bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activities of Fosfomycin, Tigecycline, Colistin, and Gentamicin against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Foreign-Body Infection Model
Authors: Corvec Stéphane , Furustrand Tafin Ulrika , Betrisey Bertrand , Borens Olivier , Trampuz Andrej 
Published: January 2013

ABSTRACT

Limited antimicrobial agents are available for the treatment of implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli. We compared the activities of fosfomycin, tigecycline, colistin, and gentamicin (alone and in combination) against a CTX-M15-producing strain of
Escherichia coli
(Bj HDE-1)
in vitro
and in a foreign-body infection model. The MIC and the minimal bactericidal concentration in logarithmic phase (MBC
log
) and stationary phase (MBC
stat
) were 0.12, 0.12, and 8 μg/ml for fosfomycin, 0.25, 32, and 32 μg/ml for tigecycline, 0.25, 0.5, and 2 μg/ml for colistin, and 2, 8, and 16 μg/ml for gentamicin, respectively. In time-kill studies, colistin showed concentration-dependent activity, but regrowth occurred after 24 h. Fosfomycin demonstrated rapid bactericidal activity at the MIC, and no regrowth occurred. Synergistic activity between fosfomycin and colistin
in vitro
was observed, with no detectable bacterial counts after 6 h. In animal studies, fosfomycin reduced planktonic counts by 4 log
10
CFU/ml, whereas in combination with colistin, tigecycline, or gentamicin, it reduced counts by >6 log
10
CFU/ml. Fosfomycin was the only single agent which was able to eradicate
E. coli
biofilms (cure rate, 17% of implanted, infected cages). In combination, colistin plus tigecycline (50%) and fosfomycin plus gentamicin (42%) cured significantly more infected cages than colistin plus gentamicin (33%) or fosfomycin plus tigecycline (25%) (
P
< 0.05). The combination of fosfomycin plus colistin showed the highest cure rate (67%), which was significantly better than that of fosfomycin alone (
P
< 0.05). In conclusion, the combination of fosfomycin plus colistin is a promising treatment option for implant-associated infections caused by fluoroquinolone-resistant Gram-negative bacilli.
Placental Transfer of Maraviroc in an
Ex Vivo
Human Cotyledon Perfusion Model and Influence of ABC Transporter Expression
Authors: Vinot C. , Gavard L. , Tréluyer J. M. , Manceau S. , Courbon E. , Scherrmann J. M. , Declèves X. , Duro D. , Peytavin G. , Mandelbrot L. , Giraud C. 
Published: January 2013

ABSTRACT

Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused
ex vivo
for 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (
n
= 10 placentas) or fetal-to-maternal (
n
= 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and
ABCC2
,
ABCC10
, and
ABCC11
placental gene expression levels (
P
< 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by
in vivo
data obtained from paired maternal and cord blood samples.
Reduced Vancomycin Susceptibility in anIn VitroCatheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus
Authors: Abdelhady Wessam , Bayer Arnold S. , Seidl Kati , Nast Cynthia C. , Kiedrowski Megan R. , Horswill Alexander R. , Yeaman Michael R. , Xiong Yan Q. 
Published: January 2013

ABSTRACTStaphylococcus aureusis the most common cause of endovascular infections, including catheter sepsis and infective endocarditis (IE). Vancomycin (VAN) is the primary choice for treatment of methicillin-resistantS. aureus(MRSA) infections. However, high rates of VAN treatment failure in MRSA infections caused by VAN-susceptible strains have been increasingly reported. Biofilm-associated MRSA infections are especially prone to clinical antibiotic failure. The present studies examined potential relationships between MRSA susceptibility to VAN in biofilmsin vitroand nonsusceptibility to VAN in endovascular infectionin vivo. Using 10 “VAN-susceptible” MRSA bloodstream isolates previously investigated for VAN responsiveness in experimental IE, we studied the mechanism(s) of suchin vivoVAN resistance, including: (i) VAN binding to MRSA organisms; (ii) the impact of VAN on biofilm formation and biofilm composition; (iii) VAN efficacy in anin vitrocatheter-related biofilm model; (iv) effects on cell wall thickness. As a group, the five strains previously categorized as VAN nonresponders (non-Rsp) in the experimental IE model differed from the five responders (Rsp) in terms of lower VAN binding, increased biofilm formation, higher survival in the presence of VAN within biofilms in the presence or absence of catheters, and greater biofilm reduction upon proteinase K treatment. Interestingly, sub-MICs of VAN significantly promoted biofilm formation only in the non-Rsp isolates. Cell wall thickness was similar among all MRSA strains. These results suggest that sublethal VAN levels that induce biofilm formation and reduce efficacy of VAN in thein vitrocatheter-associated biofilms may contribute to suboptimal treatment outcomes for endovascular infections caused by “VAN-susceptible” MRSA strains.
Single- and Multiple-Dose Study To Determine the Safety, Tolerability, and Pharmacokinetics of Ceftaroline Fosamil in Combination with Avibactam in Healthy Subjects
Authors: Riccobene Todd A. , Su Sheng Fang , Rank Douglas 
Published: January 2013

ABSTRACT
This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-β-lactam β-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option.
Activities of Drug Combinations against Mycobacterium tuberculosis Grown in Aerobic and Hypoxic Acidic Conditions
Authors: Piccaro Giovanni , Giannoni Federico , Filippini Perla , Mustazzolu Alessandro , Fattorini Lanfranco 
Published: January 2013

ABSTRACT

Mycobacterium tuberculosis
is exposed to hypoxia and acidity within granulomatous lesions. In this study, an acidic culture model of
M. tuberculosis
was used to test drug activity against aerobic 5-day-old (A5) and hypoxic 5-, 12-, and 19-day-old (H5, H12, and H19, respectively) bacilli after 7, 14, and 21 days of exposure. In A cultures, CFU and pH rapidly increased, while in H cultures growth stopped and pH increased slightly. Ten drugs were tested: rifampin (R), isoniazid (I), pyrazinamide (Z), ethambutol (E), moxifloxacin (MX), amikacin (AK), metronidazole (MZ), nitazoxanide (NZ), niclosamide (NC), and PA-824 (PA). Rifampin was the most active against A5, H5, H12, and H19 bacilli. Moxifloxacin and AK efficiently killed A5 and H5 cells, I was active mostly against A5 cells, Z was most active against H12 and H19 cells, and E showed low activity. Among nitrocompounds, NZ, NC, and PA were effective against A5, H5, H12, and H19 cells, while MZ was active against H12 and H19 cells. To kill all A and H cells, A5- and H5-active agents R, MX, and AK were used in combination with MZ, NZ, NC, or PA, in comparison with R-I-Z-E, currently used for human therapy. Mycobacterial viability was determined by CFU and a sensitive test in broth (day to positivity, MGIT 960 system). As shown by lack of regrowth in MGIT, the most potent combination was R-MX-AK-PA, which killed all A5, H5, H12, and H19 cells in 14 days. These observations demonstrate the sterilizing effect of drug combinations against cells of different
M. tuberculosis
stages grown in aerobic and hypoxic acidic conditions.
Microbial Translocation in the Pathogenesis of HIV Infection and AIDS
Authors: Marchetti Giulia , Tincati Camilla , Silvestri Guido 
Published: January 2013

SUMMARY

In pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species.
In vivo
studies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4
+
depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Direct
in situ
evidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS.
Human Rhinoviruses
Authors: Jacobs Samantha E. , Lamson Daryl M. , St. George Kirsten , Walsh Thomas J. 
Published: January 2013

SUMMARYHuman rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genusEnterovirusand the familyPicornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs.
Genome-Wide Identification of Genes Required for Fitness of Group A Streptococcus in Human Blood
Authors: Le Breton Yoann , Mistry Pragnesh , Valdes Kayla M. , Quigley Jeffrey , Kumar Nikhil , Tettelin Hervé , McIver Kevin S. 
Published: January 2013

ABSTRACT

The group A streptococcus (GAS) is a strict human pathogen responsible for a wide spectrum of diseases. Although GAS genome sequences are available, functional genomic analyses have been limited. We developed a
mariner
-based transposon,
osKaR
, designed to perform Transposon-Site Hybridization (TraSH) in GAS and successfully tested its use in several invasive serotypes. A complex
osKaR
mutant library in M1T1 GAS strain 5448 was subjected to negative selection in human blood to identify genes important for GAS fitness in this clinically relevant environment. Mutants underrepresented after growth in blood (output pool) compared to growth in rich media (input pool) were identified using DNA microarray hybridization of transposon-specific tags
en masse
. Using blood from three different donors, we identified 81 genes that met our criteria for reduced fitness in blood from at least two individuals. Genes known to play a role in survival of GAS in blood were found, including those encoding the virulence regulator Mga (
mga
), the peroxide response regulator PerR (
perR
), and the RofA-like regulator Ralp-3 (
ralp3
). We also identified genes previously reported for their contribution to sepsis in other pathogens, such as
de novo
nucleotide synthesis (
purD
,
purA
,
pyrB
,
carA
,
carB
,
guaB
), sugar metabolism (
scrB
,
fruA
), zinc uptake (
adcC
), and transcriptional regulation (
cpsY
). To validate our findings, independent mutants with mutations in 10 different genes identified in our screen were confirmed to be defective for survival in blood bactericidal assays. Overall, this work represents the first use of TraSH in GAS to identify potential virulence genes.
ToxR Recognizes a Direct Repeat Element in the
toxT
,
ompU
,
ompT
, and
ctxA
Promoters of Vibrio cholerae To Regulate Transcription
Authors: Goss Thomas J. , Morgan Sarah J. , French Emily L. , Krukonis Eric S. 
Published: January 2013

ABSTRACT

ToxR facilitates TcpP-mediated activation of the
toxT
promoter in
Vibrio cholerae
, initiating a regulatory cascade that culminates in cholera toxin secretion and toxin coregulated pilus expression. ToxR binds a region from −104 to −68 of the
toxT
promoter, from which ToxR recruits TcpP to the TcpP-binding site from −53 to −38. To precisely define the ToxR-binding site within the
toxT
promoter, promoter derivatives with single-base-pair transversions spanning the ToxR-footprinted region were tested for transcription activation and DNA binding. Nine transversions between −96 to −83 reduced
toxT
promoter activity 3-fold or greater, and all nine reduced the relative affinity of the
toxT
promoter for ToxR at least 2-fold, indicating that activation defects were due largely to reduced binding of ToxR to the
toxT
promoter. Nucleotides important for ToxR-dependent
toxT
activation revealed a consensus sequence of TNAAA-N
5
-TNAAA extending from −96 to −83, also present in other ToxR-regulated promoters. When these consensus nucleotides were mutated in the
ompU
,
ompT
, or
ctxA
promoters, ToxR-mediated regulation was disrupted. Thus, we have defined the core ToxR-binding site present in numerous ToxR-dependent promoters and we have precisely mapped the binding site for ToxR to a position three helical turns upstream of TcpP in the
toxT
promoter.
Tetraspanin CD151 Mediates Papillomavirus Type 16 Endocytosis
Authors: Scheffer Konstanze D. , Gawlitza Alexander , Spoden Gilles A. , Zhang Xin A. , Lambert Carsten , Berditchevski Fedor , Florin Luise 
Published: January 2013

ABSTRACT
Human papillomavirus type 16 (HPV16) is the primary etiologic agent for cervical cancer. The infectious entry of HPV16 into cells occurs via a so-far poorly characterized clathrin- and caveolin-independent endocytic pathway, which involves tetraspanin proteins and actin. In this study, we investigated the specific role of the tetraspanin CD151 in the early steps of HPV16 infection. We show that surface-bound HPV16 moves together with CD151 within the plane of the membrane before they cointernalize into endosomes. Depletion of endogenous CD151 did not affect binding of viral particles to cells but resulted in reduction of HPV16 endocytosis. HPV16 uptake is dependent on the C-terminal cytoplasmic region of CD151 but does not require its tyrosine-based sorting motif. Reexpression of the wild-type CD151 but not mutants affecting integrin functions restored virus internalization in CD151-depleted cells. Accordingly, short interfering RNA (siRNA) gene knockdown experiments confirmed that CD151-associated integrins (i.e., α3β1 and α6β1/4) are involved in HPV16 infection. Furthermore, palmitoylation-deficient CD151 did not support HPV16 cell entry. These data show that complex formation of CD151 with laminin-binding integrins and integration of the complex into tetraspanin-enriched microdomains are critical for HPV16 endocytosis.
“What Goes Around Comes Around”: Prohibitions to Cruelty Against Animals in Judaism
Authors: Kool Richard 
Published: January 2013

AbstractThere is a rich literature within the Jewish tradition, both from biblical exegesis and Talmudic and Midrashic commentary, of concern for animals. In particular, there are injunctions against cruelty that are reflected, for example, in the traditions of kashrut, of humane slaughtering. But the important message is that tradition maintains that caring for animals is a necessary precursor to caring for humans.
Dalforce at the Fall of Singapore in 1942: An Overseas Chinese Heroic Legend
Authors: Chew Ju Ern Daniel , Blackburn Kevin 
Published: January 2013

AbstractDalforce, or the Singapore Overseas Chinese Volunteer Army as it was more popularly known among the Chinese community, was a hastily formed volunteer army created just before the fall of Singapore in February 1942. It was made up of 1,000–3,000 Chinese volunteers from all walks of life and political persuasions. Dalforce companies, armed with limited weapons and ammunition, were sent to defend the different fronts of Singapore Island after only a short stint of training. The soldiers of Dalforce, alongside the Australian, Indian and British armies, fought the Japanese invasion during the Battle for Singapore. The Overseas Chinese community in Singapore saw Dalforce as a medium through which they could join in the struggle, together with their comrades in China, against an aggressive and belligerent Japan. This small army became a symbol of something their comrades in China failed to truly achieve — the ability to unite in one force against a common enemy. The exploits of this little army became an Overseas Chinese legend.
“You Can Never Go Home Again”: Cultural Memory and Identity Formation in the Writing of Southeast Asian Chinese
Authors: St. André James 
Published: January 2013

AbstractThe persistence of memory as a trope in works by Chinese writers in Southeast Asia demonstrates that the sense of identity among Chinese in this area is constantly being interrogated and re-negotiated. This article argues that literary texts are one important constituent factor of collective cultural memory, a purposeful activity undertaken to influence social reality. Even as they foreground the issue of an individual's memory of Chinese culture, they are themselves a type of memorializing practice which seeks to preserve certain types of cultural memory and thus shape the individual's identity. In comparing the works of Singaporean and Malaysian writers, I find a rather stark contrast between the figures used to conceptualize China, Chinese culture, and memory. I argue that Singaporean writers use certain figures to reify Chinese culture and determine its unchanging essence, whereas Malaysian Chinese often have a more fluid view of culture. I then consider some of the ramifications for the use of natural metaphors by the Malaysian writers, which I see as participating in a type of wishful colonial mentality, quite distinct from the historical reality of indentured labor and political disempowerment of the ethnic Chinese in the modern nation state of Malaysia. I conclude by proposing the use of “trunk” as a metaphor for cultural memory and identity formation.
Virtual Communities and Chinese National Identity
Authors: Chan Brenda 
Published: January 2013

AbstractWith the implementation of economic reforms in the People's Republic of China (PRC) and the relaxation of restrictions on foreign travel, a new wave of overseas migration from mainland China has taken place. Compared to the earlier waves of Chinese emigrants who were semi-literate peasants and craftsmen, many new Chinese migrants are highly educated professionals and are extremely mobile. While the earlier Chinese migrants were mostly from southern provinces in China and organized their voluntary associations based on native-place or blood ties, new Chinese migrants hail from different regions in China, and would build social organizations of different configurations. Besides setting up voluntary organizations offline, these new Chinese migrants are also forming cybercommunities on the Internet. This article investigates whether virtual communities formed by new Chinese migrants also offer identity options to migrants in terms of ethnicity and national belonging, as offline immigrant associations do. It does so by examining the varieties of Chinese national identities articulated in cyberspace and in the offline activities of two virtual communities formed by new Chinese migrants who are working and studying in Singapore. I argue that virtual communities formed by migrants may or may not offer distinct identity options to their members in terms of ethnic or national belonging. Virtual communities with very diverse user profiles may offer more distinct identity options for their members as a strategy in attracting and retaining members, compared to virtual communities with a more homogeneous membership.