HA is able to inadvertently drive the development of a more virulent virus with altered receptor binding properties. This broadens our understanding of antigenic drift.

IMPORTANCEInfluenza viruses accumulate amino acid substitutions to evade the antibody response in a process known as antigenic drift, making it necessary to vaccinate against influenza annually. Mapping human monoclonal antibody (hMAb) epitopes is a necessary step towards understanding antigenic drift in humans. We defined the specificity of an hMAb that specifically targeted the 2009 pH1N1 virus and describe a novel epitope. In addition, we identified a previously unappreciated potential for antibody escape to enhance the pathogenicity of a virus. The escape mutation that we identified within vitroimmune pressure was independently reported by other investigators usingin vivoselection in nonimmune mice. Althoughin vitrogeneration of escape mutants is unlikely to recapitulate antigenic drift in its entirety, the data demonstrate that pressure by a human monoclonal antibody targeting a novel epitope in the hemagglutinin of the 2009 pandemic H1N1 virus can inadvertently drive the development of escape mutants, of which a subset have increased virulence and altered receptor binding properties.
Secondary syphilis mimicking inflammatory bowel disease
Authors: Vasconcelos Pedro , Borges-Costa João , Loreto Helena , Marques Sacramento
Published: May 2012

This study reports the case of a 15-year-old male patient with extensive anal inflammation, cobblestone-like mucosa and areas of ulceration, loose bloody stool and weight loss for 8 weeks, suggestive of inflammatory bowel disease. Genital lesions of syphilides were later observed and Venereal Disease Research Laboratory test was positive, thus benzyl penicillin treatment was prescribed with total resolution of genital and bowel symptoms.
Heart rate variability parameters of myxomatous mitral valve disease in dogs with and without heart failure obtained using 24‐hour Holter electrocardiography
Authors: Oliveira M. S. , Muzzi R. A. L. , Araújo R. B. , Muzzi L. A. L. , Ferreira D. F. , Nogueira R. , Silva E. F.
Published: May 2012

Time‐domain heart rate variability (HRV) parameters and the correlation between echocardiography and Holter examinations in dogs with myxomatous mitral valve disease (MMVD) were determined. Holter examination was also performed at different time frames: an entire 24‐hour period, a four‐hour period during sleep, and a four‐hour period while awake. Ten healthy (control group) and 28 MMVD dogs, 15 with and 13 without heart failure, were evaluated. The SDANN (sd of the mean normal RR intervals for all five‐minute segments during 24‐hour Holter) and pNN 50 (percentage of differences between adjacent normal RR intervals that are >50 ms computed over 24‐hour Holter) variables were significantly lower in the dogs with MMVD heart failure. The differences in HRV between the groups were only detected during the 24‐hour evaluation period (P < 0.05). There were high correlations (canonical analysis) between Holter and echocardiography examinations when considering pNN 50 , SDANN, and LA/AO (left atrial to aortic root ratio) (r = 0.92; P < 0.05), indicating that both are important in evaluating MMVD dogs. SDANN and pNN 50 are measures of parasympathetic control of the heart, and thus, it is possible to infer that the MMVD dogs exhibit parasympathetic withdrawal during the development of heart failure.
Porcine circovirus type 2 infection before and during an outbreak of postweaning multisystemic wasting syndrome on a pig farm in the UK
Authors: Wieland B. , Werling D. , Nevel A. , Rycroft A. , Demmers T. G. , Wathes C. M. , Grierson S. , Cook A. J. C. , Done S. H. , Armstrong D.
Published: May 2012

The presence of porcine circovirus type 2 (PCV‐2) and other pathogens before and during an outbreak of postweaning multisystemic wasting syndrome (PWMS) in pigs is evaluated in this study. At the time of the outbreak on a large commercial pig farm in the UK, serum samples and data were collected in two independent on‐going research projects, one in weaned pigs and the other in sows. Serum samples of growing pigs and sows were PCV‐2‐antibody and PCR positive before and during the PMWS outbreak. Upon sequencing, PCV‐2 isolates collected before the outbreak were identified as PCV‐2a, and isolates collected during the outbreak were identified as PCV‐2b, suggesting a shift of PCV‐2 genotypes present on the farm. Pigs in the weaner study were from sows originating from different breeders and an association of sow origin and PCV‐2 serostatus in offspring was found. Further, pigs had higher odds to be PCV‐2 antigen positive if the sow was PCV‐2 antibody positive around farrowing, the sow was of higher parity, and were less likely to test antigen positive if the sow was sourced from a particular breeder. The findings of this study highlight the potential role of the immune status of the sow on the occurrence of PMWS.
Residual effects of Mycobacterium avium infection on susceptibility of sheep to copper toxicity and efficacy of treatment with tetrathiomolybdate
Authors: Suttle N. F.
Published: May 2012

Posthaemolytic copper poisoning (post‐HCP) in one of six, one‐year‐old, uninfected sheep (group O) on a Mycobacterium avium experiment prompted an evaluation of copper status and hepatotoxicity in 17 surviving cohorts. Group O had higher mean plasma Cu and δ‐glutamyl transferase (GGT) activity and more variable bile acid (BA) concentrations and glutamate dehydrogenase activities (GDH) than two groups infected with M avium soon after birth. Ammonium tetrathiomolybdate (TTM; 3 x 1.7 mg/kg LW) was given subcutaneously over seven days and the pelleted, complete diet replaced by hay, low in copper. Plasma BA immediately declined and was followed by GDH, but erythrocyte superoxide dismutase activity (ESOD) became severely inhibited and took 18 days to recover. Plasma BA and GDH rose sharply after 18 days in uninfected sheep and they became hypercupraemic. TTM treatment was repeated from day 42 and had removed all group differences by day 110 but only after further inhibition of ESOD. M avium infections probably lessened the severity of pre‐HCP by reducing copper retention but may predispose grazing livestock to hypocupraemia. The capacity of TTM to reduce liver Cu has probably been overestimated and side effects on cuproenzyme activity underestimated.
The landscape of fear: habitat use by a predator (Canis latrans) and its main prey (Lepus californicus and Sylvilagus audubonii)
Authors: Arias-Del Razo Itzel , Hernández Lucina , Laundré John W. , Velasco-Vázquez Lourdes
Published: May 2012

We evaluated the degree of mutual exclusivity of distributions of coyotes ( Canis latrans Say, 1823) and their main prey (two lagomorph species: the black-tailed jackrabbit, Lepus californicus Gray, 1837, and the desert cottontail rabbit, Sylvilagus audubonii (Baird, 1858)) within the landscape by testing two models. The first assumes that prey seek high resource patches and, subsequently, predators seek prey within these patches, and predicts a high degree of overlap in patch use by both. The second model assumes that predator and prey balance not only food resources but reciprocal levels of predation risk and predation success in making decisions on whether or not to use a patch. This model predicts discordance in patch use between predator and prey. We used a combination of GPS-telemetry and camera-trapping data to assess habitat use patterns of predator and prey. Results from this study support the second model regarding spatial use of the landscape by a predator and its prey. Where the use of the landscape by predators and prey seem to be mediated by environmental constraints, both will adjust their predatory or antipredatory strategies based on these constraints. This results in a partial spatial separation of predator and prey across the landscape, providing patches of relative safety for prey but sufficient areas of overlap for predators to be successful.
An experimental study of how variation in deer density affects vegetation and songbird assemblages of recently harvested boreal forests
Authors: Cardinal Etienne , Martin Jean-Louis , Tremblay Jean-Pierre , Côté Steeve D.
Published: May 2012

Intense browsing by abundant large herbivores can threaten the ecological integrity of ecosystems by inducing modifications in the structure and composition of vegetation that trigger trophic cascades affecting plant and animal communities. We investigated the relationships between density of white-tailed deer ( Odocoileus virginianus (Zimmermann, 1780)), forest succession after clear-cut, and songbird communities on Anticosti Island, Quebec, Canada. We hypothesized that lower deer densities would alter the trajectory of forest succession after clear-cutting and lead to a rapid recovery of habitat attributes favorable to songbirds associated with a dense complex shrub layer. Six years after establishing a controlled browsing experiment (0, 7.5, 15, and >27 deer·km–2) in recent clearcuts, reducing deer densities ≤7.5 deer·km–2initiated the restoration of balsam fir ( Abies balsamea (L.) Mill.) forests and increased the regeneration of paper birch ( Betula papyrifera Marshall). Increasing birch ground cover from 10% to 20% increased songbird total abundance, species richness, and diversity by 17%, 39%, and 31%, respectively. Alder Flycatcher (Empidonax alnorum Brewster, 1895) was only present at ≤7.5 deer·km–2and strongly associated with birch regeneration. The regeneration of browse-resistant plants such as white spruce ( Picea glauca (Moench) Voss) in some areas at high deer density favored the maintenance of many shrub-dependent songbirds but also species usually associated with forest canopy. Active management of deer populations in Canadian harvested boreal forests will mitigate losses in vegetation and songbirds caused by over-browsing.
Variation in reproductive success of male and female Columbian ground squirrels (Urocitellus columbianus)
Authors: Jones Philip H. , Van Zant Jeffrey L. , Dobson F. Stephen
Published: May 2012

The imbalanced reproductive success of polygynous mammals results in sexual selection on male traits like body size. Males and females might have more balanced reproductive success under polygynandry, where both sexes mate multiply. Using 4 years of microsatellite DNA analyses of paternity and known maternity, we investigated variation in reproductive success of Columbian ground squirrels, Urocitellus columbianus (Ord, 1815); a species with multiple mating by both sexes and multiple paternity of litters. We asked whether male reproductive success was more variable than that of females under this mating system. The overall percentage of confirmed paternity was 61.4% of 339 offspring. The mean rate of multiple paternity in litters with known fathers was 72.4% (n = 29 litters). Estimated mean reproductive success of males (10.27 offspring) was about thrice that of females (3.11 offspring). Even after this difference was taken into account statistically, males were about three times as variable in reproductive success as females (coefficients of variation = 77.84% and 26.74%, respectively). The Bateman gradient (regression slope of offspring production on number of successful mates) was significantly greater for males (βM = 1.44) than females (βF = 0.28). Thus, under a polygynandrous mating system, males exhibited greater variation in reproductive success than females.
Growth and maturity of a terrestrial ectotherm near its northern distributional limit: does latitude matter?
Authors: Tuttle Krysia N. , Gregory Patrick T.
Published: May 2012

High-latitude environments are challenging for terrestrial ectotherms because short and cool active seasons generally limit the time available for foraging and growth, thereby negatively influencing life-history variables such as growth rate and age at maturity and ultimately, via fitness differences, their evolution. Many species show latitudinal clines in life-history traits, including growth rate and body size. We estimated growth curves of Plains Garter Snakes ( Thamnophis radix (Baird and Girard, 1853)) near the northern limit of the species’ range in central Alberta and compared our findings to similar estimates for more southerly populations. Despite a short growing season, female T. radix at Miquelon Lake grew rapidly, reaching maturity in 1 or 2 years, similar to southern populations, and attained greater maximum sizes than snakes in southern populations. Overall, growth in this high-latitude population is comparable with what is seen in other conspecific populations. Possible reasons for lack of marked latitudinal effect include longer days at high latitudes, highly productive aquatic habitats for foraging, effective thermoregulation, reduced competition, and (or) countergradient variation in growth rate.
THE EFFECTIVE POTENTIAL AND TRANSSHIPMENT IN THERMODYNAMIC FORMALISM AT ZERO TEMPERATURE
Authors: GARIBALDI EDUARDO , LOPES ARTUR O.
Published: May 2012

For a topologically transitive subshift of finite type defined by a symmetric transition matrix, we introduce a temperature-based problem related to the usual thermodynamic formalism. This problem is described by an operator acting on Hölder continuous observables which is actually superlinear with respect to the max-plus algebra. We thus show that, for each fixed absolute temperature, such an operator admits a unique eigenfunction and a unique eigenvalue. We also study the convergence as the temperature goes to zero and we relate the limit objects to an ergodic version of Kantorovich transshipment problem.
INTERACTING TIME-FRACTIONAL AND Δν PDES SYSTEMS VIA BROWNIAN-TIME AND INVERSE-STABLE-LÉVY-TIME BROWNIAN SHEETS
Authors: ALLOUBA HASSAN , NANE ERKAN
Published: May 2012

Lately, many phenomena in both applied and abstract mathematics and related disciplines have been expressed in terms of high order and fractional PDEs. Recently, Allouba introduced the Brownian-time Brownian sheet (BTBS) and connected it to a new system of fourth order interacting PDEs. The interaction in this multiparameter BTBS-PDEs connection is novel, leads to an intimately-connected linear system variant of the celebrated Kuramoto–Sivashinsky PDE, and is not shared with its one-time-parameter counterpart. It also means that these PDEs systems are to be solved for a family of functions, a feature exhibited in well known fluids dynamics models. On the other hand, the memory-preserving interaction between the PDE solution and the initial data is common to both the single- and the multi-parameter Brownian-time PDEs. Here, we introduce a new — even in the one-parameter case — proof that combines stochastic analysis with analysis and fractional calculus to simultaneously link BTBS to a new system of temporally half-derivative interacting PDEs as well as to the fourth-order system proved earlier and differently by Allouba. We then introduce a general class of random fields we call inverse-stable-Lévy-time Brownian sheets (ISLTBSs), and we link them to β-fractional-time-derivative systems of interacting PDEs for 0 < β < 1. When β = 1/ν, ν ∈ {2, 3, …}, our proof also connects an ISLTBS to a system of memory-preserving ν-Laplacian interacting PDEs. Memory is expressed via a sum of temporally-scaled k-Laplacians of the initial data, k = 1, …, ν - 1. Using a Fourier–Laplace-transform-fractional-calculus approach, we give a conditional equivalence result that gives a necessary and sufficient condition for the equivalence between the fractional and the high order systems. In the one-parameter case this condition automatically holds.
INCREASE OF SHARPNESS OF DIFFUSION-JUNCTION HETERORECTIFIER BY USING RADIATION PROCESSING
Authors: PANKRATOV E. L. , BULAEVA E. A.
Published: May 2012

Recently it has been elaborated an approach to decrease depth of diffusive- and implanted-junction rectifiers by manufacturing the rectifiers in a semiconductor heterostructure and optimization of annealing of dopant and radiation defects. At the same time with decreasing of depth of the p-n-junction homogeneity of dopant distribution in doped area increases. In this paper we analyzed possibility to increase both the effects at one time by radiation processing of materials of the heterostructure.
VISIBLE LIGHT ACTIVECu2+/TiO2NANOCATALYST FOR DEGRADATION OF DICHLORVOS
Authors: SEGNE TESHOME ABDO , TIRUKKOVALLURI SIVA RAO , CHALLAPALLI SUBRAHMANYAM
Published: May 2012

The advantage of doping of TiO2with copper has been utilized for enhanced degradation of pesticide under visible light irradiation. The sol–gel method has been undertaken for the synthesis of copper-doped TiO2by varying the dopant loadings from 0.25 wt.% to 1.0 wt.% of Cu2+. The doped samples were characterized by UV-Visible Diffuse Reflectance Spectroscopy (DRS), N2adsorption–desorption (BET), X-ray Diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), Scanning Electron Microscopy (SEM), and Energy Dispersive Spectrometry (EDS). The photocatalytic activity of the catalyst was tested by degradation of dichlorvos under visible light illumination. The results found that 0.75 wt.% of Cu2+doped nanocatalysts have better photo catalytic activity than the rest of percentages doped, undoped TiO2and Degussa P25. The reduction of band gap was estimated and the influence of the process parameters on photo catalytic activity of the catalyst has been explained.
QUANTUM QUERY COMPLEXITY OF CONSTANT-SIZED SUBGRAPH CONTAINMENT
Authors: ZHU YECHAO
Published: May 2012

We study the quantum query complexity of constant-sized subgraph containment. Such problems include determining whether a n-vertex graph contains a triangle, clique or star of some size. For a general subgraph H with k vertices, we show that H containment can be solved with quantum query complexity [Formula: see text], with g(H) a strictly positive function of H. This is better than Õ(n2-2/k) by Magniez et al. This result is obtained in the learning graph model of Belovs.
THE PING-PONG PROTOCOL WITH A PRIOR PRIVACY AMPLIFICATION
Authors: ZAWADZKI PIOTR
Published: May 2012

A modified version of the well known ping-pong protocol is proposed and analyzed in the paper. The operation of the improved version exploits inevitable errors introduced by the eavesdropping in the message mode — a feature which has not been exploited so far. A proposed protocol improvement is in its role similar to the privacy amplification known from the quantum key distribution schemes, but no randomization of transferred information is introduced and deterministic character of communication is preserved. Messages are processed in blocks which guarantees that an eavesdropper is faced with a computationally infeasible problem as long as the system parameters are within reasonable limits. Information processing does not require quantum memory registers and confidential communication is possible without prior key agreement or some shared secret.
TOMOGRAPHIC QUANTUM CRYPTOGRAPHY PROTOCOLS ARE REFERENCE FRAME INDEPENDENT
Authors: THINH LE PHUC , SHERIDAN LANA , SCARANI VALERIO
Published: May 2012

We consider the class of reference frame independent protocols in d dimensions for quantum key distribution, in which Alice and Bob have one natural basis that is aligned and the rest of their measurement bases are unaligned. We relate existing approaches to tomographically complete protocols. We comment on two different approaches to finite key bounds in this setting, one direct and one using the entropic uncertainty relation and suggest that the existing finite key bounds can still be improved.
Deficient leukemia inhibitory factor signaling in muscle precursor cells from patients with type 2 diabetes
Authors: Broholm Christa , Brandt Claus , Schultz Ninna S. , Nielsen Anders R. , Pedersen Bente K. , Scheele Camilla
Published: May 2012

The cytokine leukemia-inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of muscle precursor cells, an important feature of skeletal muscle maintenance and repair. We hypothesized that muscle precursor cells from patients with type 2 diabetes had a deficient response to LIF. The mRNA and protein expressions of LIF and its receptor (LIFR) were measured in skeletal muscle biopsies from healthy individuals and patients with type 2 diabetes by use of qPCR and Western blot. LIF signaling and response were studied following administration of recombinant LIF and siRNA knockdown of suppressor of cytokine signaling (SOCS)3 in myoblast cultures established from healthy individuals and patients with type 2 diabetes. Myoblast proliferation rate was assessed by bromodeoxyuridine incorporation. LIF and LIFR proteins were increased in both muscle tissue and cultured myoblasts from diabetic patients. Nonetheless, in the diabetic myoblasts, LIF-induced phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 was impaired. The deficient response to LIF administration in the diabetic myoblasts was further emphasized by a lack of increase in LIF-stimulated cell proliferation and a decreased LIF-stimulated induction of the proliferation-promoting factors cyclin D1, JunB, and c-myc. SOCS3 protein was upregulated in diabetic myoblasts, and knockdown of SOCS3 rescued LIF-induced gene expression in diabetic myoblasts, whereas neither STAT1 or STAT3 signaling nor proliferation rate was affected. In conclusion, although LIF and LIFR proteins were increased in muscle tissue and myoblasts from diabetic patients, LIF signaling and LIF-stimulated cell proliferation were impaired in diabetic myoblasts, suggesting a novel mechanism by which muscle function is compromised in diabetes.
Tumor-Associated Macrophages in Pediatric Classical Hodgkin Lymphoma: Association with Epstein-Barr Virus, Lymphocyte Subsets, and Prognostic Impact
Authors: Barros Mário Henrique M. , Hassan Rocio , Niedobitek Gerald
Published: May 2012

Purpose: Tumor-infiltrating macrophages are associated with adverse outcome in adult classical Hodgkin lymphoma (cHL). We have previously shown age-related changes in the lymphocyte composition of pediatric cHL. We therefore hypothesized that the number, function, and prognostic impact of macrophages in pediatric cHL would be different from adult cases.

Experimental Design: We analyzed the number of macrophages and dendritic cells (DC) in the tumor microenvironment of pediatric cHL by immunohistochemistry. Results were analyzed in context of age, histologic characteristics, Epstein-Barr virus (EBV) status, clinical follow-up, and our previous study of T-cell populations in these cases.

Results: One hundred cHL cases were studied, including 69% nodular sclerosis and 23% mixed cellularity cases. A total of 44.8% of cases were EBV-positive. Patients ≤10 years displayed more CD14+ cells (P = 0.025). In comparison with nodular sclerosis, mixed cellularity was characterized by higher numbers of CD14+, (P = 0.003) and CD163+ cells (P = 0.027). EBV+ cases exhibited higher numbers of CD14+ (P < 0.0005), CD68+ (P = 0.005), and CD163+ cells (P = 0.02). CD68-positive cells did not display an effect on outcome. Worse overall survival was observed in cases with CD163/CD8 ratio ≥2 (P = 0.007). High numbers of CD163+ cells were associated with worse progression-free survival (PFS; P = 0.015). Furthermore, high numbers of CD163+ and granzyme B+ cells were associated with worse PFS in EBV-negative (P = 0.005) but not in EBV-positive cases.

Conclusion: Our results suggest that macrophage composition in pediatric cHL is distinct from adults. Functional status of macrophages and their value as prognostic indicators in pediatric cHL may depend on EBV status. Clin Cancer Res; 18(14); 3762–71. ©2012 AACR.
A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y
12
Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention
Authors: Welsh Robert C. , Rao Sunil V. , Zeymer Uwe , Thompson Vivian P. , Huber Kurt , Kochman Janusz , McClure Matthew W. , Gretler Daniel D. , Bhatt Deepak L. , Gibson C. Michael , Angiolillo Dominick J. , Gurbel Paul A. , Berdan Lisa G. , Paynter Gayle , Leonardi Sergio , Madan Mina , French William J. , Harrington Robert A.
Published: May 2012

Background—

We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y
12
inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention.

Methods and Results—

In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure.

Conclusions—

In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00751231.
Comparison of Hyperemic Efficacy Between Central and Peripheral Venous Adenosine Infusion for Fractional Flow Reserve Measurement
Authors: Seo Myung-Ki , Koo Bon-Kwon , Kim Ji-Hyun , Shin Dong-Ho , Yang Han-Mo , Park Kyung-Woo , Lee Hae-Young , Kang Hyun-Jae , Kim Hyo-Soo , Oh Byung-Hee , Park Young-Bae
Published: May 2012

Background—

Maximal hyperemia is a prerequisite for the accurate measurement of fractional flow reserve (FFR). Although continuous infusion of adenosine via the femoral vein is considered to be the gold standard, this requires an additional invasive procedure for femoral vein access and is difficult to use during transradial coronary catheterization. We performed this prospective study to evaluate the feasibility and efficacy of peripheral intravenous infusion of adenosine for FFR measurement.

Methods and Results—

Seventy-one patients were prospectively enrolled, and FFR was measured using a 0.014-inch coronary pressure wire. Hyperemic efficacy of adenosine was compared among intracoronary bolus injection and continuous IV infusion (140 μg/min/kg) via the femoral and via the forearm vein. In 20 patients, hyperemic mean transit time and index of microcirculatory resistance were also measured. Mean FFR after bolus administration of adenosine was 0.81±0.10. As compared with femoral vein infusion (FFR: 0.80±0.10), hyperemic efficacy of forearm vein infusion of adenosine (FFR: 0.80±0.11) was not inferior (
P
for noninferiority=0.01). The number of functionally significant stenoses (FFR <0.75) was also not different between the 2 methods (femoral vein versus forearm vein; 17 (25.0%) versus 17 (25.0%),
P
=1.0). Both hyperemic mean transit time and index of microcirculatory resistance were not different between the 2 routes of adenosine infusion. Additional bolus injection of adenosine during IV infusion did not improve the hyperemic efficacy but increased the risk of atrioventricular block.

Conclusions—

This study suggests that continuous intravenous infusion of adenosine via the forearm vein is a convenient and effective way to induce steady-state hyperemia for invasive physiological measurements.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01070420.
Epistatic Rescue of Nkx2.5 Adult Cardiac Conduction Disease Phenotypes by Prospero-Related Homeobox Protein 1 and HDAC3
Authors: Risebro Catherine A. , Petchey Louisa K. , Smart Nicola , Gomes John , Clark James , Vieira Joaquim M. , Yanni Joseph , Dobrzynski Halina , Davidson Sean , Zuberi Zia , Tinker Andrew , Shui Bo , Tallini Yvonne I. , Kotlikoff Michael I. , Miquerol Lucile , Schwartz Robert J. , Riley Paul R.
Published: May 2012

Rationale:

Nkx2.5 is one of the most widely studied cardiac-specific transcription factors, conserved from flies to man, with multiple essential roles in both the developing and adult heart. Specific dominant mutations in
NKX2.5
have been identified in adult congenital heart disease patients presenting with conduction system anomalies and recent genome-wide association studies implicate the
NKX2.5
locus, as causative for lethal arrhythmias (“sudden cardiac death”) that occur at a frequency in the population of 1 in 1000 per annum worldwide. Haploinsufficiency for Nkx2.5 in the mouse phenocopies human conduction disease pathology yet the phenotypes, described in both mouse and man, are highly pleiotropic, implicit of unknown modifiers and/or factors acting in epistasis with Nkx2.5/NKX2.5.

Objective:

To identify bone fide upstream genetic modifier(s) of Nkx2.5/NKX2.5 function and to determine epistatic effects relevant to the manifestation of
NKX2.5
-dependent adult congenital heart disease.

Methods and Results:

A study of cardiac function in prospero-related homeobox protein 1 (Prox1) heterozygous mice, using pressure-volume loop and micromannometry, revealed rescue of hemodynamic parameters in
Nkx2.5
Cre/+
;
Prox1
loxP/+
animals versus
Nkx2.5
Cre/+
controls. Anatomic studies, on a
Cx40
EGFP
background, revealed Cre-mediated knock-down of Prox1 restored the anatomy of the atrioventricular node and His-Purkinje network both of which were severely hypoplastic in
Nkx2.5
Cre/+
littermates. Steady state surface electrocardiography recordings and high-speed multiphoton imaging, to assess Ca
2+
handling, revealed atrioventricular conduction and excitation-contraction were also normalized by Prox1 haploinsufficiency, as was expression of conduction genes thought to act downstream of Nkx2.5. Chromatin immunoprecipitation on adult hearts, in combination with both gain and loss-of-function reporter assays in vitro, revealed that Prox1 recruits the corepressor HDAC3 to directly repress
Nkx2.5
via a proximal upstream enhancer as a mechanism for regulating Nkx2.5 function in adult cardiac conduction.

Conclusions:

Here we identify Prox1 as a direct upstream modifier of Nkx2.5 in the maintenance of the adult conduction system and rescue of Nkx2.5 conduction disease phenotypes. This study is the first example of rescue of Nkx2.5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease.
Impaired Skeletal Muscle Blood Flow Control With Advancing Age in Humans
Authors: Kirby Brett S. , Crecelius Anne R. , Voyles Wyatt F. , Dinenno Frank A.
Published: May 2012

Rationale:

Skeletal muscle blood flow is coupled with the oxygenation state of hemoglobin in young adults, whereby the erythrocyte functions as an oxygen sensor and releases ATP during deoxygenation to evoke vasodilation. Whether this function is impaired in humans of advanced age is unknown.

Objective:

To test the hypothesis that older adults demonstrate impaired muscle blood flow and lower intravascular ATP during conditions of erythrocyte deoxygenation.

Methods and Results:

We showed impaired forearm blood flow responses during 2 conditions of erythrocyte deoxygenation (systemic hypoxia and graded handgrip exercise) with age, which was caused by reduced local vasodilation. In young adults, both hypoxia and exercise significantly increased venous [ATP] and ATP effluent (forearm blood flow×[ATP]) draining the skeletal muscle. In contrast, hypoxia and exercise did not increase venous [ATP] in older adults, and both venous [ATP] and ATP effluent were substantially reduced compared with young people despite similar levels of deoxygenation. Next, we demonstrated that this could not be explained by augmented extracellular ATP hydrolysis in whole blood with age. Finally, we found that deoxygenation-mediated ATP release from isolated erythrocytes was essentially nonexistent in older adults.

Conclusions:

Skeletal muscle blood flow during conditions of erythrocyte deoxygenation was markedly reduced in aging humans, and reductions in plasma ATP and erythrocyte-mediated ATP release may be a novel mechanism underlying impaired vasodilation and oxygen delivery during hypoxemia with advancing age. Because aging is associated with elevated risk for ischemic cardiovascular disease and exercise intolerance, interventions that target erythrocyte-mediated ATP release may offer therapeutic potential.
Sustained Ventricular Tachycardia and Ventricular Fibrillation Complicating Non–ST-Segment–Elevation Acute Coronary Syndromes
Authors: Piccini Jonathan P. , White Jennifer A. , Mehta Rajendra H. , Lokhnygina Yuliya , Al-Khatib Sana M. , Tricoci Pierluigi , Pollack Charles V. , Montalescot Gilles , Van de Werf Frans , Gibson C. Michael , Giugliano Robert P. , Califf Robert M. , Harrington Robert A. , Newby L. Kristin
Published: May 2012

Background—

Ventricular arrhythmias remain a lethal complication of acute coronary syndromes (ACS). However, the incidence and prognosis of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) in contemporary non–ST-segment–elevation (NSTE) ACS populations are not well described.

Methods and Results—

We examined the incidence of VT/VF and subsequent survival among 9211 patients enrolled in the Early Glycoprotein IIb/IIIa Inhibition in NSTE ACS (EARLY ACS) trial. The cumulative incidence of VT/VF was 1.5% (n=141); 0.6% (n=55) had VT/VF ≤48 hours after enrollment, and 0.9% (n=86) had VT/VF >48 hours after enrollment. Patients with VT/VF more frequently had prior heart failure, an ejection fraction <30%, and triple-vessel coronary artery disease. Predictors of sustained VT/VF were similar regardless of the timing of VT/VF (≤48 versus >48 hours). Patients with VT/VF ≤48 hours after enrollment had higher 30-day mortality than those who did not have VT/VF ≤48 hours (13.0% versus 2.2%; adjusted odds ratio, 6.73; 95% confidence interval, 2.68–16.9). The increased risk of death associated with VT/VF ≤48 hours persisted at 1 year. The risk of mortality, relative to patients without VT/VF, was greater for patients with VT/VF >48 hours (hazard ratio, 20.70; 95% confidence interval, 15.39–27.85) than for those with earlier VT/VF (hazard ratio, 7.45; 95% confidence interval, 4.60–12.08;
P
=0.0003). The frequency of arrhythmic death was higher in patients with VT/VF than in those without VT/VF (26.4% versus 6.9%).

Conclusions—

Sustained VT/VF is infrequent after NSTE ACS but is as likely to occur after 48 hours as within the first 48 hours. The marked increase in all-cause death among NSTE ACS patients with both early and late sustained VT/VF raises important considerations for aggressive monitoring beyond 48 hours and interventions to prevent arrhythmic death in these patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00089895.
Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse
Authors: Tikellis Chris , Pickering Raelene J. , Tsorotes Despina , Huet Olivier , Chin-Dusting Jaye , Cooper Mark E. , Thomas Merlin C.
Published: May 2012

Dietary salt intake is a major determinant of the activation state of renin-angiotensin-aldosterone system. Given the important role of the renin-angiotensin-aldosterone system in plaque accumulation, we investigated its role in the development of atherogenesis associated with sodium intake in
apolipoprotein E
knockout mice. Six-weeks of a low-salt diet (containing 0.03% sodium) resulted in a 4-fold increase in plaque accumulation in
apolipoprotein E
knockout mice when compared with mice receiving normal chow (containing 0.30% sodium). This was associated with activation of the renin-angiotensin-aldosterone system, increased vascular expression of adhesion molecules and inflammatory cytokines, and increased adhesion of labeled leukocytes across the whole aorta on a dynamic flow assay. These changes were blocked with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg per day). A high-salt diet (containing 3% sodium) attenuated vascular inflammation and atherogenesis, associated with suppression of the renin-angiotensin-aldosterone system, although systolic blood pressure levels were modestly increased (5±1 mmHg). Constitutive activation of the renin-angiotensin-aldosterone system in
angiotensin-converting enzyme 2 apolipoprotein E
knockout mice was also associated with increased atherosclerosis and vascular adhesion, and this was attenuated by a high-salt diet associated with suppression of the renin-angiotensin-aldosterone system. By contrast, a low-salt diet failed to further activate the renin-angiotensin-aldosterone system or to increase atherosclerosis in
angiotensin-converting enzyme 2 apolipoprotein E
knockout mice. Together, these data validate a relationship between salt-mediated renin-angiotensin-aldosterone system activation and atherogenesis, which may partly explain the inconclusive or paradoxical findings of recent observational studies, despite clear effects on blood pressure.