bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca2+entry depends on intracellular Ca2+stores
Authors: Zhang Y. , Fraser J. A. , Schwiening C. , Zhang Y. , Killeen M. J. , Grace A. A. , Huang C. L.‐H. 
Published: November 2009

AbstractAim: To investigate the effect of increases in extracellular Ca2+entry produced by the L‐type Ca2+channel agonist FPL‐64176 (FPL) uponacuteatrial arrhythmogenesis in intact Langendorff‐perfused mouse hearts and its dependence upon diastolic Ca2+release from sarcoplasmic reticular Ca2+stores.Methods: Confocal microscope studies of Fluo‐3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff‐perfused mouse hearts.Results: Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre‐treatments respectively produced immediate and gradual reductions in theF/F0peaks. Such nifedipine and caffeine, or CPA pre‐treatments, abolished, or reduced, the effects of 0.1 and 1.0 μmFPL on cytosolic Ca2+signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff‐perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA.Conclusion: Enhanced extracellular Ca2+entry exertsacuteatrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+release. These findings complement reports that associate established,chronic, atrial arrhythmogenesis withdecreasedoverall inward Ca2+current.
IS NORMALISING HAEMOGLOBIN IN PATIENTS WITH CKD HARMFUL AND IF SO, WHY?
Authors: Littlewood T. J. 
Published: November 2009

SUMMARYSymptomatic anaemia is found in patients with chronic kidney disease. Correction of anaemia by erythropoiesis stimulating agents improves quality of life and life expectancy. Data from patients with both dialysis dependent and nondialysis dependent chronic kidney disease now show that the mortality from cardiovascular disease increases if the haemoglobin concentration is corrected above 13.0g/dl. The mechanism for this increased risk is uncertain.
GOING UPSTREAM: THE IMPLICATION AND OPPORTUNITIES OF EARLY DETECTION
Authors: O’Donoghue Donal J 
Published: November 2009

SUMMARYChronic kidney disease (CKD) is common, harmful and treatable but has, until recently not been recognised in its early stages. The British National Health Service (NHS) provides a unique opportunity to study CKD because it is in effect a closed‐managed care system. This single healthcare system for the United Kingdom is funded by the Government and paid for by general taxation. All UK citizens are registered with primary care physicians who control access to secondary care services. As a managed care system it should be able to offer integrated care across the whole patient pathway—allowing early identification of CKD, interventions to reduce risk and prompt management of complications. In reality, there are professional, organisational and institutional barriers to coordination and delivery of care in the NHS. The establishment of general‐practice‐based disease registers linked to a quality and outcomes framework in 2004 provides a basis for implementing the chronic disease model of care. The publication of the National Service Framework for renal services complemented by these changes in primary care has resulted in a paradigm shift from kidney disease being viewed as a secondary care condition to being a primary care priority as part of vascular control and management.In the first two years of the initiative, over 40% of the expected CKD stage 3 to 5 population has been registered in primary care. Kidney disease is now recognised as a public health problem in the United Kingdom, preventative strategies are being integrated into comprehensive vascular risk assessments and management programmes and kidney disease has become an NHS priority area.
In Vivo Activity of Ceftobiprole in Murine Skin Infections Due toStaphylococcus aureusandPseudomonas aeruginosa
Authors: Fernandez Jeffrey , Hilliard Jamese J. , Abbanat Darren , Zhang Wenyan , Melton John L. , Santoro Colleen M. , Flamm Robert K. , Bush Karen 
Published: November 2009

ABSTRACTCeftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistantStaphylococcus aureus(MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model withStaphylococcus aureusSmith OC 4172 (methicillin-susceptibleS. aureus[MSSA]),S. aureusOC 8525 (MRSA),Pseudomonas aeruginosaOC 4351 (having an inducible AmpC β-lactamase), andP. aeruginosaOC 4354 (overproducing AmpC β-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P< 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P< 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P< 0.001). AgainstP. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P< 0.001) against the inducible and overproducing AmpC β-lactamase strains ofP. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P< 0.01) in reducing the size of the lesion caused by either strain ofP. aeruginosain this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, andP. aeruginosain this murine model of skin and soft tissue infection.
Molecular Epidemiology of Metallo-β-Lactamase-Producing
Pseudomonas aeruginosa
Isolates from Norway and Sweden Shows Import of International Clones and Local Clonal Expansion
Authors: Samuelsen Ørjan , Toleman Mark A. , Sundsfjord Arnfinn , Rydberg Johan , Leegaard Truls M. , Walder Mats , Lia Astrid , Ranheim Trond E. , Rajendra Yashas , Hermansen Nils O. , Walsh Timothy R. , Giske Christian G. 
Published: November 2009

ABSTRACT

Scandinavia is considered a region with a low prevalence of antimicrobial resistance. However, the number of multidrug-resistant (MDR) Gram-negative bacteria is increasing, including metallo-β-lactamase (MBL)-producing
Pseudomonas aeruginosa
. In this study MBL-producing
P. aeruginosa
isolates identified in Norway (
n
= 4) and Sweden (
n
= 9) from 1999 to 2007 were characterized. Two international clonal complexes (CC), CC111 (
n
= 8) and CC235 (
n
= 2), previously associated with MBL-producing isolates, were dominant. CC111 isolates (ST111/229; serotype O12;
bla
VIM-2
) included clonally related isolates identified in Skåne County, Sweden (
n
= 6), and two isolates associated with importation from Greece and Denmark. In all CC111 isolates,
bla
VIM-2
was located in integron In
59.2
or In
59
variants. The two CC235 isolates (ST235/ST230; serotype O11;
bla
VIM-4
) were imported from Greece and Cyprus, were possibly clonally related, and carried
bla
VIM-4
in two different integron structures. Three isolates imported from Ghana (ST233; serotype O6;
bla
VIM-2
), Tunisia (ST654; serotype O11;
bla
VIM-2
), and Thailand (ST260; serotype O6;
bla
IMP-14
) were clonally unrelated. ST233 was part of a new CC (CC233) that included other MBL-producing isolates, while ST654 could also be part of a new CC associated with MBL producers. In the isolates imported from Ghana and Tunisia,
bla
VIM-2
was part of unusual integron structures lacking the 3′ conserved segment and associated with transposons. The
bla
VIM
gene was found to be located on the chromosome in all isolates. Known risk factors for acquisition of MBL were reported for all patients except one. The findings suggest that both import of successful international clones and local clonal expansion contribute to the emergence of MBL-producing
P. aeruginosa
in Scandinavia.
Unusual Class 1 Integron Configuration Found in
S
almonella
Genomic Island 2 from
Salmonella enterica
Serovar Emek
Authors: Wilson Neil L. , Hall Ruth M. 
Published: November 2009

ABSTRACT

Salmonella
genomic island 2 (SGI2) is an independently derived genomic island related to SGI1 with the integron in a different position. The integron in SGI2 was found to include an additional 2.1 kb derived from the
tni
module of Tn
5058
, Tn
502
, or Tn
512
that was not detected previously. Independent evolution of the backbone was confirmed with 21 single base differences found in over 11.5 kb, representing 40% of the 27.4-kb SGI2 backbone.
First Report of Extended-Spectrum-β-Lactamase-Producing
Salmonella enterica
Serovar Kentucky Isolated from Poultry in Ireland
Authors: Boyle F. , Morris D. , O'Connor J. , DeLappe N. , Ward J. , Cormican M. 
Published: November 2009

ABSTRACT

Therapy of invasive human salmonellosis is complicated by increasing antimicrobial resistance. Food animals are the principal source of infection with nontyphoid
Salmonella
. We report the emergence of broad-spectrum-cephalosporin resistance in
S
almonella enterica
serovar Kentucky in poultry in Ireland.
Effect of Antifungal Therapy Timing on Mortality in Cancer Patients with Candidemia
Authors: Taur Ying , Cohen Nina , Dubnow Sarah , Paskovaty Alla , Seo Susan K. 
Published: November 2009

ABSTRACT

Prior studies have shown that delays in treatment are associated with increased mortality in patients with candidemia. The purpose of this study was to measure three separate time periods comprising the diagnosis and treatment of candidemia and to determine which one(s) is associated with hospital mortality. Patients with blood cultures positive for
Candida
spp. were identified. Subjects were excluded if no antifungal therapy was given or if there was preexisting antifungal therapy. Collected data included the time from blood culture collection to positivity (incubation period), the time from blood culture positivity to provider notification (provider notification period), and the time from provider notification to the first dose of antifungal given (antifungal initiation period). These times were assessed as predictors of inpatient mortality. A repeat analysis was done with adjustments for age, sex, race, underlying cancer, catheter removal, APACHE III score, acute renal failure, neutropenia, and non-
Candida albicans
species. A total of 106 episodes of candidemia were analyzed. The median incubation time was 32.1 h and was associated with mortality (univariate hazard ratio per hour, 1.025;
P
= 0.001). The median provider notification and antifungal initiation periods were 0.3 and 7.5 h, respectively, and were not associated with mortality. Adjusted analysis yielded similar results. For cancer patients with candidemia, the incubation period accounts for a significant amount of time, compared with the provider notification and antifungal initiation times, and is associated with in-hospital mortality. Strategies to shorten the incubation time, such as utilizing rapid molecularly based diagnostic methods, may help reduce in-hospital mortality.
Hydrolysis and Inhibition Profiles of β-Lactamases from Molecular Classes A to D with Doripenem, Imipenem, and Meropenem
Authors: Queenan Anne Marie , Shang Wenchi , Flamm Robert , Bush Karen 
Published: November 2009

ABSTRACT
The stability of doripenem to hydrolysis by β-lactamases from molecular classes A to D was compared to the stability for imipenem and meropenem. Doripenem was stable to hydrolysis by extended-spectrum β-lactamases and AmpC type β-lactamases and demonstrated high affinity for the AmpC enzymes. For the serine carbapenemases SME-3 and KPC-2 and metallo-β-lactamases IMP-1 and VIM-2, doripenem hydrolysis was generally 2- to 150-fold slower than imipenem hydrolysis. SPM-1 hydrolyzed meropenem and doripenem fourfold faster than imipenem.
Human Platelets Recognize a Novel Surface Protein, PadA, on
Streptococcus gordonii
through a Unique Interaction Involving Fibrinogen Receptor GPIIbIIIa
Authors: Petersen Helen J. , Keane Ciara , Jenkinson Howard F. , Vickerman M. Margaret , Jesionowski Amy , Waterhouse Janet C. , Cox Dermot , Kerrigan Steven W. 
Published: November 2009

ABSTRACT

The concept of an infectious agent playing a role in cardiovascular disease is slowly gaining attention. Among several pathogens identified, the oral bacterium
Streptococcus gordonii
has been implicated as a plausible agent. Platelet adhesion and subsequent aggregation are critical events in the pathogenesis and dissemination of the infective process. Here we describe the identification and characterization of a novel cell wall-anchored surface protein, PadA (397 kDa), of
S. gordonii
DL1 that binds to the platelet fibrinogen receptor GPIIbIIIa. Wild-type
S. gordonii
cells induced platelet aggregation and supported platelet adhesion in a GPIIbIIIa-dependent manner. Deletion of the
padA
gene had no effect on platelet aggregation by
S. gordonii
but significantly reduced (>75%) platelet adhesion to
S. gordonii
. Purified N-terminal PadA recombinant polypeptide adhered to platelets. The
padA
mutant was unaffected in production of other platelet-interactive surface proteins (Hsa, SspA, and SspB), and levels of adherence of the mutant to fetuin or platelet receptor GPIb were unaffected. Wild-type
S. gordonii
, but not the
padA
mutant, bound to Chinese hamster ovary cells stably transfected with GPIIbIIIa, and this interaction was ablated by addition of GPIIbIIIa inhibitor Abciximab. These results highlight the growing complexity of interactions between
S. gordonii
and platelets and demonstrate a new mechanism by which the bacterium could contribute to unwanted thrombosis.
Neither Mosquito Saliva nor Immunity to Saliva Has a Detectable Effect on the Infectivity ofPlasmodiumSporozoites Injected into Mice
Authors: Kebaier Chahnaz , Voza Tatiana , Vanderberg Jerome 
Published: November 2009

ABSTRACTMalaria infection is initiated when a femaleAnophelesmosquito probing for blood injects saliva, together with sporozoites, into the skin of its mammalian host. Prior studies had suggested that saliva may enhance sporozoite infectivity. Using rodent malaria models (Plasmodium bergheiandP. yoelii), we were unable to show that saliva had any detectable effect on sporozoite infectivity. This is encouraging for plans to immunize humans with washed, attenuatedP. falciparumsporozoites because many individuals develop cutaneous, hypersensitivity reactions to mosquito saliva after repeated exposure. If washed sporozoites have no appreciable loss of infectivity, they likely do not have decreased immunogenicity; thus, vaccinees are unlikely to develop cutaneous reactions against mosquito saliva during attempted immunization with such sporozoites. Earlier studies also suggested that repeated prior exposure to mosquito saliva reduces infectivity of sporozoites injected by mosquitoes into sensitized hosts. However, our own studies show that prior exposure of mice to saliva had no detectable effect on numbers of sporozoites delivered by infected mosquitoes, the rate of disappearance of these sporozoites from the skin or infectivity of the sporozoites. Under natural conditions, sporozoites are delivered both to individuals who may exhibit cutaneous hypersensitivity to mosquito bite and to others who may have not yet developed such reactivity. It was tempting to hypothesize that differences in responsiveness to mosquito bite by different individuals might modulate the infectivity of sporozoites delivered into a milieu of changes induced by cutaneous hypersensitivity. Our results with rodent malaria models, however, were unable to support such a hypothesis.
A New Generation of Stable, Nonantibiotic, Low-Copy-Number Plasmids Improves Immune Responses to Foreign Antigens in
Salmonella enterica
Serovar Typhi Live Vectors
Authors: Galen James E. , Wang Jin Yuan , Chinchilla Magaly , Vindurampulle Christopher , Vogel Jeffrey E. , Levy Haim , Blackwelder William C. , Pasetti Marcela F. , Levine Myron M. 
Published: November 2009

ABSTRACT

We hypothesized that adequately engineered attenuated
Salmonella enterica
serovar Typhi strains can serve as multivalent mucosal live vector vaccines to immunize against unrelated human pathogens. Toward this ultimate goal, we have developed a novel genetic stabilization system for antigen-expressing plasmids, engineered to encode the single-stranded binding protein (SSB), an essential protein involved in DNA metabolism which was deleted from the live vector chromosome. We utilized full-length protective antigen (PA83) of anthrax toxin from
Bacillus anthracis
as a foreign antigen and expressed PA83 as a fusion with the ClyA export protein, which allows export of ClyA-PA83 to the surface of
S
. Typhi live vectors. A series of SSB-encoding multicopy expression plasmids were introduced into reengineered
S
. Typhi strains previously tested in clinical trials, i.e., CVD 908-
htrA
and its less attenuated parent CVD 908. Immunogenicity was examined using a mouse model of intranasal immunization with live vector, followed by parenteral boosting with purified PA83. PA-specific antibody responses markedly improved as the copy number of the SSB-encoding plasmids decreased, and this effect was dramatically enhanced when the foreign antigen was delivered by the less attenuated live vector CVD 908
ssb
. These results suggest that antibody responses to antigens delivered by
S
. Typhi live vectors are inversely related to the metabolic burden imposed by expression of the foreign antigen and that these responses can be improved when antigens are expressed from low-copy-number plasmids and exported out of the cytoplasm of less attenuated live vectors.
DiscordantBrucella melitensisAntigens Yield Cognate CD8+T Cells In Vivo
Authors: Durward Marina A. , Harms Jerome , Magnani Diogo M. , Eskra Linda , Splitter Gary A. 
Published: November 2009

ABSTRACTBrucellaspp. are intracellular bacteria that cause the most frequent zoonosis in the world. Although recent work has advanced the field ofBrucellavaccine development, there remains no safe human vaccine. In order to produce a safe and effective human vaccine, the immune response toBrucellaspp. requires greater understanding. Induction ofBrucella-specific CD8+T cells is considered an important aspect of the host response; however, the CD8+T-cell response is not clearly defined. Discovering the epitope containing antigens recognized byBrucella-specific CD8+T cells and correlating them with microarray data will aid in determining proteins critical for vaccine development that cover a kinetic continuum during infection. Developing tools to take advantage of the BALB/c mouse model ofBrucella melitensisinfection will help to clarify the correlates of immunity and improve the efficacy of this model. Two H-2dCD8+T-cell epitopes have been characterized, and a group of immunogenic proteins have provoked gamma interferon production by CD8+T cells. RYCINSASL and NGSSSMATV induced cognate CD8+T cells after peptide immunization that showed specific killing in vivo. Importantly, we found by microarray analysis that the genes encoding these epitopes are differentially expressed following macrophage infection, further emphasizing that these discordant genes may play an important role in the pathogenesis ofB. melitensisinfection.
Toward the Rational Design of a Malaria Vaccine Construct Using the MSP3 Family as an Example: Contribution of Antigenicity Studies in Humans
Authors: Demanga Corine G. , Daher Lena-Juliette , Prieur Eric , Blanc Catherine , Pérignon Jean-Louis , Bouharoun-Tayoun Hasnaa , Druilhe Pierre 
Published: November 2009

ABSTRACTPlasmodium falciparummerozoite surface protein (MSP3) is a main target of protective immunity against malaria that is currently undergoing vaccine development. It was shown recently to belong, together with MSP6, to a new multigene family whose C-terminal regions have a similar organization, contain both homologous and divergent regions, and are highly conserved across isolates. In an attempt to rationally design novel vaccine constructs, we extended the analysis of antigenicity and function of region-specific antibodies, previously performed with MSP3 and MSP6, to the remaining four proteins of the MSP3 family using four recombinant proteins and 24 synthetic peptides. Antibodies to each MSP3 family antigen were found to be highly prevalent among malaria-exposed individuals from the village of Dielmo (Senegal). Each of the 24 peptides was antigenic, defining at least one epitope mimicking that of the native proteins, with a distinct IgG isotype pattern for each, although with an overall predominance of the IgG3 subclass. Human antibodies affinity purified upon each of the 24 peptides exerted an antiparasite antibody-dependent cellular inhibition effect, which in most cases was as strong as that of IgG from protected African adults. The two regions with high homology were found to generate a broad network of cross-reactive antibodies with various avidities. A first multigenic construct was designed using these findings and those from related immunogenicity studies in mice and demonstrated valuable immunological properties. These results indicate that numerous regions from the MSP3 family play a role in protection and provide a rationale for the tailoring of new MSP3-derived malaria vaccines.
Air pollution, obesity, genes and cellular adhesion molecules
Authors: Madrigano Jaime , Baccarelli Andrea , Wright Robert O , Suh Helen , Sparrow David , Vokonas Pantel S , Schwartz Joel 
Published: November 2009

ObjectivesParticulate matter has been associated with acute cardiovascular outcomes, but our understanding of the mechanism is incomplete. We examined the association between particulate matter and cell adhesion molecules. We also investigated the modifying effect of genotype and phenotype variation to gain insight into the relevant biological pathways for this association.MethodsWe used mixed regression models to examine the association of PM2.5(particulate matter ≤2.5 μm in diameter) and black carbon with serum concentrations of soluble intercellular adhesion molecule (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1), markers of endothelial function and inflammation, in a longitudinal study of 809 participants in the Normative Ageing Study (1819 total observations). We also examined whether this association was modified by genotype, obesity or diabetes status. Genes selected for analyses were either related to oxidative stress, endothelial function, lipid metabolism or metal processing.ResultsBlack carbon during the 2 days prior to blood draw was significantly associated with increased sVCAM-1 (4.5% increase per 1 μg/m3, 95% CI 1.1 to 8.0). Neither pollutant was associated with sICAM-1. Larger effects of black carbon on sVCAM were seen in subjects with obesity (p=0.007) and who wereGSTM1null (p=0.02).ConclusionsBlack carbon is associated with markers of endothelial function and inflammation. Genes related to oxidative defence may modify this association.