bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mefloquine Is Active In Vitro and In Vivo againstMycobacterium aviumComplex
Authors: Bermudez Luiz E. , Kolonoski Peter , Wu Martin , Aralar Priscilla A. , Inderlied Clark B. , Young Lowell S. 
Published: October 2018

ABSTRACTDespite the development of several agents, new classes of antimicrobials with activity against theMycobacterium aviumcomplex (MAC) are needed. Based on a broad screening of compounds, we found that mefloquine has MICs of 8 to 16 μg/ml by the BACTEC system and 16 μg/ml by broth microdilution for five MAC strains tested. An expansion of the screening with broth microdilution to 24 macrolide-susceptible strains and 6 macrolide-resistant strains determined that the MIC for all strains was 16 μg/ml. To determine the intracellular activity of mefloquine, U937 macrophage monolayers infected with MAC strain 101, 100, or 109 (serovars 1, 8, and 4) were treated with mefloquine daily, and the number of intracellular bacteria was quantitated after 4 days. Significant growth inhibition against the three MAC strains at concentrations greater than or equal to 10 μg/ml (P< 0.05) was obtained. Due to the encouraging anti-MAC activity, in vivo efficacy in beige mice infected with MAC 101 was evaluated. Animals were treated with 5, 10, 20, or 40 mg/kg of body weight daily, three times a week, twice a week, or once a week for 4 weeks, and bacteria were quantitated in blood, liver, and spleen. No toxicity was observed with any of the treatment regimens. Mefloquine had borderline bactericidal activity at a dosage of 40 mg/kg daily (100% inhibition compared with a 1-week control), and significant inhibition was obtained at dosages of 40 mg/kg three times a week, as well as 20 mg/kg daily. Mefloquine had no significant effect on bacteremia. A combination of mefloquine and ethambutol showed significantly more activity than did either drug alone in liver, spleen, and blood; the combination was also bactericidal againstM. avium. Although safety is a potential concern, mefloquine and related compounds deserve further investigation as anti-MAC therapies.
In Vitro and In Vivo Activities of Syn2190, a Novel β-Lactamase Inhibitor
Authors: Nishida Kouichi , Kunugita Chieko , Uji Tatsuya , Higashitani Fusahiro , Hyodo Akio , Unemi Norio , Maiti Samarendra N. , Phillips Oludotun A. , Spevak Paul , Atchison Kevin P. , Salama Sameeh M. , Atwal Harninder , Micetich Ronald G. 
Published: October 2018

ABSTRACT

Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 β-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 μM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 β-lactamase-producing strains, such as
Pseudomonas aeruginosa
,
Enterobacter cloacae
,
Citrobacter freundii
, and
Morganella morganii
. However, against β-lactamase-derepressed mutants of
P. aeruginosa
, the MICs of ceftazidime plus Syn2190 were not affected by the amount of β-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC
50
s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC
50
s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant
P. aeruginosa
.
Unusual Antimicrotubule Activity of the Antifungal Agent Spongistatin 1
Authors: Ovechkina Yulia Y. , Pettit Robin K. , Cichacz Zbigniew A. , Pettit George R. , Oakley Berl R. 
Published: October 2018

ABSTRACT

Spongistatin 1, a macrocyclic lactone from the marine sponge
Hyrtios erecta
, has broad-spectrum antifungal activity. Since this compound is a potent antimicrotubule agent in mammalian cells, we examined its effects on the filamentous fungus
Aspergillus nidulans
to determine if its antifungal effects are due to antimicrotubule activity. At 25 μg/ml (twice the MIC), spongistatin 1 caused a greater-than-twofold elevation of the chromosome and spindle mitotic indices. Immunofluorescence microscopy revealed that mitotic spindles were smaller and shorter than in control germlings. However, late-anaphase and telophase nuclei were seen occasionally, and this suggests that the spindles are capable of segregating chromosomes. Spongistatin 1 had more dramatic effects on cytoplasmic microtubules. At 30 min after initiation of treatment, 83% of germlings contained fragmented microtubules and after 2 h of treatment, microtubules had disappeared completely from 82% of germlings. In contrast, microtubules disappeared rapidly and completely from germlings treated with benomyl. We conclude that spongistatin 1 has antimicrotubule activity in
A. nidulans
and that its mechanism of action may involve a novel microtubule-severing activity.
Identification of Functional Amino Acids in the Macrolide 2′-Phosphotransferase II
Authors: Taniguchi Kazuo , Nakamura Akio , Tsurubuchi Kazue , Ishii Aki , O’Hara Koji , Sawai Tetsuo 
Published: October 2018

ABSTRACT
Macrolide 2′-phosphotransferase [MPH(2′)] transfers the γ phosphate of ATP to the 2′-OH group of macrolide antibiotics. The role of aspartic acids in the putative ATP-binding site of MPH(2′)II was investigated through the substitution of alanine for aspartate by site-directed mutagenesis. D200A, D209A, D219A, and D231A mutant strains were unable to inactivate the substrate oleandomycin, while a D227A mutant retained 7% of the activity of the original enzyme.
Contribution of
kasA
Analysis to Detection of Isoniazid-Resistant
Mycobacterium tuberculosis
in Singapore
Authors: Lee Ann S. G. , Lim Irene H. K. , Tang Lynn L. H. , Telenti Amalio , Wong Sin Yew 
Published: October 2018

ABSTRACT

Genotypic analysis of resistance to isoniazid (INH) in
Mycobacterium tuberculosis
is complex due to the various genes potentially involved. Mutations in ketoacyl acyl carrier protein synthase (encoded by
kasA
) were present in 16 of 160 (10%) INH-resistant isolates (R121K [
n
= 1], G269S [
n
= 3], G312S [
n
= 11], G387D [
n
= 1]). However, G312S was also present in 6 of 32 (19%) susceptible strains.
kasA
analysis contributed marginally to the performance of INH genotypic testing in Singapore. The significance of
kasA
polymorphisms in INH resistance should be carefully established.
In Vitro Activities of Polycationic Peptides Alone and in Combination with Clinically Used Antimicrobial Agents against
Rhodococcus equi
Authors: Giacometti A. , Cirioni O. , Ancarani F. , Del Prete M. S. , Fortuna M. , Scalise G. 
Published: October 2018

ABSTRACT

The in vitro activities of magainin II, nisin, and ranalexin alone and in combination with other antimicrobial agents against six clinical isolates of
Rhodococcus equi
were investigated by MIC and time-kill studies. All isolates were more susceptible to nisin. A positive interaction was observed when the peptides were combined with ampicillin, ceftriaxone, rifabutin, rifampin, azithromycin, clarithromycin, and vancomycin.
Characterization of
fmtA
, a Gene That Modulates the Expression of Methicillin Resistance in
Staphylococcus aureus
Authors: Komatsuzawa Hitoshi , Ohta Kouji , Labischinski Harald , Sugai Motoyuki , Suginaka Hidekazu 
Published: October 2018

ABSTRACT

FmtA is a factor which affects the methicillin resistance level in methicillin-resistant
Staphylococcus aureus
. Since FmtA has two of three conserved motifs which are typically found in penicillin-binding proteins (PBPs) and β-lactamases, we investigated the penicillin-binding activity of recombinant FmtA and found no such activity. Immunoblotting analysis revealed that FmtA localizes in the membrane fraction. To investigate the function of FmtA, high-pressure liquid chromatography analysis of cell wall muropeptides was performed with an
fmtA
-inactivated mutant and its parent. The mutant showed a reduced cross-linking and partially reduced amidation of glutamate residues in the peptidoglycan of the mutant. The transcription of
fmtA
was dose dependently increased by the addition of β-lactam antibiotics, fosfomycin, and bacitracin, while its transcription was not changed by the addition of vancomycin or tetracycline. These results reveal that Fmt is a membrane-located, non-penicillin-binding protein and that mutation of
fmtA
affects the cell wall structure, although its precise function is still unknown.
Fluoroquinolone Resistance in
Bacteroides fragilis
following Sparfloxacin Exposure
Authors: Peterson M. L. , Hovde L. B. , Wright D. H. , Hoang A. D. , Raddatz J. K. , Boysen P. J. , Rotschafer J. C. 
Published: October 2018

ABSTRACT

In vitro pharmacodynamic studies investigating the antimicrobial properties of five fluoroquinolones, (trovafloxacin, sparfloxacin, clinafloxacin, levofloxacin, and ciprofloxacin) against
Bacteroides fragilis
ATCC 23745 were conducted. The times required to reduce the viable counts by 3 log units were as follows: clinafloxacin, 2.9 h; levofloxacin, 4.6 h; trovafloxacin, 6 h; and sparfloxacin, 10 h. Exposure to ciprofloxacin did not achieve a 3-log decrease in viable counts. The susceptibility of
B. fragilis
was determined both prior to exposure and following 24 h of exposure to each of the five fluoroquinolones tested. The MICs of clinafloxacin, levofloxacin, trovafloxacin, sparfloxacin, ciprofloxacin, metronidazole, cefoxitin, chloramphenicol, and clindamycin were determined by the broth microdilution method. The MICs for
B. fragilis
preexposure were as follows: clinafloxacin, 0.25 μg/ml; trovafloxacin, 0.5 μg/ml; sparfloxacin, 2 μg/ml; levofloxacin, 2 μg/ml; and ciprofloxacin, 8 μg/ml. Similar pre- and postexposure MICs were obtained for cultures exposed to trovafloxacin, clinafloxacin, levofloxacin, and ciprofloxacin. However, following 24 h of exposure to sparfloxacin, a fluoroquinolone-resistant strain emerged. The MICs for this strain were as follows: clinafloxacin, 1 μg/ml; trovafloxacin, 4 μg/ml; sparfloxacin, 16 μg/ml; levofloxacin, 16 μg/ml; and ciprofloxacin, 32 μg/ml. No changes in the susceptibility of
B. fragilis
pre- and postexposure to sparfloxacin were noted for metronidazole (MIC, 1 μg/ml), cefoxitin (MIC, 4 μg/ml), chloramphenicol (MIC, 4 μg/ml), and clindamycin (MIC, 0.06 μg/ml). Resistance remained stable as the organism was passaged on antibiotic-free agar for 10 consecutive days. Mutant
B. fragilis
strains with decreased susceptibility to clinafloxacin, trovafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin were selected on brucella blood agar containing 8× the MIC of levofloxacin at a frequencies of 6.4 × 10
−9
, 4× the MICs of trovafloxacin and sparfloxacin at frequencies of 2.2 × 10
−9
and 3.3 × 10
−10
, respectively, and 2× the MIC of clinafloxacin at a frequency of 5.5 × 10
−11
; no mutants were selected with ciprofloxacin. The susceptibilities of strains to trovafloxacin, levofloxacin, clinafloxacin, sparfloxacin, and ciprofloxacin before and after exposure to sparfloxacin were modestly affected by the presence of reserpine (20 μg/ml), an inhibitor of antibiotic efflux. The mechanism of fluoroquinolone resistance is being explored, but it is unlikely to be efflux due to a lack of cross-resistance to unrelated antimicrobial agents and to the fact that the MICs for strains before and after exposure to sparfloxacin are minimally affected by reserpine.
Inhibition ofEscherichia coli-Induced Meningitis by Carboxyfullerence
Authors: Tsao Nina , Kanakamma Puthuparampil P. , Luh Tien-Yau , Chou Chen-Kung , Lei Huan-Yao 
Published: October 2018

ABSTRACTThe effect of a water-soluble malonic acid derivative of carboxyfullerence (C60) againstEscherichia coli-induced meningitis was tested. C60 can protect the mice fromE. coli-induced death in a dose-dependent manner. C60 administered intraperitoneally as late as 9 h afterE. coliinjection was still protective. The C60-treated mice had less tumor necrosis factor alpha and interleukin-1β production by staining of brain tissue compared to the levels of production for nontreated mice. TheE. coli-induced increases in blood-brain barrier permeability and inflammatory neutrophilic infiltration were also inhibited. These data suggest that C60 is a potentially therapeutic agent for bacterial meningitis.
Mononuclear and Polymorphonuclear Leukocyte Dispositions of Clarithromycin and Azithromycin in AIDS Patients Requiring
Mycobacterium avium
Complex Prophylaxis
Authors: Bui Khanh Q. , McNabb JoCarol , Li Chonghua , Nightingale Charles H. , Nicolau David P. 
Published: October 2018

ABSTRACT

The intracellular dispositions of clarithromycin and azithromycin in AIDS patients requiring
Mycobacterium avium
complex (MAC) prophylaxis were studied. The dispositions of both drugs in mononuclear and polymorphonuclear leukocytes were markedly different. Our data support the proven efficacy of these agents for MAC prophylaxis since clarithromycin and azithromycin displayed sustained intracellular concentrations which exceeded their MICs for MAC throughout the dosing periods.
Comparison of simulation debriefs with traditional needs assessment methods: a qualitative exploratory study in a critical care community setting
Authors: Sarti Aimee J , Ajjawi Rola , Sutherland Stephanie , Landriault Angele , Kim John , Cardinal Pierre 
Published: October 2018

ObjectiveTo better understand the potential of a needs assessment approach using qualitative data from manikin-based and virtual patient simulation debriefing sessions compared with traditional data collection methods (ie, focus groups and interviews).DesignOriginal data from simulation debrief sessions was compared and contrasted with data from an earlier assessment of critical care needs in a community setting (using focus groups and interviews), thus undertaking secondary analysis of data. Time and cost data were also examined. Debrief sessions were coded using deductive and inductive techniques. Matrices were used to explore the commonalities, differences and emergent findings across the methods.SettingCritical care unit in a community hospital setting.ResultsInterviews and focus groups yielded 684 and 647 min of audio-recordings, respectively. The manikin-based debrief recordings averaged 22 min (total=130 min) and virtual patient debrief recordings averaged 31 min (total=186 min). The approximate cost for the interviews and focus groups was $13 560, for manikin-based simulation debriefs was $4030 and for the virtual patient debriefs was $3475. Fifteen of 20 total themes were common across the simulation debriefs and interview/focus group data. Simulation-specific themes were identified, including fidelity (environment, equipment and psychological) and the multiple roles of the simulation instructor (educative, promoting reflection and assessing needs).ConclusionsGiven current fiscal realities, the dual benefit of being educative and identifying needs is appealing. While simulation is an innovative method to conduct needs assessments, it is important to recognise that there are trade-offs with the selection of methods.
Experience of adopting faecal immunochemical testing to meet the NICE colorectal cancer referral criteria for low-risk symptomatic primary care patients in Oxfordshire, UK
Authors: Nicholson Brian D , James Tim , East James E , Grimshaw David , Paddon Maria , Justice Steve , Oke Jason L , Shine Brian 
Published: October 2018

ObjectiveTo compare the diagnostic performance of guaiac faecal occult blood (gFOB) testing with faecal immunochemical test (FIT) in a low-risk symptomatic primary care population to provide objective data on which to base local referral guidelines.DesignStool samples from routine primary care practice sent for faecal occult blood testing were analysed by a standard gFOB method and the HM-JACKarc FIT between January and March 2016. Symptoms described on the test request were recorded. Patients were followed up over 21 months for evidence of serious gastrointestinal pathology including colorectal adenocarcinoma.ResultsIn 238 patients, the sensitivity and specificity for colorectal adenocarcinoma detection using gFOB were 85.7% and 65.8%, respectively, compared with 85.7% and 89.2% for FIT. The positive predictive value (PPV) for gFOB was 7.1% and negative predictive value (NPV) was 99.3%. Comparatively, the PPV for FIT was 19.4% and NPV 99.5%. The improved performance of FIT over gFOB was due to a lower false positive rate (10.8 vs 34.2, p≤0.01) with no increase in the false negatives rate. For any significant colorectal disease, the PPV for FIT increased to 35.5% with a reduction in NPV to 95.7%.ConclusionIn this low-risk symptomatic patient group, the proportion of samples considered positive by FIT was considerably lower than gFOB with the same rate of colorectal adenocarcinoma detection. One in three of those with positive FIT had a significant colorectal disease. This supports National Institute of Health and Care Excellence recommendation that FIT can be reliably used as a triage test in primary care without overburdening endoscopy resources.
Essential components in natriuretic peptide-guided management of heart failure: an intervention synthesis
Authors: Oke Jason , Clements Alison , McLellan Julie , Bankhead Clare , Taylor Clare J , Spence Graeme , Banerjee Amitava , Perera Rafael 
Published: October 2018

AimTo identify the key components of natriuretic peptide (NP)-guided treatment interventions which reduced hospitalisation in patients with heart failure (HF).Methods and resultsWe extracted detailed information on the components of interventions from studies of NP-guided treatment of HF identified in a previous systematic review. We used meta-regression techniques to assess univariate associations between components and the strength of the reduction in HF hospitalisations and all-cause mortality. A Bayesian meta-analysis approach was used to re-estimate study-level effects in order to identify the study with the most effective NP-guided monitoring intervention. Finally, we examined the intervention options common to the studies in which the 95% credible interval excluded no effect. We identified eight components of NP-guided treatment from ten studies. Univariate comparisons produced mainly equivocal results, but single trial choice and common components analysis led to similar conclusions. Using a predefined treatment protocol, setting a stringent NP target (N-terminal pro-B-type natriuretic peptide of 1000 pg/mL or B-type natriuretic peptide 100 pg/mL) and including a relative targetwere potential key components to reducing HF hospitalisations using NP-guided therapy.ConclusionThis analysis provides a description of the key components of NP-guided treatment which could help policy makers develop specific recommendations for HF management. Our research suggests that NP-guided interventions could be simplified, but more research in relevant health settings, such as primary care, is required.
Large families of pseudorandom binary lattices by using the multiplicative inverse modulo P
Authors: Liu Huaning 
Published: October 2018

Hubert, Mauduit and Sárközy introduced pseudorandom measures for finite pseudorandom binary lattices. Gyarmati, Mauduit, Sárközy and Stewart presented some natural and flexible constructions, which are the two-dimensional extensions and modifications of a few one-dimensional constructions. The upper estimates for the pseudorandom measures of their binary lattices are based on the principle that character sums or exponential sums in two variables can be estimated by fixing one of the variables. In this paper, we constructed two large families of [Formula: see text] dimensional pseudorandom binary lattices by using the multiplicative inverse modulo [Formula: see text], and study the properties: pseudorandom measure, collision and avalanche effect.
Expression of AR-V7 and ARv567es in Circulating Tumor Cells Correlates with Outcomes to Taxane Therapy in Men with Metastatic Prostate Cancer Treated in TAXYNERGY
Authors: Tagawa Scott T. , Antonarakis Emmanuel S. , Gjyrezi Ada , Galletti Giuseppe , Kim Seaho , Worroll Daniel , Stewart John , Zaher Atef , Szatrowski Ted P. , Ballman Karla V. , Kita Katsuhiro , Tasaki Shinsuke , Bai Yang , Portella Luigi , Kirby Brian J. , Saad Fred , Eisenberger Mario A. , Nanus David M. , Giannakakou Paraskevi 
Published: October 2018

Abstract

Purpose:
Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. The presence or absence of androgen receptor (AR) splice variants, AR-V7 and ARv567es, in mCRPC patient circulating tumor cells (CTC) may be associated with taxane treatment outcomes.
Experimental Design: A novel digital droplet PCR (ddPCR) assay assessed AR-splice variant expression in CTCs from patients receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Patient outcomes were examined according to AR-splice variant expression, including prostate-specific antigen (PSA)50 response and progression-free survival (PFS).

Results:
Of the 54 evaluable patients, 36 (67%) were AR-V7+, 42 (78%) were ARv567es+, 29 (54%) were double positive, and 5 (9%) were double negative. PSA50 response rates at any time were numerically higher for AR-V7− versus AR-V7+ (78% vs. 58%; P = 0.23) and for ARv567es− versus ARv567es+ (92% vs. 57%; P = 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 (n = 24), AR-V7+ patients (n = 16) had a 0.4% decrease versus a 12.9% and 26.7% decrease in AR-V7−/ARv567es− (n = 3) and AR-V7−/ARv567es+ (n = 5) patients, respectively, suggesting a dominant role for AR-V7 over ARv567es. Median PFS was 12.02 versus 8.48 months for AR-V7− versus AR-V7+ (HR = 0.38; P = 0.01), and 12.71 versus 7.29 months for ARv567es− versus ARv567es+ (HR = 0.37; P = 0.02). For AR-V7+, AR-V7−/ARv567es+, and AR-V7−/ARv567es− patients, median PFS was 8.48, 11.17, and 16.62 months, respectively (P = 0.0013 for trend).

Conclusions:
Although detection of both CTC-specific AR-V7 and ARv567es by ddPCR influenced taxane outcomes, AR-V7 primarily mediated the prognostic impact. The absence of both variants was associated with the best response and PFS with taxane treatment.
See related commentary by Dehm et al., p. 1696