bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of 22 Antituberculosis Drugs for Inhibitory Interaction Potential on Organic Anionic Transporter Polypeptide (OATP)-Mediated Uptake
Authors: Parvez M. Masud , Jung Jin Ah , Shin Ho Jung , Kim Dong Hyun , Shin Jae-Gook 
Published: March 2016

ABSTRACT

We investigated the inhibitory interaction potential of 22 currently marketed antituberculosis (TB) drugs on organic anion-transporting polypeptide 1B1 (OATP1B1)-, OATP2B1-, and OATP1B3-mediated uptake using
in vitro
Xenopus
oocytes and HEK cells. Rifabutin, ethambutol, amoxicillin, linezolid,
p
-amino salicylic acid, and rifapentine exhibited mild to moderate inhibitory effects on OATP-mediated uptake of estrone-3 sulfate, estradiol 17β-
d
-glucuronide, and rosuvastatin. The 50% inhibitory concentration (IC
50
) values of rifabutin, amoxicillin, ethambutol,
p
-amino salicylic acid, and linezolid were 35.4, 36.2, 57.6, 72.6, and 65.9 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B1 (OATP1B1) and 28.8, 28.9, 53.9, 31.5, and 61.0 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B3 (OATP1B3). Streptomycin and linezolid showed greater inhibition of organic anionic transporter polypeptide 2B1 (OATP2B1)-mediated uptake, with IC
50
values of 33.2 and 35.6 μM, respectively, along with mild inhibition of other drugs. Furthermore, rifabutin, amoxicillin, and rifapentine significantly inhibited OATP1B1-mediated rosuvastatin uptake, with IC
50
values of 12.3, 13.0, and 11.0 μM, respectively, which showed a similar profile to estrone-3 sulfate uptake. The calculated
R
values ([
I
]

u inlet,max

/

K
i

, where [
I
]

u inlet,max

represents the maximum estimated inhibitor concentration inlet to the liver and

K
i

is the inhibition constant) as the drug-drug interaction (DDI) indexes of PAS, ethambutol, and amoxicillin were 26.1, 6.5, and 4.3 for OATP1B1 and 52.0, 8.0, and 4.6 for OATP1B3, and those for streptomycin, amikacin, and linezolid were 5.0, 4.2, and 4.4 for OATP2B1, respectively, suggesting a higher possibility of
in vivo
DDIs. This study is the first comprehensive report to show the novel inhibitory potential of 22 marketed anti-TB drugs on OATP-mediated uptake, providing evidence for future
in vivo
clinical DDI studies.
In Vitro
Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance
Authors: Soge Olusegun O. , Salipante Stephen J. , No David , Duffy Erin , Roberts Marilyn C. 
Published: March 2016

ABSTRACT

We evaluated the
in vitro
activity of delafloxacin against a panel of 117
Neisseria gonorrhoeae
strains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistant
N. gonorrhoeae
. We characterized mutations in the
gyrA
,
gyrB
,
parC
, and
parE
genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC
50
, MIC
90
, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10
−7
to <10
−9
. The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in the
gyrA
gene. We also identified new mutations in the
gyrA
and/or
parC
and
parE
genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potent
in vitro
activity against
N. gonorrhoeae
isolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellent
in vitro
data and treatment outcomes through appropriate randomized controlled clinical trials.
Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation
Authors: Osterloh Anke , Papp Stefanie , Moderzynski Kristin , Kuehl Svenja , Richardt Ulricke , Fleischer Bernhard 
Published: March 2016

ABSTRACTRickettsioses are emerging febrile diseases caused by obligate intracellular bacteria belonging to the familyRickettsiaceae. Rickettsia typhibelongs to the typhus group (TG) of this family and is the causative agent of endemic typhus, a disease that can be fatal. In the present study, we analyzed the course ofR. typhiinfection in C57BL/6 RAG1−/−mice. Although these mice lack adaptive immunity, they developed only mild and temporary symptoms of disease and survivedR. typhiinfection for a long period of time. To our surprise, 3 to 4 months after infection, C57BL/6 RAG1−/−mice suddenly developed lethal neurological disorders. Analysis of these mice at the time of death revealed high bacterial loads, predominantly in the brain. This was accompanied by a massive expansion of microglia and by neuronal cell death. Furthermore, high numbers of infiltrating CD11b+macrophages were detectable in the brain. In contrast to the microglia, these cells harboredR. typhiand showed an inflammatory phenotype, as indicated by inducible nitric oxide synthase (iNOS) expression, which was not observed in the periphery. Having shown thatR. typhipersists in immunocompromised mice, we finally asked whether the bacteria are also able to persist in resistant C57BL/6 and BALB/c wild-type mice. Indeed,R. typhicould be recultivated from lung, spleen, and brain tissues from both strains even up to 1 year after infection. This is the first report demonstrating persistence and reappearance ofR. typhi, mainly restricted to the central nervous system in immunocompromised mice.
The Cryptosporidium parvum C-Type Lectin CpClec Mediates Infection of Intestinal Epithelial Cells via Interactions with Sulfated Proteoglycans
Authors: Ludington Jacob G. , Ward Honorine D. 
Published: March 2016

ABSTRACT

The apicomplexan parasite
Cryptosporidium
causes significant diarrheal disease worldwide. Effective anticryptosporidial agents are lacking, in part because the molecular mechanisms underlying
Cryptosporidium
-host cell interactions are poorly understood. Previously, we identified and characterized a novel
Cryptosporidium parvum
C-type lectin domain-containing mucin-like glycoprotein, CpClec. In this study, we evaluated the mechanisms underlying interactions of CpClec with intestinal epithelial cells by using an Fc-tagged recombinant protein. CpClec-Fc displayed Ca
2+
-dependent, saturable binding to HCT-8 and Caco-2 cells and competitively inhibited
C. parvum
attachment to and infection of HCT-8 cells. Binding of CpClec-Fc was specifically inhibited by sulfated glycosaminoglycans, particularly heparin and heparan sulfate. Binding was reduced after the removal of heparan sulfate and following the inhibition of glycosaminoglycan synthesis or sulfation in HCT-8 cells. Like CpClec-Fc binding,
C. parvum
attachment to and infection of HCT-8 cells were inhibited by glycosaminoglycans and were reduced after heparan sulfate removal or inhibition of glycosaminoglycan synthesis or sulfation. Lastly, CpClec-Fc binding and
C. parvum
sporozoite attachment were significantly decreased in CHO cell mutants defective in glycosaminoglycan synthesis. Together, these results indicate that CpClec is a novel C-type lectin that mediates
C. parvum
attachment and infection via Ca
2+
-dependent binding to sulfated proteoglycans on intestinal epithelial cells.
Insight into the Dual Functions of Bacterial Enhancer-Binding Protein Rrp2 of Borrelia burgdorferi
Authors: Yin Yanping , Yang Youyun , Xiang Xuwu , Wang Qian , Yang Zhang-Nv , Blevins Jon , Lou Yongliang , Yang X. Frank 
Published: March 2016

ABSTRACT

It is well established that the RpoN-RpoS sigma factor (σ
54
-σ
S
) cascade plays an essential role in differential gene expression during the enzootic cycle of
Borrelia burgdorferi
, the causative agent of Lyme disease. The RpoN-RpoS pathway is activated by the response regulator/σ
54
-dependent activator (also called bacterial enhancer-binding protein [bEBP]) Rrp2. One unique feature of Rrp2 is that this activator is essential for cell replication, whereas RpoN-RpoS is dispensable for bacterial growth. How Rrp2 controls cell replication, a function that is independent of RpoN-RpoS, remains to be elucidated. In this study, by generating a series of conditional
rrp2
mutant strains, we demonstrated that the N-terminal receiver domain of Rrp2 is required for spirochetal growth. Furthermore, a D52A point mutation at the phosphorylation site within the N terminus of Rrp2 abolished cell replication. Mutation of the ATPase motif within the central domain of Rrp2 did not affect spirochetal replication, indicating that phosphorylation-dependent ATPase activity of Rrp2 for σ
54
activation is not required for cell growth. However, deletion of the C-terminal domain or a 16-amino-acid truncation of the helix-turn-helix (HTH) DNA-binding motif within the C-terminal domain of Rrp2 abolished spirochetal replication. It was shown that constitutive expression of
rpoS
is deleterious to borrelial growth. We showed that the essential nature of Rrp2 is not due to an effect on
rpoS
. These data suggest that phosphorylation-dependent oligomerization and DNA binding of Rrp2 likely function as a repressor, independently of the activation of σ
54
, controlling an essential step of cell replication in
B. burgdorferi
.

IMPORTANCE
Bacterial enhancer-binding proteins (bEBPs) are a unique group of transcriptional activators specifically required for σ
54
-dependent gene transcription. This work demonstrates that the
B. burgdorferi
bEBP, Rrp2, has an additional function that is independent of σ
54
, that of its essentiality for spirochetal growth, and such a function is dependent on its N-terminal signal domain and C-terminal DNA-binding domain. These findings expand our knowledge on bEBP and provide a foundation to further study the underlying mechanism of this new function of bEBP.
Application and Simulation Study of Stress-Dependent Weibull Lifetime Models
Authors: Juskowiak Jochen , Bertsche Bernd 
Published: March 2016

Different Weibull lifetime models are presented whose scale, shape and minimum lifetime parameters are stress-dependent. This allows describing and predicting the lifetime of products with a Weibull distribution more accurately wherever stress-dependence applies to the failure mechanism. For instance, this is the case for failures due to fatigue, on which this paper focusses. The proposed procedure encompasses a two-step maximum likelihood estimation and a Fisher matrix (FM) confidence bounds calculation, followed by a model evaluation. This model evaluation is conducted by means of a general plausibility check (PC), likelihood ratio test (LRT) and Bayesian information criterion (BIC). Their applicability to accelerated life test data is discussed and validated using test data. Finally, a simulation study confirms a wide range of applicability.
Post-glacial mud depocentre in the southern Beibu Gulf: acoustic features and sedimentary environment evolution
Authors: Ni Y. , Harff J. , Xia Z. , Waniek J. J. , Endler M. , Schulz-Bull D. E. 
Published: March 2016

Abstract

This study documents the Southern Beibu Gulf Mud Depocentre (SBGMD) for the first time using high-resolution sub-bottom seismic reflection profiles. The SBGMD is located near the southern mouth of the Beibu Gulf in water depths of 50–80 m, and covers an area of more than 11 000 km
2
. The acoustic architecture of the SBGMD is characterized by a homogenous seismic unit surrounded by an erosive area where gullies and sand/mud waves occur. The SBGMD unconformably overlies a parallel-bedded seismic unit.

Based on
14
C-dating, together with acoustic, lithological and geochemical analysis of gravity core SO31, which was sampled within the high-sedimentation-rate area of the SBGMD, the post-glacial sedimentary history may be summarized as follows: (1) from 12.8 to 11.6 cal ka BP, the SBGMD was deposited in a low-energy, brackish/freshwater and intensely terrestrial-influenced environment; (2) from 11.6 to 8.4 cal ka BP, the SBGMD underwent marine transgression; and (3) from 8.4 cal ka BP to present, a continuous shallow-marine environment has prevailed. Comparing the age and depth of the SBGMD base with the established sea-level curve, lacustrine sedimentation is predicted to have occurred in the SBGMD area before 12.8 cal ka BP.
Human Immunodeficiency Virus as a Sexually Transmitted Disease: Manitoba’s HIV Unlinked Seroprevalence Study
Authors: Sekla Laila , Hammond Gregory , Tate Robert , Stackiw Walter , Eibisch Gudrun , Shewchook Sherlyn 
Published: March 2016

Objective: To determine the prevalence of human immunodeficiency virus (HIV)‐1 infections.Design: An unlinked seroprevalence study on all ‘left over’ blood submitted for syphilis testing during three consecutive six month periods (April 1, 1990 to September 30, 1991). After the capture of demographic data, sera to be tested for antibodies were stripped of all personal identifiers and assigned a random number. The study fulfilled Canadian ethical guidelines.Participants: Persons with a valid Manitoba Health Services Commission number were included only once in a study year. Persons were enrolled into one of five categories: infants, injection drug users, pregnant women, persons investigated for sexually transmitted diseases (STD) and routine testing.Results: Of the 50,929 persons tested. 133 (0.26%) were positive, a low prevalence of HIV infections. A significant increase in positivity was noticed in the second study period. While 77.7% of those tested were women, only 10 (0.025%) were positive for HIV. The rate of positivity for pregnant women was 0.72 per 10,000 tested. Of the 11,314 males tested. 123 (1.08%) had antibodies. Most of the positives were males in the STD category residing in Winnipeg; for them, the rate of positivity increased by middle age, while the rate of testing decreased with each decade of age (from age 15 to 44 years).Discussion/Recommendation: This is the first report from a sentinel laboratory in Canada of an unlinked seroprevalence study in persons with STD. Results suggest an urgent need to target strategies for the control of HIV for persons with STD, particularly males in urban centres, by routine HIV testing for STD patients.
An epidemic of Mycoplasma pneumoniae in Manitoba: A Serological Report
Authors: Sekla Laila , Stackiw Walter , Eibisch Gudrun , Kolton Donna 
Published: March 2016

Objectives: To report an epidemic of Mycoplasma pneumoniae in Manitoba and to discuss the limitations of the serodiagnostic tests used.Design: A retrospective analysis of the results of a province‐wide serological testing for respiratory infections caused by M pneumoniae, using a complement fixation test and an indirect immunofluorescent antibody test for the detection of immunoglobulin (Ig) M antibodies.Material: From April 1, 1987, to March 31, 1991, 12,804 sera were tested and a serological diagnosis of recent M pneumoniae infections were established in 509 (3.97%). From April 1 to September 30, 1991, an additional 2088 persons were tested; the 158 (7.5%) recent cases of M pneumoniae were subjected to analysis.Results: Compared with the previous three years, an increase in the number of recent cases of M pneumoniae was first noticed in July 1990 which persisted until September 1991. Of 856 single sera tested, 59 (6.8%) were recent M pneumoniae infections and 56 (96.1%) of these were positive for IgM antibodies. Of the 616 persons who submitted paired sera, 99 (16%) were recent infections, but only 46 (46.4%) had IgM antibodies. Primary infections (ie, positive for IgM antibodies) were detected in 102 (64.5%) and reinfections (ie, positive complement fixation test only) in the remaining 56 persons with recent M pneumoniae infections. Primary infections were detected more frequently in the ‘under 16’ than in the ‘over 16’ year age group (75% versus 55.8% of the recent cases of M pneumoniae in each age group). Reinfections were more common in the older age group. Of the 158 recent cases of M pneumoniae, 30.3% had a pneumonia; of these, 21 (55.2%) were under the age of 16 years.Discussion: M pneumoniae is an important cause of morbidity. Serological tests are used for the diagnosis despite their limitations. The detection of IgM antibodies in acute serum establishes a diagnosis of primary M pneumoniae; however, their absence does not exclude M pneumoniae. A second (convalescent) blood test is required to diagnose all primary infections. To diagnose all reinfections, paired sera should be tested by complement fixation.Summary: Manitoba experienced an epidemic of M pneumoniae in 1990–91. Properly selected serological tests can provide a specific and rapid diagnosis.
A Prospective Randomized Trial of Imipenem‐Cilastatin Versus Clindamycin/Tobramycin in the Treatmentof Intra‐Abdominal and Pelvic Infections
Authors: Mandell Lionel A , Turgeon Pierre L , Ronalds Allan R , The Canadian Clinical Trials Group  
Published: March 2016

Objective: A Canadian multicentre clinical trial in the treatment of intra‐abdominal and pelvic infections to compare the efficacy and safety of monotherapy using imipenem‐cilastatin (imipenem) (500 mg intravenously every 6 h) versus combination therapy with clindamycin/tobramycin (clindamycin 600 mg intravenously every 6 h and tobramycin 1.7 mg/kg intravenously every 8 h).Methods: Two hundred and fifty patients were entered (88 definite and 162 possible infections) and all were evaluable for analysis of adverse events and intention to treat analysis of efficacy. Dichotomous outcomes used were: cured versus noncured (improved, failed, relapsed).Results: No statistically significant differences were found with the intention to treat analysis (P=0.88) or with definite infections (P=0.81). For overall bacteriological response, no significant differences were noted (P=0.1). Eleven and 15 patients on imipenem and clindamycin/tobramycin, respectively, were colonized with bacteria. Enterococci colonized four of 11 imipenem cases and five of 15 clindamycin/tobramycin cases while fungi colonized six patients on imipenem and four on clindamycin/tobramycin. Five patients on imipenem and seven on clindamycin/tobramycin developed superinfection. In the imipenem group, one case had a bacterial superinfection while four cases were due to Candida albicans. Seven of seven superinfections on clindamycin/tobramycin were bacterial. Three bacteria initially sensitive to the assigned study drug developed resistance. In two patients on imipenem, Enterococcus faecalis and Pseudomonas aeruginosa became resistant after 14 and 10 days of therapy, respectively. On clindamycin/tobramycin, one instance of Bacteroides fragilis resistance after eight days of therapy was seen. Eighty‐three adverse events occurred; 47 in the imipenem group and 36 in the clindamycin/tobramycin group. This resulted in discontinuation of antibacterial therapy in 13 patients, seven of whom were on imipenem and six on clindamycin/tobramycin. Comparison of adverse effects showed statistically significant differences for nausea (P=0.02) and hepatotoxicity (P=0.05) occurring with greater frequency in the imipenem and clindamycin/tobramycin groups, respectively.Conclusions: These data support the conclusion that monotherapy with imipenem (500 mg intravenously every 6 h) is as efficacious as clindamycin/tobramycin for treatment of intra‐abdominal and pelvic infections. Both regimens are well tolerated.
In vitro Assays of Staphylococcus epidermidis Characteristics and Outcome in an Endocarditis Model
Authors: Herndon Betty , Dall Lawrence , Barnes William 
Published: March 2016

Objective: Staphylococcus epidermidis adherence to indwelling polymers is important in prosthetic valve endocarditis. Earlier studies have related streptococcal endocarditis to isolates with high levels of cell‐associated hexoses. The objective of the present study was to determine if a relationship exists between an S epidermidis isolate assay score and production/severity of experimental endocarditis.Design: Groups of patient S epidermidis isolates were screened for surface hexoses and an animal model of endocarditis with isolates testing highest and lowest on the screen was produced. Disease severity produced by ‘high hexose’ versus ‘low hexose’ organisms was evaluated. Endocarditis responding variables were bacterial vegetation weight and log10 colony forming units (cfu) and in survival tests, comparative time to death with different isolates. Bacterial characteristics were not measured. Baseline data showed a vegetation weight difference so that with a β error of 0.20 and a two‐tailed α error of 0.05, a significant difference would be noted using 30 animals. A total of 64 animals was used.Population Studded: Bacterial isolates from two patient groups (n=42 and n=68) on which in vitro assays were run. An animal model of endocarditis (n=64) was used to evaluate four selected isolates for vegetation size, log10 cfu/g, and survival time.Main Results: In a group of S epidermidis endocarditis animals evaluated for time of death, a significantly more rapid death time resulted in the group dosed with the high hexose‐scoring organism (P<0.025). Vegetations and log10 cfu produced by test high hexose isolates averaged larger but were not significantly different.Conclusions: A significantly more rapid death rate occurs in untreated endocarditis using a high hexose isolate than with S epidermidis with low surface hexoses. Using bacterial vegetation and cfu as endpoints, however, experimental endocarditis using patient isolates of S epidermidis does not show the same strong correlation to bacterial surface hexoses as does streptococcal endocarditis.
Cefcanel Daloxate versus Penicillin in Acute Streptococcal Pharyngotonsillitis
Authors: Grunfeld A , Sinclair P , Nicolle LE , the Canadian Tonsillitis Study Group  
Published: March 2016

Objective: To determine the efficacy, safety and tolerance of cefcanel daloxate and phenoxymethylpenicillin (PcV) in the treatment of acute pharyngotonsillitis caused by beta‐hemolytic streptococci group A (bhsga).Patients and Methods: Randomized, double‐blind, multicentre study with subjects randomized 1:1:1:1 to four parallel treatment groups: cefcanel daloxate 150 mg bid, 300 mg bid, 600 mg daily and PcV 300 mg tid. Patients were treated for 10 days with clinical, bacteriological and safety evaluation at inclusion, during therapy (day 5), early after completion of therapy (day 14) and two weeks later (day 28).Results: Of 340 subjects enrolled, 324 were valid for safety analysis and 249 for efficacy analysis. At the short term visit, clinical cure rates for cefcanel daloxate 300 mg bid and PcV groups were similar at approximately 70%. The cure rates for cefcanel daloxate 150 mg bid and 600 mg daily were significantly worse at 57.4 and 54.4%. Approximately 80% of all pretherapy throat swabs grew bhsga. All bhsga were susceptible or intermediately susceptible to PcV and cefcanel. The bacterial elimination rate for cefcanel daloxate was 82.8% and for PcV it was 89.8%. The elimination rate was significantly lower in the cefcanel daloxate 150 mg bid and 600 mg daily groups. The clinical cure rates and the bacteriological elimination rates increased by about 10% for cefcanel daloxate 300 mg bid and the PcV groups at the last valid visit and remained significantly better than the other two cefcanel daloxate doses. Adverse events were not significantly different among the four treatment groups.Conclusions: Cefcanel daloxate 300 mg bid was as effective and as well tolerated as PcV 300 mg tid in the treatment of acute pharyngotonsillitis. A lower dose or once‐daily dose regimen of cefcanel daloxate was not as effective clinically or bacteriologically.