bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adiponectin negatively correlates with alcoholic and non‐alcoholic liver dysfunction: Health check‐up study of Japanese men
Authors: Hamano Mina , Kamada Yoshihiro , Kiso Shinichi , Furuta Kunimaro , Kizu Takashi , Chatani Norihiro , Egawa Mayumi , Takemura Takayo , Ezaki Hisao , Yoshida Yuichi , Watabe Kenji , Hamasaki Toshimitsu , Umeda Miyuki , Furubayashi Aiko , Kinoshita Kazuo , Kishida Osamu , Fujimoto Takashi , Yamada Akira , Tsukamoto Yoshifumi , Tsutsui Shusaku , Takehara Tetsuo , Hayashi Norio , Matsuzawa Yuji 
Published: July 2012

Aim:  Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects.Methods:  A total of 5588 Japanese male subjects who underwent a health check‐up were classified into three groups according to alcohol consumption: non‐ or light drinkers (15 g/day ≥ ethanol); mild drinkers (15 g/day < ethanol ≤ 30 g/day); and moderate‐ or heavy drinkers (30 g/day < ethanol). Central obesity and insulin resistance were assessed by waist circumference (WC) and Homeostasis Model of Assessment – Insulin Resistance (HOMA‐IR), respectively.Results:  WC was significantly increased, while HOMA‐IR was significantly decreased according to the extent of alcohol consumption. Serum alanine aminotransferase levels were significantly lower and serum APN levels were significantly higher in mild drinkers than in the other two groups. Multiple linear regression analysis showed that serum APN level served as the significant and independent determinant for liver dysfunction in the subjects with fatty liver, irrespective of alcohol consumption. However, WC became a non‐significant determinant of liver dysfunction as alcohol consumption increased.Conclusion:  Hypoadiponectinemia is a significant determinant for steatotic dysfunction for all levels of alcohol consumption, but central obesity was not a significant determinant for alcoholic fatty liver‐induced liver dysfunction.
The Presence of an
FKS
Mutation Rather than MIC Is an Independent Risk Factor for Failure of Echinocandin Therapy among Patients with Invasive Candidiasis Due to Candida glabrata
Authors: Shields Ryan K. , Nguyen M. Hong , Press Ellen G. , Kwa Andrea L. , Cheng Shaoji , Du Chen , Clancy Cornelius J. 
Published: July 2012

ABSTRACT

Echinocandins are frontline agents against invasive candidiasis (IC), but predictors for echinocandin therapeutic failure have not been well defined. Mutations in
Candida FKS
genes, which encode the enzyme targeted by echinocandins, result in elevated MICs and have been linked to therapeutic failures. In this study, echinocandin MICs by broth microdilution and
FKS1
and
FKS2
mutations among
C. glabrata
isolates recovered from patients with IC at our center were correlated retrospectively with echinocandin therapeutic responses. Thirty-five patients with candidemia and 4 with intra-abdominal abscesses were included, 92% (36/39) of whom received caspofungin. Twenty-six percent (10) and 74% (29) failed and responded to echinocandin therapy, respectively. Caspofungin, anidulafungin, and micafungin MICs ranged from 0.5 to 8, 0.03 to 1, and 0.015 to 0.5 μg/ml, respectively.
FKS
mutations were detected in 18% (7/39) of
C. glabrata
isolates (
FKS1
,
n
= 2;
FKS2
,
n
= 5). Median caspofungin and anidulafungin MICs were higher for patients who failed therapy (
P
= 0.04 and 0.006, respectively). By receiver operating characteristic (ROC) analyses, MIC cutoffs that best predicted failure were >0.5 (caspofungin), >0.06 (anidulafungin), and >0.03 μg/ml (micafungin), for which sensitivity/specificity were 60%/86%, 50%/97%, and 40%/90%, respectively. Sensitivity/specificity of an
FKS
mutation in predicting failure were 60%/97%. By univariate analysis, recent gastrointestinal surgery, prior echinocandin exposure, anidulafungin MIC of >0.06 μg/ml, caspofungin MIC of >0.5 μg/ml, and an
FKS
mutation were significantly associated with failure. The presence of an
FKS
mutation was the only independent risk factor by multivariate analysis (
P
= 0.002). In conclusion, detection of
C. glabrata FKS
mutations was superior to MICs in predicting echinocandin therapeutic responses among patients with IC.
Correlation between Triazole Treatment History and Susceptibility in Clinically Isolated Aspergillus fumigatus
Authors: Tashiro Masato , Izumikawa Koichi , Hirano Katsuji , Ide Shotaro , Mihara Tomo , Hosogaya Naoki , Takazono Takahiro , Morinaga Yoshitomo , Nakamura Shigeki , Kurihara Shintaro , Imamura Yoshifumi , Miyazaki Taiga , Nishino Tomoya , Tsukamoto Misuzu , Kakeya Hiroshi , Yamamoto Yoshihiro , Yanagihara Katsunori , Yasuoka Akira , Tashiro Takayoshi , Kohno Shigeru 
Published: July 2012

ABSTRACT

This is the first report of a detailed relationship between triazole treatment history and triazole MICs for 154
Aspergillus fumigatus
clinical isolates. The duration of itraconazole dosage increased as the itraconazole MIC increased, and a positive correlation was observed (
r
= 0.5700,
P
< 0.0001). The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for MICs exceeding 2 μg/ml (0.5 μg/ml versus 2 μg/ml,
P
= 0.03). We also examined the relationship between cumulative itraconazole usage and the MICs of other azoles. A positive correlation existed between itraconazole dosage period and posaconazole MIC (
r
= 0.5237,
P
< 0.0001). The number of itraconazole-naïve isolates also decreased as the posaconazole MIC increased, particularly for MICs exceeding 0.5 μg/ml (0.25 μg/ml versus 0.5 μg/ml,
P
= 0.004). Conversely, the correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (
r
= −0.2627,
P
= 0.001). Susceptibility to three triazole agents did not change as the duration of voriconazole exposure changed. In addition, we carried out detailed analysis, including microsatellite genotyping, for isolates obtained from patients infected with azole-resistant
A. fumigatus
. We confirmed the presence of acquired resistance to itraconazole and posaconazole due to a G54 substitution in the
cyp51A
gene for a patient with chronic pulmonary aspergillosis after oral itraconazole therapy. We should consider the possible appearance of azole-resistant
A. fumigatus
if itraconazole is used for extended periods.
Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring
Authors: Dolton Michael J. , Ray John E. , Chen Sharon C.-A. , Ng Kingsley , Pont Lisa G. , McLachlan Andrew J. 
Published: July 2012

ABSTRACT

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (
P
< 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (
P
< 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.
Optimal Control Strategies for Disinfection of Bacterial Populations with Persister and Susceptible Dynamics
Authors: Cogan N. G. , Brown Jason , Darres Kyle , Petty Katherine 
Published: July 2012

ABSTRACT
It is increasingly clear that bacteria manage to evade killing by antibiotics and antimicrobials in a variety of ways, including mutation, phenotypic variations, and formation of biofilms. With recent advances in understanding the dynamics of the tolerance mechanisms, there have been subsequent advances in understanding how to manipulate the bacterial environments to eradicate the bacteria. This study focuses on using mathematical techniques to find the optimal disinfection strategy to eliminate the bacteria while managing the load of antibiotic that is applied. In this model, the bacterial population is separated into those that are tolerant to the antibiotic and those that are susceptible to disinfection. There are transitions between the two populations whose rates depend on the chemical environment. Our results extend previous mathematical studies to include more realistic methods of applying the disinfectant. The goal is to provide experimentally testable predictions that have been lacking in previous mathematical studies. In particular, we provide the optimal disinfection protocol under a variety of assumptions within the model that can be used to validate or invalidate our simplifying assumptions and the experimental hypotheses that we used to develop the model. We find that constant dosing is not the optimal method for disinfection. Rather, cycling between application and withdrawal of the antibiotic yields the fastest killing of the bacteria.
Influence of Multidrug Resistance and Appropriate Empirical Therapy on the 30-Day Mortality Rate of Pseudomonas aeruginosa Bacteremia
Authors: Morata Laura , Cobos-Trigueros Nazaret , Martínez José A. , Soriano Álex , Almela Manel , Marco Francesc , Sterzik Holguer , Núñez Raquel , Hernández Cristina , Mensa José 
Published: July 2012

ABSTRACT

Infections due to multidrug-resistant (MDR)
Pseudomonas aeruginosa
are increasing. The aim of our study was to evaluate the influences of appropriate empirical antibiotic therapy and multidrug resistance on mortality in patients with bacteremia due to
P. aeruginosa
(PAB). Episodes of PAB were prospectively registered from 2000 to 2008. MDR was considered when the strain was resistant to ≥3 antipseudomonal antibiotics. Univariate and multivariate analyses were performed. A total of 709 episodes of PAB were studied. MDR PAB (
n
= 127 [17.9%]) was more frequently nosocomial and associated with longer hospitalization, bladder catheter use, steroid and antibiotic therapy, receipt of inappropriate empirical antibiotic therapy, and a higher mortality. Factors independently associated with mortality were age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002 to 1.033), shock (OR, 6.6; 95% CI, 4 to 10.8), cirrhosis (OR, 3.3; 95% CI, 1.4 to 7.6), intermediate-risk sources (OR, 2.5; 95% CI, 1.4 to 4.3) or high-risk sources (OR, 7.3; 95% CI, 4.1 to 12.9), and inappropriate empirical therapy (OR, 2.1; 95% CI, 1.3 to 3.5). To analyze the interaction between empirical therapy and MDR, a variable combining both was introduced in the multivariate analysis. Inappropriate therapy was significantly associated with higher mortality regardless of the susceptibility pattern, and there was a trend toward higher mortality in patients receiving appropriate therapy for MDR than in those appropriately treated for non-MDR strains (OR, 2.2; 95% CI, 0.9 to 5.4). In 47.9% of MDR PAB episodes, appropriate therapy consisted of monotherapy with amikacin. In conclusion, MDR PAB is associated with a higher mortality than non-MDR PAB. This may be related to a higher rate of inappropriate empirical therapy and probably also to amikacin as frequently the only appropriate empirical therapy given to patients with MDR PAB.
In Vitro
Synergy of Colistin Combinations against Colistin-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates
Authors: Vidaillac Céline , Benichou Lothaire , Duval Raphaël E. 
Published: July 2012

ABSTRACT

Colistin resistance, although uncommon, is increasingly being reported among Gram-negative clinical pathogens, and an understanding of its impact on the activity of antimicrobials is now evolving. We evaluated the potential for synergy of colistin plus trimethoprim, trimethoprim-sulfamethoxazole (1/19 ratio), or vancomycin against 12 isolates of
Acinetobacter baumannii
(
n
= 4),
Pseudomonas aeruginosa
(
n
= 4), and
Klebsiella pneumoniae
(
n
= 4). The strains included six multidrug-resistant clinical isolates,
K. pneumoniae
ATCC 700603,
A. baumannii
ATCC 19606,
P. aeruginosa
ATCC 27853, and their colistin-resistant derivatives (KPm1, ABm1, and PAm1, respectively). Antimicrobial susceptibilities were assessed by broth microdilution and population analysis profiles. The potential for synergy of colistin combinations was evaluated using a checkerboard assay, as well as static time-kill experiments at 0.5× and 0.25× MIC. The MIC ranges of vancomycin, trimethoprim, and trimethoprim-sulfamethoxazole (1/19) were ≥128, 4 to ≥128, and 2/38 to >128/2,432 μg/ml, respectively. Colistin resistance demonstrated little impact on vancomycin, trimethoprim, or trimethoprim-sulfamethoxazole MIC values. Isolates with subpopulations heterogeneously resistant to colistin were observed to various degrees in all tested isolates. In time-kill assays, all tested combinations were synergistic against KPm1 at 0.25× MIC and 0.5× MIC and ABm1 and PAm1 at 0.5× MIC. In contrast, none of the tested combinations demonstrated synergy against any colistin-susceptible
P. aeruginosa
isolates and clinical strains of
K. pneumoniae
isolates. Only colistin plus trimethoprim or trimethoprim-sulfamethoxazole was synergistic and bactericidal at 0.5× MIC against
K. pneumoniae
ATCC 700603. Colistin resistance seems to promote the
in vitro
activity of unconventional colistin combinations. Additional experiments are warranted to understand the clinical significance of these observations.
Mlp24 (McpX) of Vibrio cholerae Implicated in Pathogenicity Functions as a Chemoreceptor for Multiple Amino Acids
Authors: Nishiyama So-ichiro , Suzuki Daisuke , Itoh Yasuaki , Suzuki Kazuho , Tajima Hirotaka , Hyakutake Akihiro , Homma Michio , Butler-Wu Susan M. , Camilli Andrew , Kawagishi Ikuro 
Published: July 2012

ABSTRACT

The chemotaxis of
Vibrio cholerae
, the causative agent of cholera, has been implicated in pathogenicity. The bacterium has more than 40 genes for methyl-accepting chemotaxis protein (MCP)-like proteins (MLPs). In this study, we found that glycine and at least 18
l
-amino acids, including serine, arginine, asparagine, and proline, serve as attractants to the classical biotype strain O395N1. Based on the sequence comparison with
Vibrio parahaemolyticus
, we speculated that at least 17 MLPs of
V. cholerae
may mediate chemotactic responses. Among them, Mlp24 (previously named McpX) is required for the production of cholera toxin upon mouse infection.
mlp24
deletion strains of both classical and El Tor biotypes showed defects in taxis toward several amino acids, which were complemented by the expression of Mlp24. These amino acids enhanced methylation of Mlp24. Serine, arginine, asparagine, and proline were shown to bind directly to the periplasmic fragment of Mlp24. The structural information of its closest homolog, Mlp37, predicts that Mlp24 has two potential ligand-binding pockets per subunit, the membrane distal of which was suggested, by mutational analyses, to be involved in sensing of amino acids. These results suggest that Mlp24 is a chemoreceptor for multiple amino acids, including serine, arginine, and asparagine, which were previously shown to stimulate the expression of several virulence factors, implying that taxis toward a set of amino acids plays critical roles in pathogenicity of
V. cholerae
.
Phosphate Groups of Lipid A Are Essential for Salmonella enterica Serovar Typhimurium Virulence and Affect Innate and Adaptive Immunity
Authors: Kong Qingke , Six David A. , Liu Qing , Gu Lillian , Wang Shifeng , Alamuri Praveen , Raetz Christian R. H. , Curtiss Roy 
Published: July 2012

ABSTRACT

Lipid A is a key component of the outer membrane of Gram-negative bacteria and stimulates proinflammatory responses via the Toll-like receptor 4 (TLR4)-MD2-CD14 pathway. Its endotoxic activity depends on the number and length of acyl chains and its phosphorylation state. In
Salmonella enterica
serovar Typhimurium, removal of the secondary laurate or myristate chain in lipid A results in bacterial attenuation and growth defects
in vitro
. However, the roles of the two lipid A phosphate groups in bacterial virulence and immunogenicity remain unknown. Here, we used an
S
. Typhimurium
msbB pagL pagP lpxR
mutant, carrying penta-acylated lipid A, as the parent strain to construct a series of mutants synthesizing 1-dephosphorylated, 4′-dephosphorylated, or nonphosphorylated penta-acylated lipid A. Dephosphorylated mutants exhibited increased sensitivity to deoxycholate and showed increased resistance to polymyxin B. Removal of both phosphate groups severely attenuated the mutants when administered orally to BALB/c mice, but the mutants colonized the lymphatic tissues and were sufficiently immunogenic to protect the host from challenge with wild-type
S
. Typhimurium. Mice receiving
S
. Typhimurium with 1-dephosphorylated or nonphosphorylated penta-acylated lipid A exhibited reduced levels of cytokines. Attenuated and dephosphorylated
Salmonella
vaccines were able to induce adaptive immunity against heterologous (PspA of
Streptococcus pneumoniae
) and homologous antigens (lipopolysaccharide [LPS] and outer membrane proteins [OMPs]).
A Novel Phage Element of Salmonella enterica Serovar Enteritidis P125109 Contributes to Accelerated Type III Secretion System 2-Dependent Early Inflammation Kinetics in a Mouse Colitis Model
Authors: Vishwakarma Vikalp , Periaswamy Balamurugan , Bhusan Pati Niladri , Slack Emma , Hardt Wolf-Dietrich , Suar Mrutyunjay 
Published: July 2012

ABSTRACT

Salmonella enterica
subsp. I serovar Enteritidis exhibits type III secretion system 2 (TTSS2)-dependent early colonization and inflammation kinetics faster than those of closely related
S. enterica
serovar Typhimurium. To investigate the accelerated TTSS-2-dependent pathogenic potential of
S
. Enteritidis, we focused on its genome. Results of a previously published comparative genomic study revealed the presence of mutually exclusive genes in both serovars. In this study, we investigated the roles of six
S
. Enteritidis-specific genes
in vivo
by using differential fluorescence induction (DFI) through putative gene-specific promoters. The promoter construct associated with the gene locus
SEN1140
induced green fluorescent protein (GFP) expression in the gut lumen, lamina propria, mesenteric lymph nodes, and related systemic organs. To further investigate the potential role of
SEN1140
, we compared a
SEN1140
deletion mutant with
S
. Typhimurium in a TTSS1-deficient background. Interestingly, the
S
. Enteritidis mutant lacking
SEN1140
did not show the unique TTSS-2-dependent early colonization and inflammation kinetic phenotype of
S
. Typhimurium. Consistent with this result, complementation of
SEN1140
restored the TTSS-2-dependent accelerated inflammatory potential of
S
. Enteritidis. This report presents a suitable screening strategy that uses a combination of DFI, fluorescence-activated cell sorting, quantitative PCR, and wild-type isogenic tagged-strain techniques to explore the unique roles of
S
. Enteritidis-specific genes in bacterial pathogenesis.
Dissemination Bottleneck in a Murine Model of Inhalational Anthrax
Authors: Plaut Roger D. , Kelly Vanessa K. , Lee Gloria M. , Stibitz Scott , Merkel Tod J. 
Published: July 2012

ABSTRACT

Inhalational anthrax is caused by the sporulating bacterium
Bacillus anthracis
. A current model for progression in mammalian hosts includes inhalation of bacterial spores, phagocytosis of spores in the nasal mucosa-associated lymphoid tissue (NALT) and lungs by macrophages and dendritic cells, trafficking of phagocytes to draining lymph nodes, germination of spores and multiplication of vegetative bacteria in the NALT and lymph nodes, and dissemination of bacteria via the bloodstream to multiple organs. In previous studies, the kinetics of infection varied greatly among mice, leading us to hypothesize the existence of a bottleneck past which very few spores (perhaps only one) progress to allow the infection to proceed. To test this hypothesis, we engineered three strains of
B. anthracis
Sterne, each marked with a different fluorescent protein, enabling visual differentiation of strains grown on plates. Mice were infected with a mixture of the three strains, the infection was allowed to proceed, and the strains colonizing the organs were identified. Although the inoculum consisted of approximately equal numbers of each of the three strains, the distal organs were consistently colonized by a majority of only one of the three strains, with the dominant strain varying among animals. Such dominance of one strain over the other two was also found at early time points in the cervical lymph nodes but not in the mediastinal lymph nodes. These results support the existence of a bottleneck in the infectious process.