bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Locally Delivered Polyclonal Immunoglobulin against
Pseudomonas aeruginosa
Peritonitis in a Murine Model
Authors: Barekzi Nazir A. , Poelstra Kornelis A. , Felts Adrian G. , Rojas Ignacio A. , Slunt Jeffrey B. , Grainger David W. 
Published: October 2018

ABSTRACT

Infectious peritonitis results from bacterial contamination of the abdominal cavity. Conventional antibiotic treatment is complicated both by the emergence of antibiotic-resistant bacteria and by increased patient populations intrinsically at risk for nosocomial infections. To complement antibiotic therapies, the efficacy of direct, locally applied pooled human immunoglobulin G (IgG) was assessed in a murine model (strains CF-1, CD-1, and CFW) of peritonitis caused by intraperitoneal inoculations of 10
6
or 10
7
CFU of
Pseudomonas aeruginosa
(strains IFO-3455, M-2, and MSRI-7072). Various doses of IgG (0.005 to 10 mg/mouse) administered intraperitoneally simultaneously with local bacterial challenge significantly increased survival in a dose-dependent manner. Local intraperitoneal application of 10 mg of IgG increased animal survival independent of either the
P. aeruginosa
or the murine strains used. A local dose of 10 mg of IgG administered up to 6 h prophylactically or at the time of bacterial challenge resulted in 100% survival. Therapeutic 10-mg IgG treatment given up to 12 h postinfection also significantly increased survival. Human IgG administered to the mouse peritoneal cavity was rapidly detected systemically in serum. Additionally, administered IgG in peritoneal lavage fluid samples actively opsonized and decreased the bacterial burden via phagocytosis at 2 and 4 h post-bacterial challenge. Tissue microbial quantification studies showed that 1.0 mg of locally applied IgG significantly reduced the bacterial burden in the liver, peritoneal cavity, and blood and correlated with reduced levels of interleukin-6 in serum.
Effective Treatment of Acute and Chronic Murine Tuberculosis with Liposome-Encapsulated Clofazimine
Authors: Adams Linda B. , Sinha Indu , Franzblau Scott G. , Krahenbuhl James L. , Mehta Reeta T. 
Published: October 2018

ABSTRACT

The therapeutic efficacy of liposomal clofazimine (L-CLF) was studied in mice infected with
Mycobacterium tuberculosis
Erdman. Groups of mice were treated with either free clofazimine (F-CLF), L-CLF, or empty liposomes twice a week for five treatments beginning on day 1 (acute), day 21 (established), or day 90 (chronic) postinfection. One day after the last treatment, the numbers of CFU of
M. tuberculosis
in the spleen, liver, and lungs were determined. F-CLF at the maximum tolerated dose of 5 mg/kg of body weight was ineffective; however, 10-fold-higher doses of L-CLF demonstrated a dose response with significant CFU reduction in all tissues without any toxic effects. In acutely infected mice, 50 mg of L-CLF/kg reduced CFU 2 to 3 log units in all three organs. In established or chronic infection, treated mice showed no detectable CFU in the spleen or liver and 1- to 2-log-unit reduction in the lungs. A second series of L-CLF treatments cleared
M. tuberculosis
in all three tissues. L-CLF appears to be bactericidal in the liver and spleen, which remained negative for
M. tuberculosis
growth for 2 months. Thus, L-CLF could be useful in the treatment of tuberculosis.
Comparative Efficacies of Antibiotics in a Rat Model of Meningoencephalitis Due to
Listeria monocytogenes
Authors: Michelet Christian , Leib Stephen L. , Bentue-Ferrer Daniele , Täuber Martin G. 
Published: October 2018

ABSTRACT

The antibacterial activities of amoxicillin-gentamicin, trovafloxacin, trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of trovafloxacin with TMP-SMX were compared in a model of meningoencephalitis due to
Listeria monocytogenes
in infant rats. At 22 h after intracisternal infection, the cerebrospinal fluid was cultured to document meningitis, and the treatment was started. Treatment was instituted for 48 h, and efficacy was evaluated 24 h after administration of the last dose. All tested treatment regimens exhibited significant activities in brain, liver, and blood compared to infected rats receiving saline (
P
< 0.001). In the brain, amoxicillin plus gentamicin was more active than all of the other regimens, and trovafloxacin was more active than TMP-SMX (bacterial titers of 4.1 ± 0.5 log
10
CFU/ml for amoxicillin-gentamicin, 5.0 ± 0.4 log
10
CFU/ml for trovafloxacin, and 5.8 ± 0.5 log
10
CFU/ml for TMP-SMX;
P
< 0.05). In liver, amoxicillin-gentamicin and trovafloxacin were similarly active (2.8 ± 0.8 and 2.7 ± 0.8 log
10
CFU/ml, respectively) but more active than TMP-SMX (4.4 ± 0.6 log
10
CFU/ml;
P
< 0.05). The combination of trovafloxacin with TMP-SMX did not alter the antibacterial effect in the brain, but it did reduce the effect of trovafloxacin in the liver. Amoxicillin-gentamicin was the most active therapy in this study, but the activity of trovafloxacin suggests that further studies with this drug for the treatment of
Listeria
infections may be warranted.
Sequence Diversity of the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 from Untreated Brazilian Individuals
Authors: Brindeiro Rodrigo , Vanderborght Bart , Caride Elena , Correa Letícia , Oravec Rejane M. , Berro Oscar , Stuyver Lieven , Tanuri Amilcar 
Published: October 2018

ABSTRACT

The presence of human immunodeficiency virus type 1 (HIV-1) bearing mutations resistant to nucleosidic inhibitors of the viral reverse transcriptase (RT) derived from HIV-seropositive asymptomatic and untreated volunteer blood donors was examined. The RT amplicons of 32 specimens were analyzed by using a reverse hybridization line probe assay technique that detects resistance against zidovudine (3′-azido-3′-deoxythymidine [AZT], didanosine (2′,3′-dideoxyinosine [ddI], zalcitabine (2′,3′-dideoxycytidine [ddC]), and lamivudine {(−)-β-
l
-2′,3′-dideoxy-3′-thiacytidine [3TC]} at amino acid positions 41, 69, 70, 74, 184, and 215 of the HIV RT. One sample (brp004, subtype B) showed an AZT resistance secondary mutation at position K70R. Fifteen specimens revealed one or more sites of nonreactivity to both wild-type- and mutant-specific probes (dual nonreactivity). Samples were also submitted to RT direct sequencing and phylogenetic analysis. Nine of 32 specimens belonged to non-B subtypes (C, D, F, and F/B or B/F mosaics). Three of these non-B isolates, named brp004, brp063, and brp069, revealed three other relevant AZT resistance mutations—a T215F mutation and two M41L mutations, respectively—hidden by the nonreactivity to line probe assay strips on the respective codon regions. The isolate brp004 also carried a D67N AZT resistance mutation revealed by direct sequencing. No nonnucleosidic RT inhibitor-resistant mutation was found. The analysis revealed a frequency of 2.26 × 10
−4
mutations per nucleotide for independent samples related to RT resistance. These findings emphasize the magnitude of naturally occurring reservoirs of drug-resistant virus among untreated HIV-1-positive individuals in Brazil.
Structural Alterations in the Translational Attenuator of Constitutively Expressed
ermC
Genes
Authors: Werckenthin Christiane , Schwarz Stefan , Westh Henrik 
Published: October 2018

ABSTRACT

Sequence deletions of 16, 59, and 111 bp as well as a tandem duplication of 272 bp with respect to the corresponding sequence of pT48 were identified in the regulatory regions of constitutively expressed
ermC
genes. Constitutive
ermC
gene expression as a consequence of these structural alterations is based on either the prevention of the formation of mRNA secondary structures in the translational attenuator or the preferential formation of those mRNA secondary structures which do not interfere with the translation of the
ermC
transcripts. A model for the development of sequence deletions in the
ermC
translational attenuator by homologous recombination is presented and experimentally tested by in vitro selection of constitutively expressed mutants in staphylococcal strains deficient and proficient in homologous recombination.
Purification, Reconstitution, and Inhibition of Cytochrome P-450 Sterol Δ
22
-Desaturase from the Pathogenic Fungus
Candida glabrata
Authors: Lamb David C. , Maspahy Segula , Kelly Diane E. , Manning Nigel J. , Geber Antonia , Bennett John E. , Kelly Steven L. 
Published: October 2018

ABSTRACT

Sterol Δ
22
-desaturase has been purified from a strain of
Candida glabrata
with a disruption in the gene encoding sterol 14α-demethylase (cytochrome P-45051; CYP51). The purified cytochrome P-450 exhibited sterol Δ
22
-desaturase activity in a reconstituted system with NADPH–cytochrome P-450 reductase in dilaurylphosphatidylcholine, with the enzyme kinetic studies revealing a

K
m

for ergosta-5,7-dienol of 12.5 μM and a
V
max
of 0.59 nmol of this substrate metabolized/min/nmol of P-450. This enzyme is encoded by CYP61 (
ERG5
) in
Saccharomyces cerevisiae
, and homologues have been shown in the
Candida albicans
and
Schizosaccharomyces pombe
genome projects. Ketoconazole, itraconazole, and fluconazole formed low-spin complexes with the ferric cytochrome and exhibited type II spectra, which are indicative of an interaction between the azole moiety and the cytochrome heme. The azole antifungal compounds inhibited reconstituted sterol Δ
22
-desaturase activity by binding to the cytochrome with a one-to-one stoichiometry, with total inhibition of enzyme activity occurring when equimolar amounts of azole and cytochrome P-450 were added. These results reveal the potential for sterol Δ
22
-desaturase to be an antifungal target and to contribute to the binding of drugs within the fungal cell.
Effects of Novel 6-Desfluoroquinolones and Classic Quinolones on Pentylenetetrazole-Induced Seizures in Mice
Authors: De Sarro A. , Cecchetti V. , Fravolini V. , Naccari F. , Tabarrini O. , De Sarro G. 
Published: October 2018

ABSTRACT
There have been several reports that convulsions, although rare, occur in patients who receive fluoroquinolones. In this study, the proconvulsant effects exhibited by a novel series of 6-desfluoroquinolones and some classic quinolones on pentylenetetrazole (PTZ)-induced seizures in mice were evaluated and compared. Animals were intraperitoneally injected with vehicle or quinolone derivatives (5 to 100 μg/g of body weight) 30 min before the subcutaneous (s.c.) administration of PTZ (40 μg/g). In each experiment, mice were then observed for 1 h to monitor for the incidence and onset of clonic seizures. The order of proconvulsant activity in our epileptic model was MF5184 > MF5187 > pefloxacin > MF5189 > ofloxacin > ciprofloxacin > MF5140 > MF5181 > MF5137 > rufloxacin > MF5143 > MF5158 > MF5191 > MF5128 > MF5138 > cinoxacin > MF5142 > norfloxacin > nalidixic acid. The relationship between the chemical structure and the proconvulsant activity of 6-desfluoroquinolone derivatives was studied. We observed that, in terms of toxicity to the central nervous system (CNS), besides the heterocyclic side chain (moiety) at the C-7 position, the C-6 substituent also appears to play an important role. In particular, a hydrogen at the C-6 position seemed to be responsible for major neurotoxic activity in comparison to an amino group located in the same position. The relationship between lipophilicity and proconvulsant activity was also investigated. We did not find any clear relationship between a higher level of lipophilicity and major proconvulsant properties. Although the principal mechanism by which quinolones induce potentiation of the proconvulsant effects of PTZ cannot be easily determined, it is possible that the convulsions are caused by drug interactions, because both PTZ and quinolones are believed to increase excitation of the CNS by inhibition of γ-aminobutyric acid binding to receptors.
Activation of the 2′- N -Acetyltransferase Gene [
aac
(
2′
)-
Ia
] in
Providencia stuartii
by an Interaction of AarP with the Promoter Region
Authors: Macinga David R. , Paradise Michael R. , Parojcic Milica M. , Rather Philip N. 
Published: October 2018

ABSTRACT

The
aac
(
2′
)-
Ia
gene in
Providencia stuartii
encodes a 2′-
N
-acetyltransferase capable of acetylating both peptidoglycan and certain aminoglycoside antibiotics. Regulation of the
aac
(
2′
)-
Ia
gene is influenced in a positive manner by the product of the
aarP
gene, which encodes a small transcriptional activator of the AraC (XylS) family. In this study, we demonstrate the sequence requirements at the
aac
(
2′
)-
Ia
promoter for AarP binding and activation.
Anti-
Toxoplasma gondii
Activities and Structure-Activity Relationships of Novel Fluoroquinolones Related to Trovafloxacin
Authors: Khan Anis A. , Araujo Fausto G. , Brighty Katherine E. , Gootz Thomas D. , Remington Jack S. 
Published: October 2018

ABSTRACT

Eleven novel fluoroquinolones closely related to trovafloxacin were evaluated for their in vitro activity against
Toxoplasma gondii
, and their structure-activity relationships were examined. The 50% inhibitory concentration (IC
50
) of trovafloxacin against
T. gondii
was 2.93 μM; the IC
50
of the 11 analogs ranged from 0.53 to 14.09 μM. Six analogs had IC
50
s lower than that of trovafloxacin. Examination of the structure-activity relationships of the compounds revealed that addition of a -CH
3
at C-5 of the 1,8-naphthyridone ring, at C-2 of the azabicyclohexane ring, or on the -NH
2
at the 6 position of the azabicyclohexane ring resulted in a four- to sixfold increase in activity. Moreover, replacement of 2,4-difluorophenyl by cyclopropyl at N-1 of the 1,8-naphthyridone ring increased activity twofold, and moving the -NH
2
one atom further away from the azabicyclohexane ring decreased activity. There was no difference between the naphthyridone and quinolone analogs. These results indicate that structure-activity studies of compounds related to drugs active against
T. gondii
may be useful in producing compounds with more potent activities against the parasite.
In Vitro and In Vivo Activities of Tea Catechins against
Helicobacter pylori
Authors: Mabe Katsuhiro , Yamada Masami , Oguni Itaro , Takahashi Tsuneo 
Published: October 2018

ABSTRACT

The catechin epigallocatechin gallate showed the strongest activity of the six tea catechins tested against
Helicobacter pylori
(MIC for 50% of the strains tested, 8 μg/ml). It had bactericidal activity at pH 7 but not at pH ≤5.0. In infected Mongolian gerbils,
H. pylori
was eradicated in 10 to 36% of the catechin-treated animals, with significant decreases in mucosal hemorrhage and erosion. Tea catechins, therefore, may have therapeutic effects on
H. pylori
infection.
Altered Pharmacokinetics of Ceftazidime in Critically Ill Patients
Authors: Gómez C. M. H. , Cordingly J. J. , Palazzo M. G. A. 
Published: October 2018

ABSTRACT

Many critically ill patients have increased extracellular fluid which might affect ceftazidime pharmacokinetics. We investigated the pharmacokinetics of ceftazidime in 15 adult intensive care patients receiving 2 g of ceftazidime intravenously three times a day. The ceftazidime mean (standard deviation) apparent volume of distribution and terminal-phase half-life were 56.91 (25.93) liters and 4.75 (1.85) h, respectively, significantly greater than values reported previously for healthy controls (
P
< 0.001). The mean ceftazidime clearance and area under the curve at steady state were not significantly different from those previously reported for controls. We conclude that ceftazidime pharmacokinetics in critically ill patients were altered by an increased volume of drug distribution and elevated elimination half-life.
Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2′-Deoxy-3′-Oxa-4′-Thiocytidine
Authors: de Muys Jean-Marc , Gourdeau Henriette , Nguyen-Ba Nghe , Taylor Debra L. , Ahmed Parvin S. , Mansour Tarek , Locas Celine , Richard Nathalie , Wainberg Mark A. , Rando Robert F. 
Published: October 2018

ABSTRACT

The racemic nucleoside analogue 2′-deoxy-3′-oxa-4′-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5′-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The

K
i

values for dOTC-TP obtained against human DNA polymerases α, β, and γ were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 μM, rising to only 2.53 and 2.5 μM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [
3
H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 μM for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 μM, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid.
Effect of Carbon Dioxide on Testing of Susceptibilities of Respiratory Tract Pathogens to Macrolide and Azalide Antimicrobial Agents
Authors: Johnson M. M. , Hill S. L. , Piddock Laura J. V. 
Published: October 2018

ABSTRACT
The in vitro activities of erythromycin, azithromycin, and clarithromycin against 178 clinical isolates from the lower respiratory tract of patients with chronic obstructive pulmonary disease were determined by an agar dilution method. The plates were incubated in air alone or in 5% carbon dioxide. The MICs measured in air alone were lower for most isolates than those measured in 5% carbon dioxide, illustrating the “pH effect” of incubation in carbon dioxide. Testing of isolates in 5% carbon dioxide on pH-adjusted medium (pH 8.4) resulted in MICs of one or two doubling dilutions lower than those obtained on agar with a neutral pH. A bioassay of the three agents incubated in air and in 5% carbon dioxide resulted in a significant loss of activity of all three agents in the carbon dioxide-enriched atmosphere. However, this loss-of-activity effect was significantly reduced when the bioassay medium was adjusted to pH 8.4 prior to incubation in 5% carbon dioxide.
Inhibition of Polyamine Synthesis Arrests Trichomonad Growth and Induces Destruction of Hydrogenosomes
Authors: Reis Isabela A. , Martinez Martha P. , Yarlett Nigel , Johnson Patricia J. , Silva-Filho Fernando C. , Vannier-Santos Marcos A. 
Published: October 2018

ABSTRACT

Trichomonad parasites such as
Tritrichomonas foetus
produce large amounts of putrescine (1,4-diaminobutane), which is transported out of the cell via an antiport mechanism which results in the uptake of a molecule of spermine. The importance of putrescine to the survival of the parasite and its role in the biology of
T. foetus
was investigated by use of the putrescine analogue 1,4-diamino-2-butanone (DAB). Growth of
T. foetus
in vitro was significantly inhibited by 20 mM DAB, which was reversed by the addition of exogenous 40 mM putrescine. High-performance liquid chromatography analysis of 20 mM DAB-treated
T. foetus
revealed that putrescine, spermidine, and spermine levels were reduced by 89, 52, and 43%, respectively, compared to those in control cells. The DAB treatment induced several ultrastructural alterations, which were primarily observed in the redox organelles termed hydrogenosomes. These organelles were progressively degraded, giving rise to large vesicles that displayed material immunoreactive with an antibody to β-succinyl-coenzyme A synthetase, a hydrogenosomal enzyme. A protective role for polyamines as stabilizing agents in the trichomonad hydrogenosomal membrane is proposed.
Emergence of Drug-Resistant Populations of Woodchuck Hepatitis Virus in Woodchucks Treated with the Antiviral Nucleoside Lamivudine
Authors: Zhou Tianlun , Saputelli Jeffry , Aldrich Carol E. , Deslauriers Manon , Condreay Lynn D. , Mason William S. 
Published: October 2018

ABSTRACT

Lamivudine [(−)-β-
l
-2′,3′-dideoxy-3′-thiacytidine] reduces woodchuck hepatitis virus (WHV) titers in the sera of chronically infected woodchucks by inhibiting viral DNA synthesis. However, after 6 to 12 months, WHV titers begin to increase toward pretreatment levels. Three WHV variants with mutations in the active site of the DNA polymerase gene are present at this time (W. S. Mason et al., Virology 245:18–32, 1998). We have asked if these mutant viruses were responsible for the lamivudine resistance and if their emergence caused an immediate rise in virus titers. Cell cultures studies implied that the mutants were resistant to lamivudine. Emergence of mutant WHV was not always associated, however, with an immediate rise in virus titers in the serum. One of the three types of mutant viruses became prominent in serum up to 7 months before titers in serum actually began to increase, at a time when wild-type virus was still predominant in the liver. The two other mutants did not show this behavior but were detected in serum and liver later, just at the time that virus titers began to rise. A factor linking all three mutants was that a similar duration of drug administration preceded the rise in titers, irrespective of which mutant ultimately prevailed. A simple explanation for these results is that the increase in virus titers following emergence of drug-resistant mutants can occur only as the preexisting wild-type virus is cleared from the hepatocyte population, allowing spread of the mutants. Thus, prolonged suppression of virus titers in the serum may sometimes be a measure of the stability of hepatocyte infection rather than of a successful therapeutic outcome.