bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pretreatment of Epithelial Cells with Rifaximin Alters Bacterial Attachment and Internalization Profiles
Authors: Brown Eric L. , Xue Qiong , Jiang Zhi-Dong , Xu Yi , DuPont Herbert L. 
Published: October 2009

ABSTRACT

Rifaximin is a poorly absorbed semisynthetic antibiotic derivative of rifampin licensed for use in the treatment of traveler's diarrhea. Rifaximin reduces the symptoms of enteric infection, often without pathogen eradication and with limited effects on intestinal flora. Epithelial cells (HEp-2 [laryngeal], HCT-8 [ileocecal], A549 [lung], and HeLa [cervical]) were pretreated with rifaximin (or control antibiotics) prior to the addition of enteroaggregative
Escherichia coli
(EAEC). EAEC adherence was significantly reduced following rifaximin pretreatment compared to pretreatment with rifampin or doxycycline for three of the four cell lines tested. The rifaximin-mediated changes to epithelial cells were explored further by testing the attachment and internalization of either
Bacillus anthracis
or
Shigella sonnei
into A549 or HeLa cells, respectively. The attachment and internalization of
B. anthracis
were significantly reduced following rifaximin pretreatment. In contrast, neither the attachment nor the internalization of
S. sonnei
was affected by rifaximin pretreatment of HeLa cells, suggesting that rifaximin-mediated modulation of host cell physiology affected bacteria utilizing distinct attachment/internalization mechanisms differently. In addition, rifaximin pretreatment of HEp-2 cells led to reduced concentrations of inflammatory cytokines from uninfected cells. The study provides evidence that rifaximin-mediated changes in epithelial cell physiology are associated with changes in bacterial attachment/internalization and reduced inflammatory cytokine release.
Pharmacokinetic Properties of Azithromycin in Pregnancy
Authors: Salman Sam , Rogerson Stephen J. , Kose Kay , Griffin Susan , Gomorai Servina , Baiwog Francesca , Winmai Josephine , Kandai Josin , Karunajeewa Harin A. , O'Halloran Sean J. , Siba Peter , Ilett Kenneth F. , Mueller Ivo , Davis Timothy M. E. 
Published: October 2009

ABSTRACT

Azithromycin (AZI) is an azalide antibiotic with antimalarial activity that is considered safe in pregnancy. To assess its pharmacokinetic properties when administered as intermittent preventive treatment in pregnancy (IPTp), two 2-g doses were given 24 h apart to 31 pregnant and 29 age-matched nonpregnant Papua New Guinean women. All subjects also received single-dose sulfadoxine-pyrimethamine (SP) (1,500 mg or 75 mg) or chloroquine (450-mg base daily for 3 days). Blood samples were taken at 0, 1, 2, 3, 6, 12, 24, 32, 40, 48, and 72 h and on days 4, 5, 7, 10, and 14 for AZI assay by ultra-high-performance liquid chromatography-tandem mass spectrometry. The treatments were well tolerated. Using population pharmacokinetic modeling, a three-compartment model with zero-order followed by first-order absorption and no lag time provided the best fit. The areas under the plasma concentration-time curve (AUC
0-∞
) (28.7 and 31.8 mg·h liter
−1
for pregnant and nonpregnant subjects, respectively) were consistent with the results of previous studies, but the estimated terminal elimination half-lives (78 and 77 h, respectively) were generally longer. The only significant relationship for a range of potential covariates, including malarial parasitemia, was with pregnancy, which accounted for an 86% increase in the volume of distribution of the central compartment relative to bioavailability without a significant change in the AUC
0-∞
. These data suggest that AZI can be combined with compounds with longer half-lives, such as SP, in combination IPTp without the need for dose adjustment.
Mapping Simocyclinone D8 Interaction with DNA Gyrase: Evidence for a New Binding Site on GyrB
Authors: Sissi C. , Vazquez E. , Chemello A. , Mitchenall L. A. , Maxwell A. , Palumbo M. 
Published: October 2009

ABSTRACT

Simocyclinone D8, a coumarin derivative isolated from
Streptomyces antibioticus
Tü 6040, represents an interesting new antiproliferative agent. It was originally suggested that this drug recognizes the GyrA subunit and interferes with the gyrase catalytic cycle by preventing its binding to DNA. To further characterize the mode of action of this antibiotic, we investigated its binding to the reconstituted DNA gyrase (A
2
B
2
) as well as to its GyrA and GyrB subunits and the individual domains of these proteins, by performing protein melting and proteolytic digestion studies as well as inhibition assays. Two binding sites were identified, one (anticipated) in the N-terminal domain of GyrA (GyrA59) and the other (unexpected) at the C-terminal domain of GyrB (GyrB47). Stabilization of the A subunit appears to be considerably more effective than stabilization of the B subunit. Our data suggest that these two distinct sites could cooperate in the reconstituted enzyme.
Factors Influencing Pharmacokinetics of Prophylactic Posaconazole in Patients Undergoing Allogeneic Stem Cell Transplantation
Authors: Kohl V. , Müller C. , Cornely O. A. , Abduljalil K. , Fuhr U. , Vehreschild J. J. , Scheid C. , Hallek M. , Rüping M. J. G. T. 
Published: October 2009

ABSTRACT
The objectives of the present study were to elucidate the factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic hematopoietic stem cell transplant (SCT) recipients. Between May 2007 and November 2008, clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75.8 liters/h (95% confidence interval [CI], 65.2 to 86.4 liters/h) and the apparent volume being distribution of 835 liters (95% CI, 559 to 1,111 liters). Among the covariates tested, significant effects were found for age (decrease in the volume of distribution of 123 liters per year of age) and the presence of diarrhea (59% loss of bioavailability). A basis for prediction of the mean posaconazole concentrations in allogeneic SCT recipients with hematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to the presence of diarrhea and according to age appear to be justified before TDM results are available.
Major Surface Protease of Trypanosomatids: One Size Fits All?
Authors: Yao Chaoqun 
Published: October 2009

ABSTRACTMajor surface protease (MSP or GP63) is the most abundant glycoprotein localized to the plasma membrane ofLeishmaniapromastigotes. MSP plays several important roles in the pathogenesis of leishmaniasis, including but not limited to (i) evasion of complement-mediated lysis, (ii) facilitation of macrophage (Mø) phagocytosis of promastigotes, (iii) interaction with the extracellular matrix, (iv) inhibition of natural killer cellular functions, (v) resistance to antimicrobial peptide killing, (vi) degradation of Mø and fibroblast cytosolic proteins, and (vii) promotion of survival of intracellular amastigotes. MSP homologues have been found in all other trypanosomatids studied to date including heteroxenous members ofTrypanosoma cruzi, the extracellularTrypanosoma brucei, unusual intraerythrocyticEndotrypanumspp., phytoparasiticPhytomonasspp., and numerous monoxenous species. These proteins are likely to perform roles different from those described forLeishmaniaspp. Multiple MSPs in individual cells may play distinct roles at some time points in trypanosomatid life cycles and collaborative or redundant roles at others. The cellular locations and the extracellular release of MSPs are also discussed in connection with MSP functions in leishmanial promastigotes.
Helicobacter pylori
Lipopolysaccharides Upregulate Toll-Like Receptor 4 Expression and Proliferation of Gastric Epithelial Cells via the MEK1/2-ERK1/2 Mitogen-Activated Protein Kinase Pathway
Authors: Yokota Shin-ichi , Okabayashi Tamaki , Rehli Michael , Fujii Nobuhiro , Amano Ken-ichi 
Published: October 2009

ABSTRACT

Helicobacter pylori
is recognized as an etiological agent of gastroduodenal diseases.
H. pylori
produces various toxic substances, including lipopolysaccharide (LPS). However,
H. pylori
LPS exhibits extremely weakly endotoxic activity compared to the typical LPS, such as that produced by
Escherichia coli
, which acts through Toll-like receptor 4 (TLR4) to induce inflammatory molecules. The gastric epithelial cell lines MKN28 and MKN45 express TLR4 at very low levels, so they show very weak interleukin-8 (IL-8) production in response to
E. coli
LPS, but pretreatment with
H. pylori
LPS markedly enhanced IL-8 production induced by
E. coli
LPS by upregulating TLR4 via TLR2 and the MEK1/2-ERK1/2 pathway. The transcription factor NF-Y was activated by this signal and promoted transcription of the
tlr4
gene. These MEK1/2-ERK1/2 signal-mediated activities were more potently activated by LPS carrying a weakly antigenic epitope, which is frequently found in gastric cancers, than by LPS carrying a highly antigenic epitope, which is associated with chronic gastritis.
H. pylori
LPS also augmented the proliferation rate of gastric epithelial cells via the MEK1/2-ERK1/2 pathway.
H. pylori
LPS may be a pathogenic factor causing gastric tumors by enhancing cell proliferation and inflammation via the MEK1/2-ERK1/2 mitogen-activated protein kinase cascade in gastric epithelial cells.
The Stability of Cytadherence Proteins in
Mycoplasma pneumoniae
Requires Activity of the Protein Kinase PrkC
Authors: Schmidl Sebastian R. , Gronau Katrin , Hames Claudine , Busse Julia , Becher Dörte , Hecker Michael , Stülke Jörg 
Published: October 2009

ABSTRACT

Mycoplasma pneumoniae
belongs to the mollicutes, a group of bacteria that have strongly reduced genomes but that are nevertheless capable of independent life. With only three transcription factors, the regulatory features of these bacteria are very limited. Thus, posttranslational regulation might be important for
M. pneumoniae
. In addition to the highly specific HPr kinase, the
M. pneumoniae prkC
gene encodes the serine/threonine protein kinase C. In order to study the function(s) of this kinase, we isolated an
M. pneumoniae
mutant affected in PrkC. This mutation resulted in nonadherent growth and loss of cytotoxicity. Examination of the phosphorylation profile of the
prkC
mutant suggested that phosphorylation of cytadherence proteins was affected by the loss of this kinase. In contrast, inactivation of the
prpC
gene affecting the protein phosphatase that antagonizes PrkC-dependent phosphorylation resulted in more intensive phosphorylation of the cytadherence proteins HMW1 and HMW3 of the major adhesin P1 and of the surface protein MPN474. Moreover, loss of PrkC affects not only the phosphorylation state of the cytadherence proteins but also their intracellular accumulation. However, the expression of the corresponding genes was not affected by PrkC, suggesting that PrkC-dependent phosphorylation results in stabilization of the cytadherence proteins. The HMW proteins and P1 are part of the so-called terminal organelle of
M. pneumoniae
that is involved in gliding motility, cell division, and adhesion to host epithelial tissues. Our observations suggest that the posttranslational modification of cytadherence proteins by PrkC is essential for the development and function of the
M. pneumoniae
terminal organelle.
Candida albicans
Releases Soluble Factors That Potentiate Cytokine Production by Human Cells through a Protease-Activated Receptor 1- and 2-Independent Pathway
Authors: Cheng Shih-Chin , Chai Louis Y. A. , Joosten Leo A. B. , Vecchiarelli Anna , Hube Bernhard , Van Der Meer Jos W. , Kullberg Bart Jan , Netea Mihai G. 
Published: October 2009

ABSTRACT

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRR) and transduces downstream signaling to activate the host defense. Here we report that in addition to direct PAMP-PRR interactions, live
Candida albicans
cells can release soluble factors to actively potentiate interleukin-6 (IL-6) and IL-8 production induced in human mononuclear cells by the fungi. Although protease-activated receptor 1 (PAR1) and PAR2 ligation can moderately upregulate Toll-like receptor 4 (TLR4)-mediated IL-8 production, no effect on the
C. albicans
-induced cytokine was apparent. Similarly, the blockade of PAR signaling did not reverse the potentiation of cytokine production induced by soluble factors released by
C. albicans
. In conclusion,
C. albicans
releases soluble factors that potentiate cytokine release in a PAR1/2-independent manner. Thus, human PAR1 and PAR2 have a redundant role in the activation of human cells by
C. albicans
.
ECG as a part of the preparticipation screening programme: an old and still present international dilemma
Authors: Hevia A Carro , Fernández M M , Palacio J M A , Martín E H , Castro M G , Reguero J J Rodríguez 
Published: October 2009

IntroductionLong-term Italian experience has provided evidence that preparticipation screening in competitive athletes with 12-lead ECG, history and physical examination is effective in identifying potentially lethal cardiovascular diseases. However, it is not being routinely practised in other countries.ObjectivesTo evaluate the usefulness of a preparticipation screening programme in a sample of players belonging to different disciplines.Material and methodsFrom September 2006 to June 2008, 1220 young athletes from different sports disciplines underwent a cardiovascular examination that included personal and family history, physical examination and a resting 12-lead ECG. Those with abnormal findings were referred for additional tests.Results1220 Athletes were screened: 96% males; mean age 23 (4) years. 90 (7.4%) players were referred for additional tests because of abnormal findings on baseline examination: 11 (0.9%) personal or family history, 4 (0.08%) physical examination and 75 (6.14%) 12-lead ECG. Echocardiographic assessment fulfilled left ventricular hypertrophy criteria in 8 of the 90 players. Of those, one case was considered an athlete's heart and one case was diagnosed with hypertrophic cardiomyopathy (septal thickness 23 mm). Further tests were needed in the remaining six, included in the “grey area”, with one additional case of hypertrophic cardiomyopathy (apical variant) suggested by cardiac MRI.ConclusionGiven the ability of 12-lead ECG to detect individuals with structural heart disease, we suggest its inclusion as a part of preparticipation screening programmes.
Heat injury in youth sport: Table 1
Authors: Marshall S W 
Published: October 2009

Heat injury is a potentially lethal condition that is considered to be completely preventable. Fatal heat injury is relatively rare (0.20 per 100 000 player-seasons in US high school football) and there are very limited data on non-fatal incidence. Expert recommendations for prevention include gradual acclimatisation of youth athletes to hot conditions, reductions in activity in hot and humid conditions, wearing light and light-coloured clothing, careful monitoring of athletes for signs of heat injury to facilitate immediate detection, having the resources to immediately and rapidly cool affected athletes, and education of athletes, care givers, and coaches about heat injury. Although a base of observational case data, physiological information, and expert opinion exists, the science surrounding this field is devoid of health communication and health behaviour research, and there is a pressing need for analytical studies to evaluate intervention programmes and/or identify new risk factors. There is also a need for ongoing data collection on heat injury incidence and on the knowledge, attitudes and behaviours towards heat injury among youth athletes, their care givers and their coaches.
The significance of tumour cell immunophenotype in myeloma and its impact on clinical outcome
Authors: Ngo N-T , Brodie C , Giles C , Horncastle D , Klammer M , Lampert I A , Rahemtulla A , Naresh K N 
Published: October 2009

Background and aims:Antigen expression of multiple myeloma (MM) cells is heterogeneous. We have investigated the clinical impact of expression of some of the commonly used immunohistochemical markers in the diagnostic work-up of bone marrow trephine biopsy (BMTB) samples in MM.Patients and methods:BMTB samples from 107 MM patients who had received an autologous stem cell transplant (ASCT) following chemotherapy were evaluated. In 75 cases, the immunophenotype had been evaluated on two or more occasions on further follow-up.Results:In the cases evaluated, 32%, 79%, 73%, 39% and 60% of cases had been scored positive for CD20, CD79a, CD56, cyclin D1 and epithelial membrane antigen (EMA) respectively. Absence of CD79a was predictive of poor overall survival (OS) from the time of transplant (p = 0.029) and poor event-free survival (EFS) from the time of transplant (p = 0.003). Absence of EMA (p = 0.02) was predictive of poor EFS from the time of diagnosis. Presence of CD56 was predictive of poor EFS from the time of diagnosis (p = 0.026). On multivariate analysis, only CD79a expression (OS and EFS from the time of transplant) and EMA expression (EFS from the time of diagnosis) maintained their significance. 13 of 75 patients showed an immunophenotypic drift during the disease course. Loss of CD20 (four cases) during the disease course in cases that were previously scored positive correlated with significant worsening both, of OS (p = 0.02) and EFS (p = 0.009) from the time of diagnosis.Conclusion:Immunophenotype impacts on clinical outcome in MM.
Energy-efficient register caching with compiler assistance
Authors: Jones Timothy M. , O'Boyle Michael F. P. , Abella Jaume , González Antonio , Ergin Oğuz 
Published: October 2009

The register file is a critical component in a modern superscalar processor. It must be large enough to accommodate the results of all in-flight instructions. It must also have enough ports to allow simultaneous issue and writeback of many values each cycle. However, this makes it one of the most energy-consuming structures within the processor with a high access latency. As technology scales, there comes a point where register accesses are the bottleneck to performance and so must be pipelined over several cycles. This increases the pipeline depth, lowering performance.
To overcome these challenges, we propose a novel use of compiler analysis to aid register caching. Adding a register cache allows us to preserve single-cycle register accesses, maintaining performance and reducing energy consumption. We do this by passing information to the processor using free bits in a real ISA, allowing us to cache only the most important registers. Evaluating the register cache over a variety of sizes and associativities and varying the read ports into the cache, our best scheme achieves an energy-delay-squared (EDD) product of 0.81, with a performance increase of 11%. Another configuration saves 13% of register system energy. Using four register cache read ports brings both performance gains and energy savings, consistently outperforming two state-of-the-art hardware approaches.
ReconOS
Authors: Lübbers Enno , Platzner Marco 
Published: October 2009

Rising logic densities together with the inclusion of dedicated processor cores push reconfigurable devices from being applied for glue logic and prototyping towards implementing complete reconfigurable systems-on-chip. The mix of fast CPU cores and fine-grained reconfigurable logic allows to map both sequential, control-dominated code and highly parallel data-centric computations onto one platform. However, traditional design techniques that view specialized hardware circuits as passive coprocessors are ill-suited for programming these reconfigurable computers. In particular, the programming models for software—running on an embedded operating system—and digital hardware—synthesized to an FPGA—lack commonalities, which hinders design space exploration and severely impairs the potential for code reuse.
In this article, we present ReconOS, an execution environment based on existing embedded operating systems that extends the multithreaded programming model established in the software domain to reconfigurable hardware. Using threads and common synchronization and communication services as an abstraction layer, ReconOS allows for the creation of portable and flexible multithreaded applications targeting CPU/FPGA systems. This article discusses the ReconOS programming model and its execution environment, presents implementations based on modern platform FPGAs and the operating systems eCos and Linux, evaluates time and area overheads of the proposed mechanisms and, finally, demonstrates the feasibility of the multithreading design approach on several case studies.
Seasonally Modulated Tropical Drought Induced by Volcanic Aerosol
Authors: Joseph Renu , Zeng Ning 
Published: October 2009

Abstract
Major volcanic events with a high loading of stratospheric aerosol have long been known to cause cooling, but their impact on precipitation has only recently been emphasized, especially as an analog for potential geoengineering of climate. Here, the authors use a coupled atmosphere–ocean–land–vegetation model in conjunction with observations to study the effects of volcanic aerosol on the tropical and subtropical precipitation. The small internal variability in the model enables a clear identification of the volcanic impact, which is broadly supported by observations, especially for the large Pinatubo event. Area averaged rainfall over land between 40°S and 40°N decreases by about 0.15 mm day−1, 4–5 months after the height of a major volcanic aerosol loading, such as from Pinatubo, with regional changes as large as 0.6 mm day−1 or higher, such as over the Amazon and equatorial Africa. These anomalies migrate seasonally, following the movement of monsoon rainfall. This is because the low heat capacity of the land leads to rapid response of rainfall there, owing to the energy imbalance caused by volcanic aerosol cooling. In contrast, precipitation response over the ocean is much slower and considerably damped because of the much larger heat capacity. In addition, the difference in heat capacities over land and over ocean leads to an anomalous land–sea thermal contrast, which could further contribute to the reduction of rainfall over land. The volcano-induced drought may have significant impact on the ecosystem, agriculture, and the carbon cycle, especially in the monsoon regions.