bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of a Putative Novel Wolinella Species in Patients with Squamous Cell Carcinoma of the Esophagus
Authors: Bohr Ulrich R. M. , Segal Isidor , Primus Anett , Wex Thomas , Hassan Hashiem , Ally Reidwaan , Malfertheiner Peter 
Published: November 2003

ABSTRACTBackground.  Certain regions of South Africa exhibit an extraordinarily high incidence of esophageal carcinoma that develops via an esophagitis–dysplasia–carcinoma sequence. Bacteria belonging to the family Helicobacteraceae are candidates for involvement in the initiation of the esophagitis. We investigated patients with esophageal carcinoma for the occurrence of Helicobacter‐related species.Methods.  Biopsies from tumor and nonlesional tissue of the esophagus from nine patients with squamous cell carcinoma were investigated for Helicobacteraceae using a PCR‐based method targeting the 16S rRNA gene.Results.  Four out of nine patients tested negative, while samples from the other five patients revealed an infection by different Helicobacter species. Sequence analysis of the PCR fragments led to the identification of a hitherto unknown bacterium in three of these patients. Phylogenetically, this bacterium was assigned to the genus Wolinella within the family of Helicobacteraceae. Helicobacter pylori was identified in three patients, and one revealed a coinfection with the novel Wolinella species.Conclusions.  Helicobacteraceae were detected in approximately 50% of South African patients with esophageal carcinoma. Furthermore, a novel bacterium was identified that might be linked to the enhanced incidence of esophagitis and subsequent malignant disease in South Africa.
In VivoEfficacy of a New Quinolone, DQ-113, against
Streptococcuspneumoniae
in a MouseModel
Authors: Otsu Yoshiko , Yanagihara Katsunori , Fukuda Yuichi , Miyazaki Yoshitsugu , Tsukamoto Kazuhiro , Hirakata Yoichi , Tomono Kazunori , Kadota Jun-ichi , Tashiro Takayoshi , Murata Ikuo , Kohno Shigeru 
Published: November 2003

ABSTRACT

DQ-113
is a new quinolone with potent activity against gram-positive
pathogens. The in vivo activity of DQ-113 against
Streptococcus
pneumoniae
was compared with those of gatifloxacin and
ciprofloxacin in a mouse model. For this purpose, two strains of
S.
pneumoniae
were used: penicillin-susceptible
S.
pneumoniae
(PSSP) and penicillin-resistant
S. pneumoniae
(PRSP). The survival rates of mice infected with PSSP and PRSP at 14
days after infection were 80% in the DQ-113-treated group and 0
to 10% in the other three groups. In murine infections caused by
PSSP, the 50% effective doses (ED
50
s) of DQ-113,
gatifloxacin, and ciprofloxacin were 6.0, 41.3, and 131.6 mg/kg,
respectively. Against PRSP-caused pneumonia in mice, the
ED
50
s of DQ-113, gatifloxacin, and ciprofloxacin were 7.6,
64.7, and 125.9 mg/kg, respectively. Compared with the other drugs,
DQ-113 showed excellent therapeutic efficacy and eradicated viable
bacteria in both PSSP- and PRSP-infected mice. The means ±
standard errors of the means of viable bacterium counts in the lungs of
gatifloxacin-treated, ciprofloxacin-treated, and untreated control mice
infected with PSSP were 2.91 ± 0.34, 3.13 ± 0.48, and
3.86 ± 0.80 log
10
CFU/ml, respectively. The same
counts in mice infected with PRSP treated with the same three agents
were 6.57 ± 0.99, 6.54 ± 0.40, and 7.17 ± 0.43
log
10
CFU/ml, respectively. DQ-113 significantly decreased
the number of viable bacteria in the lungs compared with gatifloxacin
and ciprofloxacin. Of the drugs analyzed, the
pharmacokinetic-pharmacodynamic parameter of area under the
concentration-time curve (AUC)/MIC ratio for DQ-113 was significantly
higher than those for gatifloxacin and ciprofloxacin. Our results
suggest that DQ-113 has potent in vivo efficacy against both PSSP and
PRSP.
Antimalarial 9-Anilinoacridine Compounds Directed atHematin
Authors: Auparakkitanon Saranya , Noonpakdee Wilai , Ralph Raymond K. , Denny William A. , Wilairat Prapon 
Published: November 2003

ABSTRACT

Antimalarial
9-anilinoacridines are potent inhibitors of parasite DNA topoisomerase
II both in vitro and in situ. 3,6-Diamino substitution on the acridine
ring greatly improves parasiticidal activity against
Plasmodium
falciparum
by targeting DNA topoisomerase II. A series of
9-anilinoacridines were investigated for their abilities to inhibitβ
-hematin formation, to form drug-hematin complexes, and to
enhance hematin-induced lysis of red blood cells. Inhibition ofβ
-hematin formation was minimal with 3,6-diamino analogs of
9-anilinoacridine and greatest with analogs with a 3,6-diCl
substitution together with an electron-donating group in the
1′-anilino position. On the other hand, the presence of a
1′-N(CH
3
)
2
group in the anilino ring
produced compounds that strongly inhibited β-hematin formation
but which did not appear to be sensitive to the nature of the
substitutions in the acridine nucleus. The derivatives bound hematin,
and Job's plots of UV-visible absorbance changes in drug-hematin
complexes at various molar ratios indicated a stoichiometric ratio of
1:2. The drugs enhanced hematin-induced red blood cell lysis at low
concentrations (<4 μM). These studies open up the novel
possibility of development of 9-anilinoacridine antimalarials that
target not only DNA topoisomerase II but alsoβ
-hematin formation, which should help delay the rapid onset of
resistance to drugs acting at only a single
site.
In Vitro Evaluation of a New Treatment for UrinaryTract Infections Caused by Nitrate-ReducingBacteria
Authors: Carlsson S. , Govoni M. , Wiklund N. P. , Weitzberg E. , Lundberg J. O. 
Published: November 2003

ABSTRACT

Dietary
and endogenous nitrates are excreted in urine, and during infection
with nitrate-reducing bacteria they are reduced to nitrite. At a low pH
nitrite is converted to a variety of nitrogen oxides that are toxic to
bacteria. We hypothesized that acidification of nitrite-rich infected
urine would result in the killing of the nitrate-reducing bacteria. An
Escherichia coli
control strain and a mutant lacking nitrate
reductase activity were preincubated in urine supplemented with sodium
nitrate (0 to 10 mM) at pH 7.0. Then, the nitrite-containing bacterial
culture was transferred (and diluted 1/10) to slightly acidic urine (pH
5 and 5.5) containing ascorbic acid (10 mM) and growth was monitored.
The control strain produced nitrite in amounts related to the amount of
nitrate added. This strain was killed when the culture was transferred
to acidic urine. In contrast, the mutant that did not produce nitrite
retained full viability. When control bacteria were grown in acidic
urine with nitrate and ascorbic acid present from the start of the
experiment, no inhibition of growth was noted. The MICs and minimal
bactericidal concentrations of sodium nitrite-ascorbic
acid in acidic urine were comparable to those of conventional
antibiotics. Preincubation of nitrate-reducing
E. coli
in
nitrate-rich urine leads to the accumulation of nitrite. Subsequent
acidification of the urine results in generation of nitrogen oxides
that are bactericidal. Killing, however, requires a sequential
procedure in which the bacteria are first allowed to grow in a
nitrate-rich neutral environment, later followed by acidification. We
speculate that ingestion of nitrate followed some hours later by
acidification of urine could be a new therapeutic strategy for the
treatment of urinary tract
infections.
EfrAB, an ABC Multidrug Efflux Pump in
Enterococcusfaecalis
Authors: Lee Eun-Woo , Huda M. Nazmul , Kuroda Teruo , Mizushima Tohru , Tsuchiya Tomofusa 
Published: November 2003

ABSTRACT

A
DNA fragment responsible for resistance to antimicrobial agents was
cloned from the chromosomal DNA of
Enterococcus faecalis
ATCC
29212 by using drug-hypersensitive mutant
Escherichia coli
KAM32 as a host cell. Cells of
E. coli
KAM32 harboring a
recombinant plasmid (pAEF82) carrying the DNA fragment became resistant
to many structurally unrelated antimicrobial agents, such as
norfloxacin, ciprofloxacin, doxycycline, acriflavine,
4′,6-diamidino-2-phenylindole, tetraphenylphosphonium chloride,
daunorubicin, and doxorubicin. Since the sequence of the whole genome
of
E. faecalis
is known, we sequenced several portions of the
DNA insert in plasmid pAEF82 and identified two open reading frames
within the insert. We designated the genes
efrA
and
efrB
. A search of the deduced amino acid sequences of EfrA and
EfrB revealed that they are similar to each other and that they belong
to the ATP-binding cassette (ABC) family of multidrug efflux
transporters. Transformed
E. coli
KAM32 cells harboring
efrAB
showed energy-dependent efflux of acriflavine. The
efflux activity was inhibited by reserpine, verapamil, and
sodium-
o
-vanadate, known inhibitors of ABC efflux
pumps.
FusidicAcid-Resistant Mutants of
Salmonella enterica
SerovarTyphimurium with Low Fitness In Vivo Are Defective in RpoSInduction
Authors: Macvanin Mirjana , Björkman Johanna , Eriksson Sofia , Rhen Mikael , Andersson Dan I. , Hughes Diarmaid 
Published: November 2003

ABSTRACT

Mutants
of
Salmonella enterica
serovar Typhimurium resistant to
fusidic acid (Fus
r
) have mutations in
fusA
, the
gene encoding translation elongation factor G (EF-G). Most
Fus
r
mutants have reduced fitness in vitro and in vivo, in
part explained by mutant EF-G slowing the rate of protein synthesis and
growth. However, some Fus
r
mutants with normal rates of
protein synthesis still suffer from reduced fitness in vivo. As shown
here, Fus
r
mutants could be similarly ranked in their
relative fitness in mouse infection models, in a macrophage infection
model, in their relative hypersensitivity to hydrogen peroxide in vivo
and in vitro, and in the amount of RpoS production induced upon entry
into the stationary phase. We identify a reduced ability to induce
production of RpoS (σ
s
) as a defect associated with
Fus
r
strains. Because RpoS is a regulator of the general
stress response, and an important virulence factor in
Salmonella
, an inability to produce RpoS in appropriate
amounts can explain the low fitness of Fus
r
strains in vivo.
The unfit Fus
r
mutants also produce reduced levels of the
regulatory molecule ppGpp in response to starvation. Because ppGpp is a
positive regulator of RpoS production, we suggest that a possible cause
of the reduced levels of RpoS is the reduction in ppGpp production
associated with mutant EF-G. The low fitness of Fus
r
mutants
in vivo suggests that drugs that can alter the levels of global
regulators of gene expression deserve attention as potential
antimicrobial
agents.
Increased Killing of Staphylococci and Streptococciby Daptomycin Compared with Cefazolin and Vancomycin in an InVitro Peritoneal DialysateModel
Authors: Hermsen Elizabeth D. , Hovde Laurie B. , Hotchkiss John R. , Rotschafer John C. 
Published: November 2003

ABSTRACT

Peritoneal
dialysate fluid (PDF) is a bacteriostatic medium that compromises the
antibacterial activity of cell wall-active agents. By use of an in
vitro static model, methicillin-resistant
Staphylococcus
aureus
(MRSA), methicillin-susceptible
S. aureus
(MSSA),
methicillin-susceptible
Staphylococcus epidermidis
(MSSE), and
Streptococcus sanguis
were exposed to daptomycin
at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125
mg/liter, and vancomycin at 25 mg/liter in cation-adjusted
Mueller-Hinton Broth or Todd Hewitt Broth (for
S. sanguis
) and
PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial
activity. Neither cefazolin nor vancomycin produced a bactericidal or a
bacteriostatic effect versus MRSA, MSSA, MSSE, or
S. sanguis
in PDF, while all concentrations of daptomycin were bactericidal
against all organisms in PDF. Daptomycin did not exhibit
concentration-dependent activity in PDF. Daptomycin appears to be a
promising agent for use in peritoneal dialysis-associated peritonitis,
producing bacterial kill to a greater extent and at a higher rate than
cefazolin or vancomycin in
PDF.
Efficacies of Vancomycin, Arbekacin, and GentamicinAlone or in Combination against Methicillin-Resistant
Staphylococcus aureus
in an In Vitro InfectiveEndocarditisModel
Authors: Lee Dong-Gun , Chun Hye-Sun , Yim Dong-Seok , Choi Su-Mi , Choi Jung-Hyun , Yoo Jin-Hong , Shin Wan-Shik , Kang Moon-Won 
Published: November 2003

ABSTRACT

We
adopted an in vitro infective endocarditis model (IVIEM) to compare the
efficacy of vancomycin (VAN), arbekacin (ABK), and gentamicin (GEN)
alone or in combination. Using two strains of clinically isolated
methicillin-resistant
Staphylococcus aureus
, one GEN
susceptible (GS171) and one GEN resistant (GR153), fibrin clots were
prepared and suspended in the IVIEM. Antibiotics were given as boluses
every 6 h (q6h), q12h, or q24h or by continuous infusion with
VAN, q12h or q24h with ABK, and q8h or q24h with GEN. For combination
treatment, VAN q12h plus ABK q24h and VAN q12h plus GEN q24h were
given. Fibrin clots were removed from each model at 0, 8, 24, 32, 48,
and 72 h, and the bacterial densities were determined. The
number of colonies within the fibrin clot was significantly decreased
in all study groups compared with control groups (
P
<
0.001). When VAN and ABK were administered alone, the number of
colonies was significantly lower in GS171 than in GR153 by 8
h after administration (
P
= 0.02) and was lowest in
GS171 when ABK was administered q12h (
P
= 0.01). At
72 h, ABK or VAN alone produced equivalent bacterial
reductions regardless of dosing frequency and GEN resistance. In GR153,
VAN plus ABK showed an additive effect till 24 h, although
VAN plus GEN showed indifference. Our data suggest that ABK could be
used as an alternative to VAN in GEN-resistant staphylococcal
endocarditis. An additive effect was seen when VAN and ABK were used
together in GEN-resistant strains until 24 h; however,
further studies are warranted for the clinical application of this
combination.
Toxicity and Antileishmanial Activity of a New StableLipid Suspension of AmphotericinB
Authors: Larabi Malika , Yardley Vanessa , Loiseau Philippe M. , Appel Martine , Legrand Philippe , Gulik Annette , Bories Christian , Croft Simon L. , Barratt Gillian 
Published: November 2003

ABSTRACT

The
aim of the present study was to evaluate the toxicity and the activity
of a new lipid complex formulation of amphotericin B (AMB) (LC-AMB;
dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, and
AMB) that can be produced by a simple process. Like other lipid
formulations, this new complex reduced both the hemolytic activity of
AMB (the concentration causing 50% hemolysis of human
erythrocytes, >100 μg/ml) and its toxicity
toward murine peritoneal macrophages (50% inhibitory
concentration, >100 μg/ml at 24 h). The in
vivo toxicity of the new formulation (50% lethal dose,>
200 mg/kg of body weight for CD1 mice) was similar to those of
other commercial lipid formulations of AMB. The complex was the most
effective formulation against the DD8 strain of
Leishmania
donovani
. It was unable to reverse the resistance of an
AMB-resistant
L. donovani
strain. In vivo LC-AMB was less
efficient than AmBisome against
L.
donovani
.
Concentrations in Plasma, Urinary Excretion, andBactericidal Activity of Linezolid (600 Milligrams) versusThose of Ciprofloxacin (500 Milligrams) inHealthy Volunteers Receiving a Single OralDose
Authors: Wagenlehner Florian M. E. , Wydra Stephan , Onda Hajime , Kinzig-Schippers Martina , Sörgel Fritz , Naber Kurt G. 
Published: November 2003

ABSTRACT

In
a randomized crossover study, 12 volunteers (6 males, 6 females)
received a single oral dose of 600 mg of linezolid or 500 mg of
ciprofloxacin to assess the concentrations in plasma (up to
24 h), urinary excretion (by high-pressure liquid
chromatography), and bactericidal titers in urine (UBT) at intervals up
to 120 h. The mean maximum concentration of linezolid in
plasma was 13.1 mg/liter, and that of ciprofloxacin was 2.46 mg/liter.
The median cumulative levels of renal excretion of the administered
dose of the parent drug were 44% for linezolid (range, 28 to
47%; mean ± standard deviation, 40% ±
7.8%) and 43% for ciprofloxacin (range, 20 to 56%;
mean ± standard deviation, 40% ± 9.3%).
The UBTs, i.e., the highest twofold dilution (with antibiotic-free
urine used as the diluent) of urine that was still bactericidal, were
determined for a reference strain and five gram-positive clinical
uropathogens for which the MICs of linezolid and
ciprofloxacin were as follows:
Staphylococcus aureus
ATCC
27278, 2 and 0.25 mg/liter, respectively;
Staphylococcus aureus
(methicillin susceptible), 1 and 16
mg/liter, respectively;
Staphylococcus aureus
(methicillin
resistant), 2 and 64 mg/liter, respectively;
Staphylococcus
saprophyticus
(methicillin susceptible), 1 and 0.25 mg/liter,
respectively;
Enterococcus faecalis
, 2 and 1 mg/liter,
respectively; and
Enterococcus faecium
, 2 and 1 mg/liter,
respectively. The median UBTs of linezolid measured within the first
6 h were 1:96 for each of the two enterococcal strains and
between 1:128 and 1:256 for the four staphylococcal strains. The median
UBTs of ciprofloxacin were 1:64 for the two enterococcal strains;
between 1:384 and 1:512 for the two ciprofloxacin-susceptible strains;
and 1 (bactericidal activity of undiluted urine only) and 1:2 for the
two resistant staphylococcal strains, respectively. The areas under the
UBT-time curve (AUBT) for linezolid and ciprofloxacin showed no
statistically significant (
P
< 0.05) differences
except for a better AUBT for linezolid for the two
ciprofloxacin-resistant staphylococcal strains. For linezolid there
were no statistically significant differences in UBTs or AUBTs for
ciprofloxacin-susceptible and -resistant strains. Thus, the
bactericidal activities of linezolid and ciprofloxacin against
susceptible strains in urine were comparable, whereas linezolid also
exhibited the same good bactericidal activity against
ciprofloxacin-resistant strains. Therefore, linezolid should be tested
for use as empirical treatment for complicated urinary tract infections
due to gram-positive uropathogens in an appropriate clinical
trial.
Artemether Bioavailability after Oral or IntramuscularAdministration in Uncomplicated FalciparumMalaria
Authors: Silamut Kamolrat , Newton Paul N. , Teja-Isavadharm Paktiya , Suputtamongkol Yupin , Siriyanonda Duangsuda , Rasameesoraj Maneerat , Pukrittayakamee Sasithon , White Nicholas J. 
Published: November 2003

ABSTRACT

The
antimalarial activity of artemether following oral or intramuscular
administration in the plasma of 15 adults with acute uncomplicated
Plasmodium falciparum
malaria was measured by bioassay. The
peak concentrations in plasma following oral administration were higher
in patients with acute illness (median, 1,905 mmol of
dihydroartemisinin [DHA] equivalents per liter; range, 955 to
3,358 mmol of DHA equivalents per liter) than in patients in the
convalescent phase (median, 955 mmol of DHA equivalents per liter;
range, 576 to 1,363 mmol of DHA equivalents per liter), and clearance
(CL/F) was lower in patients in the acute phase (1.11 liters/kg/h;
range, 0.21 to 3.08 liters/kg/h) than in patients in the convalescent
phase (median, 2.76 liters/kg/h; range, 1.56 to 5.74 liters/kg/h)
(
P
≤ 0.008). Antimalarial activity in terms of the
peak concentration in plasma (
C
max
) after oral
administration was a median of 16 times higher than that after
intramuscular administration. The ratio of the area under the plasma
concentration-time curve during the first 24 h
(AUC
0-24
) after oral administration of artemether to the
AUC
0-24
after intramuscular administration was a median of
3.3 (range, 1 to 11) (
P
= 0.0001). In the acute phase,
the time to
C
max
was significantly shorter after
oral administration (median, 1 h; range, 0.5 to 3.0
h) than after intramuscular administration (median, 8 h;
range, 4 to 24 h) (
P
= 0.001). Intramuscular
artemether is absorbed very slowly in patients with acute
malaria.
5HT1A Serotonin Receptor Agonists InhibitPlasmodium falciparumby Blocking a MembraneChannel
Authors: Locher Christopher P. , Ruben Peter C. , Gut Jiri , Rosenthal Philip J. 
Published: November 2003

ABSTRACTToidentify new leads for the treatment ofPlasmodiumfalciparummalaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth ofP. falciparumin vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth ofLeishmania infantum,Trypanosomacruzi,Trypanosoma brucei brucei, orTrichostrongylus colubriformisin vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several differentP. falciparumisolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked aP. falciparumsurface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterizeP. falciparummembrane channels.
Antimalarial Activities of Novel SyntheticCysteine ProteaseInhibitors
Authors: Lee Belinda J. , Singh Ajay , Chiang Peggy , Kemp Scott J. , Goldman Erick A. , Weinhouse Michael I. , Vlasuk George P. , Rosenthal Philip J. 
Published: November 2003

ABSTRACT

Among
promising new targets for antimalarial chemotherapy are the cysteine
protease hemoglobinases falcipain-2 and falcipain-3. We evaluated the
activities of synthetic peptidyl aldehyde and α-ketoamide
cysteine protease inhibitors against these proteases, against cultured
Plasmodium falciparum
parasites, and in a murine malaria
model. Optimized compounds inhibited falcipain-2 and falcipain-3,
blocked hemoglobin hydrolysis, and prevented the development of
P.
falciparum
at nanomolar concentrations. The compounds were equally
active against multiple strains of
P. falciparum
with varied
sensitivities to standard antimalarial agents. The peptidyl inhibitors
were consistently less active against vinckepain-2, the putative
falcipain-2 and falcipain-3 ortholog of the rodent malaria parasite
Plasmodium vinckei
. The lead compound
morpholinocarbonyl-leucine-homophenylalanine aldehyde, which blocked
P. falciparum
development at low nanomolar concentrations, was
tested in a murine
P. vinckei
model. When infused continuously
at a rate of 30 mg/kg of body weight/day, the compound delayed the
progression of malaria but did not eradicate infections. Our data
demonstrate the potent antimalarial activities of novel cysteine
protease inhibitors. Additionally, they highlight the importance of
consideration of the specific enzyme targets of animal model parasites.
In the case of falcipains, differences between
P. falciparum
and rodent parasites complicate the use of the rodent malaria model in
the drug discovery
process.