bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlated firing among major ganglion cell types in primate retina
Authors: Greschner Martin , Shlens Jonathon , Bakolitsa Constantina , Field Greg D. , Gauthier Jeffrey L. , Jepson Lauren H. , Sher Alexander , Litke Alan M. , Chichilnisky E. J. 
Published: October 2010

Non‐technical summaryThis paper examines the correlated firing among multiple ganglion cell types in the retina. For many years it has been known that ganglion cells exhibit a tendency to fire simultaneously more or less frequently than would be predicted by chance. However, the particular patterns of correlated activity in the primate retina have been unclear. Here we reveal systematic, distance‐dependent correlations between different ganglion cell types. For the most part, the patterns of activity are consistent with a model in which noise in cone photoreceptors propagates through common retinal circuitry, creating correlations among ganglion cell signals.
Serotype Distribution and Susceptibility of
Streptococcus pneumoniae
Isolates from Pleural Fluid in Spain from 1997 to 2008
Authors: Fenoll A. , Aguilar L. , Vicioso M. D. , Gimenez M. J. , Robledo O. , Granizo J. J. , Mendez C. 
Published: October 2010

ABSTRACT

Trends in serotype incidence and susceptibility (1997 to 2008) of Spanish
Streptococcus pneumoniae
pleural isolates (
n
= 831) were explored. Penicillin (oral) nonsusceptibility rates and the incidence of 7-valent pneumococcal conjugate vaccine (PCV-7) serotypes showed decreasing trends (
R
2
≥ 0.600;
P
≤ 0.002). The incidence of serotypes 1 and 19A showed increasing trends (
R
2
≥ 0.759;
P
< 0.001), with no trends for serotype 3. Serotypes 19A, 1, and 3 represented 85% of pediatric isolates in 2008. In serotype 19A, the penicillin nonsusceptibility rate was 82.4% in 2008, associated with amoxicillin and cefotaxime nonsusceptibility in 21.4% of isolates. Inclusion of these serotypes in new vaccines offers the broadest coverage.
In Vivo
Pharmacodynamic Activity of Tomopenem (formerly CS-023) against
Pseudomonas aeruginosa
and Methicillin-Resistant
Staphylococcus aureus
in a Murine Thigh Infection Model
Authors: Sugihara Kiyoshi , Sugihara Chika , Matsushita Yoko , Yamamura Naotoshi , Uemori Mitsutoshi , Tokumitsu Akane , Inoue Harumi , Kakuta Masayo , Namba Eiko , Nasu Hatsumi , Koga Tetsufumi 
Published: October 2010

ABSTRACT

Tomopenem (formerly CS-023) is a novel carbapenem with broad-spectrum activities against diverse hospital pathogens, including
Pseudomonas aeruginosa
and methicillin-resistant
Staphylococcus aureus
(MRSA). We examined the
in vivo
pharmacodynamic characteristics of tomopenem against
P. aeruginosa
and MRSA by using a neutropenic murine thigh infection model with
P. aeruginosa
12467 (MIC, 1 μg/ml) and MRSA 12372 (MIC, 2 μg/ml). The mice had 10
6
to 10
7
CFU/thigh of each strain 2 h after inoculation and were treated for 24 h with a fractionated administration of tomopenem given at intervals of 3, 6, 12, and 24 h. The serum protein binding of tomopenem was 17.4%. The efficacy of tomopenem in both infection models was enhanced by frequent dosing, which indicates that the efficacy is driven by the time above MIC (
T
MIC
). In a sigmoid model, the cumulative percentages of the 24-h period that the concentrations of free, unbound fractions of the drug exceeded the MIC under steady-state pharmacokinetic conditions (
f
%
T
MIC
s) were best correlated with efficacy when
R
2
was 0.79 and 0.86 against
P. aeruginosa
and MRSA, respectively. Other pharmacokinetic and pharmacodynamic (PK-PD) indexes for the free, unbound fractions, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) and the maximum concentration of the drug in serum divided by the MIC (
C
max
/MIC), showed poor correlation with efficacy when
R
2
was ≤0.42. The
f
%
T
MIC
values required for a static effect, 1-log kill, and 2-log kill against
P. aeruginosa
were 29, 39, and 51, respectively, which were similar to those for meropenem, for which the values were 24, 33, and 45, respectively. Against MRSA, the values for tomopenem were 27, 35, and 47. In conclusion, the pharmacodynamic characteristics of tomopenem were similar to those of meropenem against
P. aeruginosa
, and there was no difference between the target values for
P. aeruginosa
and MRSA required for efficacy in this study.
In Vitro
Evaluation of Viability, Integrity, and Inflammation in Genital Epithelia upon Exposure to Pharmaceutical Excipients and Candidate Microbicides
Authors: Gali Youssef , Delezay Olivier , Brouwers Joachim , Addad Noura , Augustijns Patrick , Bourlet Thomas , Hamzeh-Cognasse Hind , Ariën Kevin K. , Pozzetto Bruno , Vanham Guido 
Published: October 2010

ABSTRACT

The use of microbicides is a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the
in vivo
efficiency/toxicity rate, including
in vitro
assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicities of various active pharmaceutical ingredients (APIs; TMC-120, UC-781, tenofovir [PMPA], PRO-2000, and glycerol monolaurate [GML]) and excipients (preservatives, cosolvents, surfactants, and cyclodextrins) were evaluated using an
in vitro
dual-chamber model and uterine cervical explants. Epithelial viability and permeation of fluorescent virus-sized beads, as well as induction of interleukin-8 (IL-8; as a sensitive marker of an inflammatory response), were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels, and a significant increase in the production of IL-8 was observed at subtoxic concentrations. Within the APIs, TMC-120, UC-781, and PMPA showed higher selectivity indices than PRO-2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparations.
Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase Inhibitor
Authors: Stachyra Thérèse , Péchereau Marie-Claude , Bruneau Jean-Michel , Claudon Monique , Frère Jean-Marie , Miossec Christine , Coleman Kenneth , Black Michael T. 
Published: October 2010

ABSTRACT

NXL104 is a potent inhibitor of class A and C serine β-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 β-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 β-lactamases were determined, including partition ratios, dissociation constants (
K
), rate constants for deactivation (
k
2
), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (
k
2
/
K
of 3.7 × 10
5
M
−1
s
−1
for TEM-1 and 1 × 10
4
M
−1
s
−1
for P99) and slow decarbamylation. Complete loss of β-lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a
k
3
value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC
50
s) were evaluated on selected β-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C β-lactamases. IC
50
s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the β-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex.
In Vivo
Selection of a Missense Mutation in
adeR
and Conversion of the Novel
bla
OXA-164
Gene into
bla
OXA-58
in Carbapenem-Resistant
Acinetobacter baumannii
Isolates from a Hospitalized Patient
Authors: Higgins Paul G. , Schneiders Thamarai , Hamprecht Axel , Seifert Harald 
Published: October 2010

ABSTRACT

The mechanism of stepwise acquired multidrug resistance in
Acinetobacter baumannii
isolates from a hospitalized patient was investigated. Thirteen consecutive multidrug-resistant isolates were recovered from the same patient over a 2-month period. The Vitek 2 system identified the isolates as meropenem-sensitive
Acinetobacter lwoffii
; however, molecular identification showed that the isolates were
A. baumannii
. Etest revealed that the isolates were meropenem resistant. The presence of oxacillinase (OXA)-type enzymes were investigated by sequencing. The clonal relatedness of isolates was assessed by pulsed-field gel electrophoresis (PFGE). Expression of the genes encoding the efflux pumps AdeB and AdeJ was performed by semiquantitative real-time reverse transcription-PCR (qRT-PCR). The
adeRS
two-component system was sequenced. All isolates had identical PFGE fingerprints, suggesting clonal identity. The first six isolates were positive for the novel
bla
OXA-164
gene. The following seven isolates, recovered after treatment with a combination of meropenem, amikacin, ciprofloxacin, and co-trimoxazole showed an increase of >7-fold in
adeB
mRNA transcripts and a missense mutation in
bla
OXA-164
, converting it to
bla
OXA-58
. Sequencing revealed a novel mutation in
adeR
. These data illustrate how
A. baumannii
can adapt during antimicrobial therapy, leading to increased antimicrobial resistance.
Rv1218c, an ABC Transporter of
Mycobacterium tuberculosis
with Implications in Drug Discovery
Authors: Balganesh Meenakshi , Kuruppath Sanjana , Marcel Nimi , Sharma Sreevalli , Nair Anju , Sharma Umender 
Published: October 2010

ABSTRACT

Efflux systems are important in determining the efficacy of antibiotics used in the treatment of bacterial infections. In the last decade much attention has been paid to studying the efflux pumps of mycobacteria. New classes of compounds are under investigation for development into potential candidate drugs for the treatment of tuberculosis. Quite often, these have poor bactericidal activities but exhibit excellent target (biochemical) inhibition. Microarray studies conducted in our laboratories for deciphering the mode of action of experimental drugs revealed the presence of putative ABC transporters. Among these transporters, Rv1218c was chosen for studying its physiological relevance in mediating efflux in
Mycobacterium tuberculosis
. A Δ
Rv1218c
mutant of
M. tuberculosis
displayed a 4- to 8-fold increase in the inhibitory and bactericidal potency for different classes of compounds. The MICs and MBCs were reversed to wild-type values when the full-length
Rv1218c
gene was reintroduced into the Δ
Rv1218c
mutant on a multicopy plasmid. Most of the compound classes had significantly better bactericidal activity in the Δ
Rv1218c
mutant than in the wild-type H37Rv, suggesting the involvement of
Rv1218c
gene product in effluxing these compounds from
M. tuberculosis
. The implication of these findings on tuberculosis drug discovery is discussed.
Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using
In Vivo
Microdialysis
Authors: Bulik Catharine C. , Wiskirchen Dora E. , Shepard Ashley , Sutherland Christina A. , Kuti Joseph L. , Nicolau David P. 
Published: October 2010

ABSTRACT

Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent
in vivo
recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC
0-24
) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 μg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (
P
= 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 μg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue
f
AUC/plasma
f
AUC) were 99% in the thigh and 100% in the wound (
P
= 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.
Surface Expression of MPT64 as a Fusion with the PE Domain of PE_PGRS33 EnhancesMycobacterium bovisBCG Protective Activity againstMycobacterium tuberculosisin Mice
Authors: Sali Michela , Di Sante Gabriele , Cascioferro Alessandro , Zumbo Antonella , Nicolò Chiara , Donà Valentina , Rocca Stefano , Procoli Annabella , Morandi Matteo , Ria Francesco , Palù Giorgio , Fadda Giovanni , Manganelli Riccardo , Delogu Giovanni 
Published: October 2010

ABSTRACTTo improve the current vaccine against tuberculosis, a recombinant strain ofMycobacterium bovisbacillus Calmette-Guérin (rBCG) expressing aMycobacterium tuberculosisvaccine candidate antigen (MPT64) in strong association with the mycobacterial cell wall was developed. To deliver the candidate antigen on the surface, we fused thempt64gene to the sequence encoding the PE domain of the PE_PGRS33 protein ofM. tuberculosis(to create strainHPE-ΔMPT64-BCG), which we have previously shown to transport proteins to the bacterial surface. In a series of protection experiments in the mouse model of tuberculosis, we showed that (i) immunization of mice withHPE-ΔMPT64-BCG provides levels of protection significantly higher than those afforded by the parental BCG strain, as assessed by bacterial colonization in lungs and spleens and by lung involvement (at both 28 and 70 days postchallenge), (ii) rBCG strains expressing MPT64 provide better protection than the parental BCG strain only when this antigen is surface expressed, and (iii) theHPE-ΔMPT64-BCG-induced MPT64-specific T cell repertoire when characterized by β chain variable region-β chain joining region (BV-BJ) spectratyping indicates that protection is correlated with the ability to recruit gamma interferon (IFN-γ)-secreting T cells carrying the BV8.3-BJ1.5 (172 bp) shared rearrangement. These results demonstrate thatHPE-ΔMPT64-BCG is one of the most effective new vaccines tested so far in the mouse model of tuberculosis and underscore the impact of antigen cellular localization on the induction of the specific immune response induced by rBCG.
Evidence for the Horizontal Transfer of an Unusual Capsular Polysaccharide Biosynthesis Locus in Marine Bacteria
Authors: Nakhamchik Alina , Wilde Caroline , Chong Henry , Rowe-Magnus Dean A. 
Published: October 2010

ABSTRACT

The most intensely studied of the
Vibrio vulnificus
virulence factors is the capsular polysaccharide (CPS). All virulent strains produce copious amounts of CPS. Acapsular strains are avirulent. The structure of the CPS from the clinical isolate ATCC 27562 is unusual. It is serine modified and contains, surprisingly,
N
-acetylmuramic acid. We identified the complete 25-kb CPS biosynthesis locus from ATCC 27562. It contained 21 open reading frames and was allelic to O-antigen biosynthesis loci. Two of the genes,
murA
CPS
and
murB
CPS
, were paralogs of the
murA
PG
and
murB
PG
genes of the peptidoglycan biosynthesis pathway; only a single copy of these genes is present in the strain CMCP6 and YJ016 genomes. Although MurA
CPS
and MurB
CPS
were functional when expressed in
Escherichia coli
, lesions in either gene had no effect on CPS production, virulence, or growth in
V. vulnificus
; disruption of 8 other genes within the locus resulted in an acapsular phenotype and attenuated virulence. Thus,
murA
CPS
and
murB
CPS
were functional but redundant. Comparative genomic analysis revealed that while completely different CPS biosynthesis loci were found in the same chromosomal region in other
V. vulnificus
strains, most of the CPS locus of ATCC 27562 was conserved in another marine bacterium,
Shewanella putrefaciens
strain 200. However, the average GC content of the CPS locus was significantly lower than the average GC content of either genome. Furthermore, several of the encoded proteins appeared to be of Gram-positive and archaebacterial origin. These data indicate that the horizontal transfer of intact and partial CPS loci drives CPS diversity in marine bacteria.
Interleukin-17 Is Not Required for Classical Macrophage Activation in a Pulmonary Mouse Model ofCryptococcus neoformansInfection
Authors: Hardison Sarah E. , Wozniak Karen L. , Kolls Jay K. , Wormley Floyd L. 
Published: October 2010

ABSTRACTCryptococcus neoformansis an opportunistic fungal pathogen that causes disease in individuals with suppressed cell-mediated immunity. Recent studies in our laboratory have shown that increases in pulmonary Th1-type and interleukin-17A (IL-17A) cytokine production, classical macrophage activation, and sterilizing immunity are elicited in response to infection with a gamma interferon (IFN-γ)-producingC. neoformansstrain, H99γ. IL-17A-treated macrophages, compared to IL-4-treated macrophages, have been demonstrated to exhibit increased microbicidal activityin vitro, a characteristic consistent with classical macrophage activation. The purpose of these studies is to determine the role of IL-17A in the induction of classically activated macrophages following infection withC. neoformans. Immunohistochemistry and real-time PCR were used to characterize the macrophage activation phenotype in lung tissues of mice treated with isotype control or anti-IL-17A antibodies and given an experimental pulmonary infection withC. neoformansstrain H99γ. The pulmonary fungal burden was resolved, albeit more slowly, in mice depleted of IL-17A compared to the fungal burden in isotype control-treated mice. Nonetheless, no difference in classical macrophage activation was observed in IL-17A-depleted mice. Similarly, classical macrophage activation was evident in mice deficient in IL-17A or the IL-17 receptor A, which mediates IL-17A signaling, following pulmonary infection with wild-typeC. neoformansstrain H99 or H99γ. These studies suggest that IL-17A may play a role in the early immune response toC. neoformansbut is not required for classical macrophage activation in mice experimentally infected withC. neoformans.
Pharmacokinetics and efficacy of teicoplanin against intramammary infections in sheep
Authors: Naccari C. , Niutta P. P. , Trombetta D. , De Domenico A. , Pizzimenti F. , Cagnardi P. , Carli S. , Naccari F. 
Published: October 2010

The pharmacokinetics of teicoplanin were evaluated in 10 healthy sheep. After intravenous injection it showed monophasic behaviour, with a short mean (sd) elimination half‐life (5 [0.24] hours). After intramuscular injection its bioavailability was 100 per cent but it was absorbed slowly; its elimination half‐life was satisfactorily slow (9.23 [0.74] hours). Its efficacy was evaluated in 26 crossbreed sheep with milk positive to strains of Staphylococcus aureus, coagulase‐negative staphylococci and Streptococcus agalactiae, and clinical signs of disease. In 19 of them a single intramuscular dose of 6 mg/kg bodyweight resulted in a complete resolution of the clinical signs, and no microorganisms were detected in milk by the fifth day; in the other seven sheep, with more severe intramammary infections, three consecutive daily intramuscular doses of 6 mg/kg bodyweight were necessary. There were no local or systemic side effects and no relapses during 30 days after the treatments in any of the sheep.
Evaluation of flea control programmes for cats using fenthion and lufenuron
Authors: Fisher M. A. , Jacobs D. E. , Hutchinson M. J. , Dick I. G. C. 
Published: October 2010

Four groups of six cats were kept in carpeted pens similarly infected withCtenocephalides felis. One group was left untreated, but the other groups were treated every 28th day with either an insecticide (fenthion at 30 mg); or an inhibitor of insect development (lufenuron at 133 or 266 mg) or with both. A sudden upsurge in the numbers of fleas occurred on the control cats after 50 days. At this time, the three control strategies had reduced the counts by 91.3, 72.5 and 98.6 per cent, respectively. Thereafter, welfare considerations demanded the limitation of the flea burden on the control cats, but conditions were shown to be favourable for flea development throughout the study. The mean numbers of fleas on the treated groups after six months were 1.2, 11.0 and 0.4, respectively. After this, in addition to the fleas acquired in the pen, the cats were each infected weekly with five fleas to mimic roaming animals introducing extraneous fleas into the home. This produced no obvious effect on the counts and the mean values three months later were 0.5, 11.0 and 0.2, respectively. None of the strategies eradicated the flea population but they all reduced the numbers considerably and worked equally well whether or not small numbers of new fleas were introduced into the system. Significantly lower flea counts were maintained in the early and later stages of the study by the strategies including the insecticide.