bluuebunny/crossref_metadata_2025 huggingface dataset:
Can Government Policies Induce Earnings Management Behavior? ‐Evidence from Chinese Public Listed Firms
Authors: Hu Nan , Li Xu , Liu Ling , Qi Baolei , Tian Gaoling
Published: October 2012

Earnings management behavior is a concern of standard setters, regulators, and investors. This study predicts that government policies can induce earnings management behavior. Based on a sample of 8,765 firm years ranging from 2002 to 2009, this study uses two methods to detect the effect of government policies on managers' earnings management behavior. One is the earnings distribution method developed by Burgstahler and Dichev (1997), and the other is the modified Jones model proposed by DeFond and Jiambalvo (1994). We find that policies issued by the China Securities Regulatory Commission (CSRC) can induce managers of listed firms to engage in earnings management to either avoid negative consequences (e.g., delisting) or to meet requirements (e.g., refinancing). So, although the purpose of government is to protect investors as well as to promote the healthy development of the securities market, its policies are a double‐edged sword: if there is no strict and effective control mechanism, government policies can harm investors and disturb the normal order of the securities market.
The Effect of Arthur Andersen's Demise on Clients' Audit Fees and Auditor Conservatism: International Evidence
Authors: Srinidhi Bin , Hossain Mahmud , Lim Chee Yeow
Published: October 2012

Using samples from 12 non‐U.S.A. countries, we find that following Arthur Andersen's failure in the United States of America, successor Big‐N auditors charged an audit fee premium for ex‐Andersen clients compared to existing clients and non‐Andersen switch‐ins. We show that this audit fee premium is not attributable to the Andersen switch‐ins having lower prior earnings quality or lower bargaining power than non‐Andersen switch‐ins. We also show that ex‐Andersen clients exhibit higher earnings quality after the switch than do ongoing clients and other switch‐ins. These results suggest that the audit fee premium is attributable to auditor conservatism. Furthermore, we find that risk assessments for ex‐Andersen clients are higher in countries with weak legal and extra‐legal institutions. We interpret this result as suggesting that the effect of lost auditor reputation is stronger when objective evidence of earnings quality is uncertain because of weaker supporting institutions. This is the first study to document a direct effect of countrywide institutions on audit risk assessment.
Least tail‐trimmed squares for infinite variance autoregressions
Authors: Hill Jonathan B.
Published: October 2012

We develop a robust least squares estimator for autoregressions with possibly heavy tailed errors. Robustness to heavy tails is ensured by negligibly trimming the squared error according to extreme values of the error and regressors. Tail‐trimming ensures asymptotic normality and super‐‐convergence with a rate comparable to the highest achieved amongst M‐estimators for stationary data. Moreover, tail‐trimming ensures robustness to heavy tails in both small and large samples. By comparison, existing robust estimators are not as robust in small samples, have a slower rate of convergence when the variance is infinite, or are not asymptotically normal. We present a consistent estimator of the covariance matrix and treat classic inference without knowledge of the rate of convergence. A simulation study demonstrates the sharpness and approximate normality of the estimator, and we apply the estimator to financial returns data. Finally, tail‐trimming can be easily extended beyond least squares estimation for a linear stationary AR model. We discuss extensions to quasi‐maximum likelihood for GARCH, weighted least squares for a possibly non‐stationary random coefficient autoregression, and empirical likelihood for robust confidence region estimation, in each case for models with possibly heavy tailed errors.
A mixed portmanteau test for ARMA‐GARCH models by the quasi‐maximum exponential likelihood estimation approach
Authors: Zhu Ke.
Published: October 2012

This paper investigates the joint limiting distribution of the residual autocorrelation functions and the absolute residual autocorrelation functions of ARMA‐GARCH models. This leads a mixed portmanteau test for diagnostic checking of the ARMA‐GARCH model fitted by using the quasi‐maximum exponential likelihood estimation approach inZhu and Ling (2011). Simulation studies are carried out to examine our asymptotic theory, and assess the performance of this mixed test and other two portmanteau tests inLi and Li (2008). A real example is given.
The adaptive potential of Populus balsamifera L. to phenology requirements in a warmer global climate
Authors: Olson Matthew S. , Levsen Nicholas , Soolanayakanahally Raju Y. , Guy Robert D. , Schroeder William R. , Keller Stephen R. , Tiffin Peter
Published: October 2012

The manner in which organisms adapt to climate change informs a broader understanding of the evolution of biodiversity as well as conservation and mitigation plans. We apply common garden and association mapping approaches to quantify genetic variance and identify loci affecting bud flush and bud set, traits that define a tree's season for height growth, in the boreal forest tree Populus balsamifera L. (balsam poplar). Using data from 478 genotypes grown in each of two common gardens, one near the southern edge and another near the northern edge of P. balsamifera's range, we found that broad‐sense heritability for bud flush and bud set was generally high (H2 > 0.5 in most cases), suggesting that abundant genetic variation exists for phenological response to changes in the length of the growing season. To identify the molecular genetic basis of this variation, we genotyped trees for 346 candidate single nucleotide polymorphisms (SNPs) from 27 candidate genes for the CO/FT pathway in poplar. Mixed‐model analyses of variance identified SNPs in 10 genes to be associated with variation in either bud flush or bud set. Multiple SNPs within FRIGIDA were associated with bud flush, whereas multiple SNPs in LEAFY and GIGANTEA 5 were associated with bud set. Although there was strong population structure in stem phenology, the geographic distribution of multilocus association SNP genotypes was widespread except at the most northern populations, indicating that geographic regions may harbour sufficient diversity in functional genes to facilitate adaption to future climatic conditions in many sites.
Environmental margin and island evolution in Middle Eastern populations of the Egyptian fruit bat
Authors: Hulva P. , Marešová T. , Dundarova H. , Bilgin R. , Benda P. , Bartonička T. , Horáček I.
Published: October 2012

Here, we present a study of the population genetic architecture and microevolution of the Egyptian fruit bat (Rousettus aegyptiacus) at the environmental margins in the Middle East using mitochondrial sequences and nuclear microsatellites. In contrast to the rather homogenous population structure typical of cave‐dwelling bats in climax tropical ecosystems, a relatively pronounced isolation by distance and population diversification was observed. The evolution of this pattern could be ascribed to the complicated demographic history at higher latitudes related to the range margin fragmentation and complex geomorphology of the studied area. Lineages from East Africa and Arabia show divergent positions. Within the northwestern unit, the most marked pattern of the microsatellite data set is connected with insularity, as demonstrated by the separate status of populations from Saharan oases and Cyprus. These demes also exhibit a reduction in genetic variability, which is presumably connected with founder effects, drift and other potential factors related to island evolution as site‐specific selection. Genetic clustering indicates a semipermeability of the desert barriers in the Sahara and Arabian Peninsula and a corridor role of the Nile Valley. The results emphasize the role of the island environment in restricting the gene flow in megabats, which is also corroborated by biogeographic patterns within the family, and suggests the possibility of nascent island speciation on Cyprus. Demographic analyses suggest that the colonization of the region was connected to the spread of agricultural plants; therefore, the peripatric processes described above might be because of or strengthened by anthropogenic changes in the environment.
Effector memory T‐cell frequencies in relation to tumour stage, location and HPV status in HNSCC patients
Authors: Turksma AW , Bontkes HJ , van den Heuvel H , de Gruijl TD , von Blomberg BME , Braakhuis BJM , Leemans CR , Bloemena E , Meijer CJLM , Hooijberg E
Published: October 2012

Background

The immune system plays an important role in tumour immune surveillance. Head and neck squamous cell carcinoma patients are often immune compromised.

Objective

To chart the baseline levels of T‐cell subpopulation frequencies in patients with cancer prior to treatment.

Subjects and methods

Blood samples of patients were taken at the time of diagnosis, analysed with flowcytometry and compared with blood samples of healthy donors.

Results

Compared to healthy donors, a significant shift from naive to effector memory T cells was observed. This effect was most prominent in stage II patients. A similar shift from naive to effector memory T cells was noted in patients with oropharynx or larynx squamous cell carcinomas. Furthermore, the percentage of effector memory and effector T cells was higher in the group of patients with human papillomavirus‐positive oropharyngeal squamous cell carcinomas, compared with patients with human papillomavirus‐negative tumours, suggestive of virus‐induced T‐cell activation.

Conclusion

Here, we provide a simple and easily implementable tool to document T lymphocyte subsets in the peripheral blood of head and neck cancer patients, which might be useful for prognosis and/or therapy response prediction.
Gene targeting in maize by somatic ectopic recombination
Authors: Ayar Ayhan , Wehrkamp‐Richter Sophie , Laffaire Jean‐Baptiste , Le Goff Samuel , Levy Julien , Chaignon Sandrine , Salmi Hajer , Lepicard Alexandra , Sallaud Christophe , Gallego Maria E. , White Charles I. , Paul Wyatt
Published: October 2012

Low transformation efficiency and high background of non‐targeted events are major constraints to gene targeting in plants. We demonstrate here applicability in maize of a system that reduces the constraint from transformation efficiency. The system requires regenerable transformants in which all of the following elements are stably integrated in the genome: (i) donor DNA with the gene of interest adjacent to sequence for repair of a defective selectable marker, (ii) sequence encoding a rare‐cutting endonuclease such as I‐SceI, (iii) a target locus (TL) comprising the defective selectable marker and I‐SceI cleavage site. Typically, this requires additional markers for the integration of the donor and target sequences, which may be assembled through cross‐pollination of separate transformants. Inducible expression of I‐SceI then cleaves the TL and facilitates homologous recombination, which is assayed by selection for the repaired marker. We used bar and gfp markers to identify assembled transformants, a dexamethasone‐inducible I‐SceI::GR protein, and selection for recombination events that restored an intact nptII. Applying this strategy to callus permitted the selection of recombination into the TL at a frequency of 0.085% per extracted immature embryo (29% of recombinants). Our results also indicate that excision of the donor locus (DL) through the use of flanking I‐SceI cleavage sites may be unnecessary, and a source of unwanted repair events at the DL. The system allows production, from each assembled transformant, of many cells that subsequently can be treated to induce gene targeting. This may facilitate gene targeting in plant species for which transformation efficiencies are otherwise limiting.
Hydrogen gas acts as a novel bioactive molecule in enhancing plant tolerance to paraquat‐induced oxidative stress via the modulation of heme oxygenase‐1 signalling system
Authors: JIN QIJIANG , ZHU KAIKAI , CUI WEITI , XIE YANJIE , HAN BIN , SHEN WENBIAO
Published: October 2012

Hydrogen gas (H2) was recently proposed as a novel antioxidant and signalling molecule in animals. However, the physiological roles of H2 in plants are less clear. Here, we showed that exposure of alfalfa seedlings to paraquat stress increased endogenous H2 production. When supplied with exogenous H2 or the heme oxygenase‐1 (HO‐1)‐inducer hemin, alfalfa plants displayed enhanced tolerance to oxidative stress induced by paraquat. This was evidenced by alleviation of the inhibition of root growth, reduced lipid peroxidation and the decreased hydrogen peroxide and superoxide anion radical levels. The activities and transcripts of representative antioxidant enzymes were induced after exposure to either H2 or hemin. Further results showed that H2 pretreatment could dramatically increase levels of the MsHO‐1 transcript, levels of the protein it encodes and HO‐1 activity. The previously mentioned H2‐mediated responses were specific for HO‐1, given that the potent HO‐1‐inhibitor counteracted the effects of H2. The effects of H2 were reversed after the addition of an aqueous solution of 50% carbon monoxide (CO). We also discovered enhanced tolerance of multiple environmental stresses after plants were pretreated with H2. Together, these results suggested that H2 might function as an important gaseous molecule that alleviates oxidative stress via HO‐1 signalling.
Rehabilitation of the Geriatric Dialysis Patient
Authors: Farragher Janine , Jassal Sarbjit Vanita
Published: October 2012

Dialysis is offered to patients with end‐stage renal disease as a life‐sustaining therapy. However, studies have shown that elderly patients experience high rates of functional disability, hospitalization, institutionalization, and mortality on chronic dialysis therapy, and that the initiation of dialysis is in fact associated with an acceleration in functional decline. These findings have sparked debate about the utility of dialysis for elderly renal patients. In this article, it is proposed that geriatric rehabilitation can prevent, reverse or delay the onset of functional disability and associated adverse outcomes in older dialysis patients, and thus should be incorporated routinely into standard geriatric dialysis care. We outline the causes of disability in elderly dialysis patients, and demonstrate the potential impact of rehabilitation using a case scenario. Models of rehabilitation that have been shown to be effective in improving outcomes for elderly renal and nonrenal populations, including inpatient rehabilitation, exercise training, falls prevention, and home‐based models, are reviewed.
Quantitative Image Analysis of Cellular Heterogeneity in Breast Tumors Complements Genomic Profiling
Authors: Yuan Yinyin , Failmezger Henrik , Rueda Oscar M. , Ali H. Raza , Gräf Stefan , Chin Suet-Feung , Schwarz Roland F. , Curtis Christina , Dunning Mark J. , Bardwell Helen , Johnson Nicola , Doyle Sarah , Turashvili Gulisa , Provenzano Elena , Aparicio Sam , Caldas Carlos , Markowetz Florian
Published: October 2012

Image analysis of breast cancer tissue improves and complements genomic data to predict patient survival.
Targeting Cancer with a Lupus Autoantibody
Authors: Hansen James E. , Chan Grace , Liu Yanfeng , Hegan Denise C. , Dalal Shibani , Dray Eloise , Kwon Youngho , Xu Yuanyuan , Xu Xiaohua , Peterson-Roth Elizabeth , Geiger Erik , Liu Yilun , Gera Joseph , Sweasy Joann B. , Sung Patrick , Rockwell Sara , Nishimura Robert N. , Weisbart Richard H. , M. Glazer Peter
Published: October 2012

A cell-penetrating lupus anti-DNA antibody inhibits DNA repair, sensitizes cancer cells to DNA-damaging therapy in vitro and in vivo, and is synthetically lethal to BRCA2-deficient human cancer cells.
Comment on “Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model”
Authors: Tsao Jack W.
Published: October 2012

In their recent paper, Goldstein
et al.
show murine brain tau neuropathology after explosive blast with head rotation but do not present additional evidence that would delineate whether this neuropathology was principally caused by blast exposure alone or by blast exposure plus head rotational injury.
NADPH Oxidase Inhibits the Pathogenesis of Systemic Lupus Erythematosus
Authors: Campbell Allison M. , Kashgarian Michael , Shlomchik Mark J.
Published: October 2012

Antigen produced by NADPH oxidase–dependent neutrophil extracellular traps is not required to drive disease pathology.
Vessel and Nerve Growth Go Hand in Hand
Authors: Methe Heiko
Published: October 2012

Prostacyclin secreted by new blood vessels drives neuronal remodeling in central nervous system disease.
Stepwise Development of a Homozygous S80P Substitution in Fks1p, Conferring Echinocandin Resistance in Candida tropicalis
Authors: Jensen Rasmus Hare , Johansen Helle Krogh , Arendrup Maiken Cavling
Published: October 2012

Three
Candida tropicalis
isolates were obtained from a patient with acute lymphoblastic leukemia. The first isolate was susceptible to all drug classes, while isolates 2 and 3, obtained after 8 and 8.5 weeks of caspofungin treatment, respectively, were resistant to the three echinocandins. Multilocus sequence genotyping suggested a clonal relation among all isolates.
FKS1
sequencing revealed a stepwise development of a heterozygous and finally a homozygous mutation, leading to S80S/P and S80P amino acid substitutions.
Innate Aminoglycoside Resistance of Achromobacter xylosoxidans Is Due to AxyXY-OprZ, an RND-Type Multidrug Efflux Pump
Authors: Bador Julien , Amoureux Lucie , Blanc Emmanuel , Neuwirth Catherine
Published: October 2012

Achromobacter xylosoxidans
is an innately multidrug-resistant pathogen which is emerging in cystic fibrosis (CF) patients. We characterized a new resistance-nodulation-cell division (RND)-type multidrug efflux pump, AxyXY-OprZ. This system is responsible for the intrinsic high-level resistance of
A. xylosoxidans
to aminoglycosides (tobramycin, amikacin, and gentamicin). Furthermore, it can extrude cefepime, carbapenems, some fluoroquinolones, tetracyclines, and erythromycin. Some of the AxyXY-OprZ substrates are major components widely used to treat pulmonary infections in CF patients.
Evaluation of Caspofungin Susceptibility Testing by the New Vitek 2 AST-YS06 Yeast Card Using a Unique Collection of
FKS
Wild-Type and Hot Spot Mutant Isolates, Including the Five Most Common Candida Species
Authors: Astvad Karen M. , Perlin David S. , Johansen Helle K. , Jensen Rasmus H. , Arendrup Maiken C.
Published: October 2012

FKS
mutant isolates associated with breakthrough or failure cases are emerging in clinical settings. Discrimination of these from wild-type (wt) isolates in a routine laboratory setting is complicated. We evaluated the ability of caspofungin MIC determination using the new Vitek 2 AST-Y06 yeast susceptibility card to correctly identify the
fks
mutants from wt isolates and compared the performance to those of the CLSI and EUCAST reference methods. A collection of 98
Candida
isolates, including 31
fks
hot spot mutants, were included. Performance was evaluated using the
FKS
genotype as the “gold standard” and compared to those of the CLSI and EUCAST methodologies. The categorical agreement for Vitek 2 was 93.9%, compared to 88.4% for the CLSI method and 98.7% for the EUCAST method. Vitek 2 misclassified 19.4% (6/31) of the
fks
mutant isolates as susceptible, in contrast to <4% for each of the reference methods. The overall essential agreement between the CLSI method and Vitek 2 MICs was 92.6% (88/95) but was substantially lower for
fks
mutant isolates (78.6% [22/28]). Correct discrimination between susceptible and intermediate
Candida glabrata
isolates was not possible, as the revised species-specific susceptibility breakpoint was not included in the Vitek 2 detection range (MIC of ≤0.250 to ≥4 mg/liter). In conclusion, the Vitek 2 allowed correct categorization of all wt isolates as susceptible. However, despite an acceptable categorical agreement, it failed to reliably classify isolates harboring
fks
hot spot mutations as intermediate or resistant, which was in part due to the fact that the detection range did not span the susceptibility breakpoint for
C. glabrata
.
Wide Dissemination of GES-Type Carbapenemases in Acinetobacter baumannii Isolates in Kuwait
Authors: Bonnin Rémy A. , Rotimi Vincent O. , Al Hubail Mona , Gasiorowski Elise , Al Sweih Noura , Nordmann Patrice , Poirel Laurent
Published: October 2012

Acinetobacter baumannii
is an opportunistic pathogen that is an important source of nosocomial infections. Production of extended-spectrum β-lactamases (ESBLs) of the GES type in
A. baumannii
has been increasingly reported, and some of these GES-type enzymes possess some carbapenemase activity. Our aim was to analyze the resistance determinants and the clonal relationships of carbapenem-nonsusceptible
A. baumannii
clinical isolates recovered from hospitals in Kuwait. A total of 63 isolates were analyzed, and all were found to be positive for
bla
GES
-type genes. One isolate harbored the
bla
GES-14
gene encoding an ESBL with significant carbapenemase activity, whereas the other isolates harbored the
bla
GES-11
ESBL gene. Thirty-three isolates coharbored the
bla
OXA-23
and
bla
GES-11
genes. Analyses of the genetic locations indicated that the
bla
GES-11/-14
genes were plasmid located. It is noteworthy that the
bla
OXA-23
and
bla
GES-11
genes were colocated onto a single plasmid. Nine different pulsotypes were observed among the 63 isolates. This study showed the emergence of GES-type ESBLs in
A. baumannii
in Kuwait, further suggesting that the Middle East region might be a reservoir for carbapenemase-producing
A. baumannii
.
Pharmacodynamics of a Simulated Single 1,200-Milligram Dose of Oritavancin in an
In Vitro
Pharmacokinetic/Pharmacodynamic Model of Methicillin-Resistant Staphylococcus aureus Infection
Authors: Belley Adam , Arhin Francis F. , Sarmiento Ingrid , Deng Hong , Rose Warren , Moeck Greg
Published: October 2012

The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an
in vitro
pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant
Staphylococcus aureus
(MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC
0-24
), 48 h (AUBKC
0-48
), and 72 h (AUBKC
0-72
). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC
0-24
s for the three MRSA strains than with vancomycin (
P
< 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC
0-48
and AUBKC
0-72
against one MRSA strain and a lower AUBKC
0-48
for another strain than did vancomycin exposure (
P
< 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC
0-48
and AUBKC
0-72
for one of the MRSA isolates than did vancomycin exposure (
P
< 0.05). Lower AUBKC
0-24
s for two of the MRSA strains (
P
< 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an
in vitro
pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.
Elevated Chitin Content Reduces the Susceptibility of Candida Species to Caspofungin
Authors: Walker Louise A. , Gow Neil A. R. , Munro Carol A.
Published: October 2012

The echinocandin antifungal drugs inhibit synthesis of the major fungal cell wall polysaccharide β(1,3)-glucan. Echinocandins have good efficacy against
Candida albicans
but reduced activity against other
Candida
species, in particular
Candida parapsilosis
and
Candida guilliermondii
. Treatment of
Candida albicans
with a sub-MIC level of caspofungin has been reported to cause a compensatory increase in chitin content and to select for sporadic echinocandin-resistant
FKS1
point mutants that also have elevated cell wall chitin. Here we show that elevated chitin in response to caspofungin is a common response in various
Candida
species. Activation of chitin synthesis was observed in isolates of
C. albicans
,
Candida tropicalis
,
C. parapsilosis
, and
C. guilliermondii
and in some isolates of
Candida krusei
in response to caspofungin treatment. However,
Candida glabrata
isolates demonstrated no exposure-induced change in chitin content. Furthermore, isolates of
C. albicans
,
C. krusei
,
C. parapsilosis
, and
C. guilliermondii
which were stimulated to have higher chitin levels via activation of the calcineurin and protein kinase C (PKC) signaling pathways had reduced susceptibility to caspofungin. Isolates containing point mutations in the
FKS1
gene generally had higher chitin levels and did not demonstrate a further compensatory increase in chitin content in response to caspofungin treatment. These results highlight the potential of increased chitin synthesis as a potential mechanism of tolerance to caspofungin for the major pathogenic
Candida
species.
pSK41-Like Plasmid Is Necessary for Inc18-Like
vanA
Plasmid Transfer from Enterococcus faecalis to Staphylococcus aureus
In Vitro
Authors: Zhu Wenming , Clark Nancye , Patel Jean B.
Published: October 2012

Vancomycin-resistant
Staphylococcus aureus
(VRSA) is thought to result from the
in vivo
conjugative transfer of a
vanA
plasmid from an
Enterococcus
sp. to
S. aureus
. We studied bacterial isolates from VRSA cases that occurred in the United States to identify microbiological factors which may contribute to this plasmid transfer. First, vancomycin-susceptible, methicillin-resistant
S. aureus
(MRSA) isolates from five VRSA cases were tested for their ability to accept foreign DNA by conjugation in mating experiments with
Enterococcus faecalis
JH2-2 containing pAM378, a pheromone-response conjugative plasmid. All of the MRSA isolates accepted the plasmid DNA with similar transfer efficiencies (∼10
−7
/donor CFU) except for one isolate, MRSA8, for which conjugation was not successful. The MRSA isolates were also tested as recipients in mating experiments between an
E. faecalis
isolate with an Inc18-like
vanA
plasmid that was isolated from a VRSA case patient. Conjugative transfer was successful for 3/5 MRSA isolates. Successful MRSA recipients carried a pSK41-like plasmid, a staphylococcal conjugative plasmid, whereas the two unsuccessful MRSA recipients did not carry pSK41. The transfer of a pSK41-like plasmid from a successful MRSA recipient to the two unsuccessful recipients resulted in conjugal transfer of the Inc18-like
vanA
plasmid from
E. faecalis
at a frequency of 10
−7
/recipient CFU. In addition, conjugal transfer could be achieved for pSK41-negative MRSA in the presence of a cell-free culture filtrate from
S. aureus
carrying a pSK41-like plasmid at a frequency of 10
−8
/recipient CFU. These results indicated that a pSK41-like plasmid can facilitate the transfer of an Inc18-like
vanA
plasmid from
E. faecalis
to
S. aureus
, possibly via an extracellular factor produced by pSK41-carrying isolates.
Daptomycin Concentrations in Valve Tissue and Vegetation in Patients with Bacterial Endocarditis
Authors: Tascini Carlo , Di Paolo Antonello , Poletti Roberta , Flammini Sarah , Emdin Michele , Ciullo Ilaria , Tagliaferri Enrico , Moter Annette , Menichetti Francesco
Published: October 2012

In a patient with mitral-aortic native-valve
Streptococcus oralis
endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 μg/g, respectively, and 26 μg/g in the mitral vegetation. In the case of porcine-aortic-valve
Staphylococcus epidermidis
endocarditis, the daptomycin concentrations were 53.1 μg/g in the valve and 18.1 μg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations.
S. epidermidis
was eradicated, whereas
Streptococcus oralis
persisted, and its daptomycin MIC displayed a 4-fold increase.
A Purified Capsular Polysaccharide Markedly Inhibits Inflammatory Response during Endotoxic Shock
Authors: Piccioni M. , Monari C. , Kenno S. , Pericolini E. , Gabrielli E. , Pietrella D. , Perito S. , Bistoni F. , Kozel T. R. , Vecchiarelli A.
Published: October 2012

Capsular material of the opportunistic fungus
Cryptococcus neoformans
is composed mainly of a polysaccharide named glucuronoxylomannan (GXM). In this study, the effects of GXM were analyzed in an
in vivo
experimental system of lipopolysaccharide (LPS)-induced shock. Endotoxic shock was induced in mice by a single intraperitoneal injection of LPS from
Escherichia coli
. GXM treatment reduced the mortality of mice at early stages. Mice treated with LPS alone showed markedly increased plasma levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6, whereas mice that were also treated with GXM showed significantly lower plasma levels of these cytokines. This effect was related to a marked suppression of Akt and IκBα activation. Importantly, the inhibitory effect of GXM on proinflammatory cytokine secretion was reproduced by treatment with wortmannin, an inhibitor of the Akt transcription pathway. Our results indicate that GXM has a beneficial effect on endotoxic shock, resulting in a significant increase in the rate of survival by dampening the hyperinflammatory response.
Innate Immune Response to Streptococcus iniae Infection in Zebrafish Larvae
Authors: Harvie Elizabeth A. , Green Julie M. , Neely Melody N. , Huttenlocher Anna
Published: October 2012

Streptococcus iniaecauses systemic infection characterized by meningitis and sepsis. Here, we report a larval zebrafish model ofS. iniaeinfection. Injection of wild-typeS. iniaeinto the otic vesicle induced a lethal infection by 24 h postinfection. In contrast, anS. iniaemutant deficient in polysaccharide capsule (cpsAmutant) was not lethal, with greater than 90% survival at 24 h postinfection. Live imaging demonstrated that both neutrophils and macrophages were recruited to localized otic infection with mutant and wild-typeS. iniaeand were able to phagocytose bacteria. Depletion of neutrophils and macrophages impaired host survival following infection with wild-typeS. iniaeand thecpsAmutant, suggesting that leukocytes are critical for host survival in the presence of both the wild-type and mutant bacteria. However, zebrafish larvae with impaired neutrophil function but normal macrophage function had increased susceptibility to wild-type bacteria but not thecpsAmutant. Taking these findings together, we have developed a larval zebrafish model ofS. iniaeinfection and have found that although neutrophils are important for controlling infection with wild-typeS. iniae, neutrophils are not necessary for host defense against thecpsAmutant.
Characterization of the AggR Regulon in Enteroaggregative Escherichia coli
Authors: Morin Nicholas , Santiago Araceli E. , Ernst Robert K. , Guillot Stacey J. , Nataro James P.
Published: October 2012

AggR is a transcriptional regulator of enteroaggregative
Escherichia coli
(EAEC) and has been proposed as the defining factor for typical EAEC strains. Expression of multiple putative virulence factors, including the aggregative adherence fimbriae (AAF), dispersin, the dispersin translocator Aat, and the Aai type VI secretion system, have been found to be regulated by AggR. Here, we confirm the existence of at least 44 AggR-regulated genes using DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR); these genes include chromosomal and plasmid-borne loci and 19 previously unsuspected genes. Two previously uncharacterized virulence plasmid-encoded open reading frames (ORFs) (designated ORF3 and ORF4) exhibit significant identity with isoprenoid biosynthesis genes of
Bacteria
and
Archaea
. The predicted ORF4 product is closely related to isopentenyl isomerase (IDI) enzymes, whereas the predicted product of the adjacent ORF3 exhibits an aspartate-rich region that is common among
trans
-isoprenyl phosphate synthases. We show that mutations in these ORFs confer changes in bacterial surface properties. AggR coordinately controls expression of a large number of EAEC genes.
Transcriptional Responses of Uropathogenic Escherichia coli to Increased Environmental Osmolality Caused by Salt or Urea
Authors: Withman Benjamin , Gunasekera Thusitha S. , Beesetty Pavani , Agans Richard , Paliy Oleg
Published: October 2012

UropathogenicEscherichia coli(UPEC) is the most common causative agent of urinary tract infections in humans. The majority of urinary infections develop via ascending route through the urethra, where bacterial cells come in contact with human urine prior to reaching the bladder or kidneys. Since urine contains significant amounts of inorganic ions and urea, it imposes osmotic and denaturing stresses on bacterial cells. In this study, we determined the transcriptional adaptive responses of UPEC strain CFT073 to the presence of 0.3 M NaCl or 0.6 M urea in the growth medium. The cell responses to these two osmolytes were drastically different. Although most of the genes of the osmotically inducible regulon were overexpressed in medium with salt, urea failed to stimulate osmotic stress response. At the same time, UPEC colonization genes encoding type 1 and F1C fimbriae and capsule biosynthesis were transcriptionally induced in the presence of urea but did not respond to increased salt concentration. We speculate that urea can potentially be sensed by uropathogenic bacteria to initiate infection program. In addition, several molecular chaperone genes were overexpressed in the presence of urea, whereas adding NaCl to the medium led to an upregulation of a number of anaerobic metabolism pathways.
Genome Expression Analysis of Nonproliferating Intracellular Salmonella enterica Serovar Typhimurium Unravels an Acid pH-Dependent PhoP-PhoQ Response Essential for Dormancy
Authors: Núñez-Hernández Cristina , Tierrez Alberto , Ortega Álvaro D. , Pucciarelli M. Graciela , Godoy Marta , Eisman Blanca , Casadesús Josep , García-del Portillo Francisco
Published: October 2012

Genome-wide expression analyses have provided clues on how
Salmonella
proliferates inside cultured macrophages and epithelial cells. However,
in vivo
studies show that
Salmonella
does not replicate massively within host cells, leaving the underlying mechanisms of such growth control largely undefined.
In vitro
infection models based on fibroblasts or dendritic cells reveal limited proliferation of the pathogen, but it is presently unknown whether these phenomena reflect events occurring
in vivo
. Fibroblasts are distinctive, since they represent a nonphagocytic cell type in which
S. enterica
serovar Typhimurium actively attenuates intracellular growth. Here, we show in the mouse model that
S
. Typhimurium restrains intracellular growth within nonphagocytic cells positioned in the intestinal lamina propria. This response requires a functional PhoP-PhoQ system and is reproduced in primary fibroblasts isolated from the mouse intestine. The fibroblast infection model was exploited to generate transcriptome data, which revealed that ∼2% (98 genes) of the
S
. Typhimurium genome is differentially expressed in nongrowing intracellular bacteria. Changes include metabolic reprogramming to microaerophilic conditions, induction of virulence plasmid genes, upregulation of the pathogenicity islands SPI-1 and SPI-2, and shutdown of flagella production and chemotaxis. Comparison of relative protein levels of several PhoP-PhoQ-regulated functions (PagN, PagP, and VirK) in nongrowing intracellular bacteria and extracellular bacteria exposed to diverse PhoP-PhoQ-inducing signals denoted a regulation responding to acidic pH. These data demonstrate that
S
. Typhimurium restrains intracellular growth
in vivo
and support a model in which dormant intracellular bacteria could sense vacuolar acidification to stimulate the PhoP-PhoQ system for preventing intracellular overgrowth.
Toward an Understanding of Changes in Diversity Associated with Fecal Microbiome Transplantation Based on 16S rRNA Gene Deep Sequencing
Authors: Shahinas Dea , Silverman Michael , Sittler Taylor , Chiu Charles , Kim Peter , Allen-Vercoe Emma , Weese Scott , Wong Andrew , Low Donald E. , Pillai Dylan R.
Published: October 2012

Fecal microbiome transplantation by low-volume enema is an effective, safe, and inexpensive alternative to antibiotic therapy for patients with chronic relapsing
Clostridium difficile
infection (CDI). We explored the microbial diversity of pre- and posttransplant stool specimens from CDI patients (
n
= 6) using deep sequencing of the 16S rRNA gene. While interindividual variability in microbiota change occurs with fecal transplantation and vancomycin exposure, in this pilot study we note that clinical cure of CDI is associated with an increase in diversity and richness. Genus- and species-level analysis may reveal a cocktail of microorganisms or products thereof that will ultimately be used as a probiotic to treat CDI.

IMPORTANCE
Antibiotic-associated diarrhea (AAD) due to
Clostridium difficile
is a widespread phenomenon in hospitals today. Despite the use of antibiotics, up to 30% of patients are unable to clear the infection and suffer recurrent bouts of diarrheal disease. As a result, clinicians have resorted to fecal microbiome transplantation (FT). Donor stool for this type of therapy is typically obtained from a spouse or close relative and thoroughly tested for various pathogenic microorganisms prior to infusion. Anecdotal reports suggest a very high success rate of FT in patients who fail antibiotic treatment (>90%). We used deep-sequencing technology to explore the human microbial diversity in patients with
Clostridium difficile
infection (CDI) disease after FT. Genus- and species-level analysis revealed a cocktail of microorganisms in the
Bacteroidetes
and
Firmicutes
phyla that may ultimately be used as a probiotic to treat CDI.
Effects of Crude Oil, Dispersant, and Oil-Dispersant Mixtures on Human Fecal Microbiota in an
In Vitro
Culture System
Authors: Kim Jong Nam , Kim Bong-Soo , Kim Seong-Jae , Cerniglia Carl E.
Published: October 2012

The Deepwater Horizon oil spill of 2010 raised concerns that dispersant and dispersed oil, as well as crude oil itself, could contaminate shellfish and seafood habitats with hazardous residues that had potential implications for human health and the ecosystem. However, little is known about the effects of crude oil and dispersant on the human fecal microbiota. The aim of this research was to evaluate the potential effects of Deepwater Horizon crude oil, Corexit 9500 dispersant, and their combination on human fecal microbial communities, using an
in vitro
culture test system. Fecal specimens from healthy adult volunteers were made into suspensions, which were then treated with oil, dispersant, or oil-dispersant mixtures under anaerobic conditions in an
in vitro
culture test system. Perturbations of the microbial community, compared to untreated control cultures, were assessed using denaturing gradient gel electrophoresis (DGGE), real-time PCR, and pyrosequencing methods. DGGE and pyrosequencing analysis showed that oil-dispersant mixtures reduced the diversity of fecal microbiota from all individuals. Real-time PCR results indicated that the copy numbers of 16S rRNA genes in cultures treated with dispersed oil or oil alone were significantly lower than those in control incubations. The abundance of the
Bacteroidetes
decreased in crude oil-treated and dispersed-oil-treated cultures, while the
Proteobacteria
increased in cultures treated with dispersed oil. In conclusion, the human fecal microbiota was affected differently by oil and dispersed oil, and the influence of dispersed oil was significantly greater than that of either oil or dispersant alone compared to control cultures.

IMPORTANCE
There have been concerns whether human health is adversely affected by exposure to spilled crude oil, which contains regulated carcinogens, such as polycyclic aromatic hydrocarbons. In this study, we determined the effect of BP Deepwater Horizon crude oil and oil dispersant on the human intestinal microbiota, since there is the potential that low-level residues of petrochemicals could contaminate seafood. The results of this study will increase our understanding of the ecophysiological changes in the microbial communities of the human gastrointestinal tract with respect to crude oil exposure.
Prevention of stent thrombosis with reduced dose of prasugrel in two patients undergoing treatment of cerebral aneurysms with pipeline embolisation devices
Authors: Jones G Morgan , Twilla Jennifer D , Hoit Daniel A , Arthur Adam S
Published: October 2012

Prevention of intracranial stent thrombosis with dual-antiplatelet therapy is widely used in neuroendovascular procedures. However, the rising incidence of inadequate platelet inhibition with clopidogrel may increase complications following stent placement, especially with newer devices that possess a larger total metal surface area. While there are recent reports of prasugrel as an alternative to clopidogrel, there is no clinical evidence in neurointerventional patients regarding the use of a lower maintenance dose as an alternative strategy to gain adequate platelet inhibition while possibly reducing the risk of bleeding. We present 6-month efficacy and safety outcomes of two patients undergoing elective pipeline embolisation that were found to have inadequate platelet response to clopidogrel and subsequently transitioned to prasugrel 5 mg daily for the prevention of stent thrombosis.
Ventricular arrhythmias associated with long-term endurance sports: what is the evidence?
Authors: Heidbuchel Hein , Prior David L , La Gerche André
Published: October 2012

Athletic performance tests the limits of the human body and mind. Awe-inspiring achievements is what makes sports so fascinating. It is well appreciated however that top-level sports may sometimes overtax the body, and can lead to injuries, most notably of musculo-skeletal nature. This paper defends the thesis that the heart can also develop sports injuries at the ventricular level. We will elaborate on our hypothesis, originally put forward in 2003, that intense endurance activities put a particularly high strain on the right ventricle (RV), which over time, may lead to a proarrhythmic state resembling right (or less often) left ventricular cardiomyopathy. This can develop even in the absence of underlying demonstrable genetic abnormalities, probably just as a result of excessive RV wall stress during exercise. The syndrome of ‘exercise-induced arrhythmogenic RV cardiomyopathy’ may easily be overlooked. Sports cardiologists, like orthopaedic specialists, should be prepared to realise that excessive sports activity can lead to cardiac sports injuries in some, which will help to council on safe participation in all.
Peripheral vascular structure and function in hypertrophic cardiomyopathy
Authors: Rowley Nicola Jayne , Green Daniel J , George Keith , Thijssen Dick H J , Oxborough David , Sharma Sanjay , Somauroo John D , Jones Julia , Sheikh Nabeel , Whyte Greg
Published: October 2012

Background

Hypertrophic cardiomyopathy (HCM) is characterised by idiopathic cardiac enlargement and represents the most frequent cause of sudden cardiac death in athletes under the age of 35 years. Differentiation between physiological (ie, exercise-related) and pathological (ie, HCM-related) cardiac remodelling is challenging. In line with cardiac remodelling, vascular structure and function are altered following training, but little is known about peripheral vascular adaptations in HCM. We hypothesised that, while HCM patients and athletes would exhibit similar cardiac characteristics, differences would be apparent in their brachial and carotid arteries.

Methods

In age-matched groups of HCM patients (n=18, 39±15 years), highly competitive athletes (n=18, 38±12 years) and recreational controls (n=10, 37±14 years), we used high-resolution ultrasound to assess the diameter and wall thickness of the carotid and brachial arteries, with flow-mediated dilator function (FMD) of the brachial arteries also assessed.

Results

A significant difference between athletes and HCM was evident in arterial wall thickness (carotid 519±60 vs 586±102 µm, p<0.05; brachial 345±80 vs 456±76 µm, p<0.05) and the brachial artery peak blood flow response following forearm ischaemia, an index of resistance artery remodelling (998±515 vs 725±248 ml/min, p<0.05). Similar differences were noted between athletes and controls, while controls and HCM did not differ. Brachial FMD% was not different between groups.

Conclusions

Athletes and HCM subjects, who can be difficult to differentiate on the basis of cardiac measures, exhibit differences in indices of arterial structure. While this may be a disease-related effect, we cannot discount a generic impact of physical activity on arterial structure, as the athlete's arteries were also different to untrained control subjects. Future studies should assess artery function and structure in athletic HCM subjects.
Aetiology of sudden cardiac death in sport: a histopathologist's perspective
Authors: Sheppard Mary N
Published: October 2012

In the UK, when a young person dies suddenly, the coroner is responsible for establishing the cause of death. They will ask a consultant pathologist to carry out an autopsy in order to ascertain when, where and how that person died. Once the cause of death is established and is due to natural causes, the coroner can issue a death certificate. Importantly, the coroner is not particularly interested in the cause of death as long as it is due to natural causes, which avoids the need for an inquest (a public hearing about the death). However, if no identifiable cause is established at the initial autopsy, the coroner can refer the heart to a cardiac pathologist, since the cause of death is usually due to heart disease in most cases. Consultant histopathologists are responsible for the analysis of human tissue from both living individuals and the dead in order to make a diagnosis of disease. With recent advancements in the management protocols for routine autopsy practice and assessment following the sudden death of a young individual, this review describes the role of the consultant histopathologist in the event of a sudden death of a young athletic individual, together with the older middle-aged ‘weekend warrior’ athlete. It provides concise mechanisms for the main causes of sudden cardiac death (including coronary artery disease, cardiomyopathies, valve abnormalities, major vessel ruptures and electrical conduction abnormalities) based on detailed autopsy data from our specialised cardiac pathology laboratory. Finally, the review will discuss the role of the histopathologist in the event of a ‘negative’ autopsy.