bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Brief Risk Stratification Tool to Predict Functional Decline in Older Adults Discharged from Emergency Departments
Authors: Hustey Fredric M. , Mion Lorraine C. , Connor Jason T. , Emerman Charles L. , Campbell James , Palmer Robert M. 
Published: June 2007

OBJECTIVES: To determine the effectiveness of the six‐item Triage Risk Screening Tool (TRST) to assess baseline functional status and predict subsequent functional decline in older community‐dwelling adults discharged home from the emergency department (ED).DESIGN: Secondary data analysis of a randomized, controlled trial.SETTING: EDs of two urban academic hospitals.PARTICIPANTS: Six hundred fifty community‐dwelling adults aged 65 and older presenting to the ED and discharged home. Patients were categorized a priori as “high risk” if they had cognitive impairment or two or more risk factors on the TRST.MEASUREMENTS: Functional status: summed activity of daily living (ADL) and instrumental activity of daily living (IADL) scores at baseline, 30 days, and 120 days. Self‐perceived physical health: standardized physical health component of the Medical Outcomes Study 36‐Item Short‐Form Health Survey (SF‐36). Functional decline: loss of one or more ADLs and one or more IADLs from ED baseline at 30 and 120 days. Decline in self‐perceived physical health: follow‐up SF‐36 standardized physical health component scores four or more points lower than baseline.RESULTS: TRST scores correlated with baseline ADL impairments, IADL impairments, and self‐perceived physical health at all endpoints (P<.001). A TRST score of two or more was moderately predictive of decline in ADLs or IADLs (30‐day ADL area under the receiver operating characteristic curve (AUC)=0.64; 95% confidence interval (CI)=0.56–0.72; 120‐day ADL AUC=0.66; 95% CI=0.58–0.74) but not perceived physical health.CONCLUSION: The TRST identifies baseline functional impairment in older ED patients and is moderately predictive of subsequent functional decline after an initial ED visit. The TRST provides a valid proxy measure for assessing functional status in the ED and may be useful in identifying high‐risk patients who would benefit from referrals for further evaluation or surveillance upon ED discharge.
Roles of P-Glycoprotein, Bcrp, and Mrp2 in Biliary Excretion of Spiramycin in Mice
Authors: Tian Xianbin , Li Jun , Zamek-Gliszczynski Maciej J. , Bridges Arlene S. , Zhang Peijin , Patel Nita J. , Raub Thomas J. , Pollack Gary M. , Brouwer Kim L. R. 
Published: June 2007

ABSTRACT

The multidrug resistance proteins P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and multidrug resistance-associated protein 2 (Mrp2) are the three major canalicular transport proteins responsible for the biliary excretion of most drugs and metabolites. Previous in vitro studies demonstrated that P-gp transported macrolide antibiotics, including spiramycin, which is eliminated primarily by biliary excretion. Bcrp was proposed to be the primary pathway for spiramycin secretion into breast milk. In the present study, the contributions of P-gp, Bcrp, and Mrp2 to the biliary excretion of spiramycin were examined in single-pass perfused livers of male C57BL/6 wild-type, Bcrp-knockout, and Mrp2-knockout mice in the presence or absence of GF120918 (GW918), a P-gp and Bcrp inhibitor. Spiramycin was infused to achieve steady-state conditions, followed by a washout period, and parameters governing spiramycin hepatobiliary disposition were recovered by using pharmacokinetic modeling. In the absence of GW918, the rate constant governing spiramycin biliary excretion was decreased in Mrp2
−
knockout mice (0.0013 ± 0.0009 min
−1
) relative to wild-type mice (0.0124 ± 0.0096 min
−1
). These data are consistent with the ∼8-fold decrease in the recovery of spiramycin in the bile of Mrp2-knockout mice and suggest that Mrp2 is the major canalicular transport protein responsible for spiramycin biliary excretion. Interestingly, biliary recovery of spiramycin in Bcrp-knockout mice was increased in both the absence and presence of GW918 compared to wild-type mice. GW918 significantly decreased the rate constant for spiramycin biliary excretion and the rate constant for basolateral efflux of spiramycin. In conclusion, the biliary excretion of spiramycin in mice is mediated primarily by Mrp2 with a modest P-gp component.
In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 2 with Decreased Susceptibility to Lopinavir
Authors: Masse Sherie , Lu Xiaozhi , Dekhtyar Tatyana , Lu Liangjun , Koev Gennadiy , Gao Feng , Mo Hongmei , Kempf Dale , Bernstein Barry , Hanna George J. , Molla Akhteruzzaman 
Published: June 2007

ABSTRACTLopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2MSand HIV-2CBL-23) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2CDC310319. Passage of HIV-2MSwith increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2RODmolecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
Tetracyclines as an Oral Treatment Option for Patients with Community Onset Skin and Soft Tissue Infections Caused by Methicillin-ResistantStaphylococcus aureus
Authors: Ruhe Jörg J. , Menon Anupama 
Published: June 2007

ABSTRACTFew data exist on the clinical utility of the expanded-spectrum tetracyclines doxycycline and minocycline for the treatment of community-associated methicillin-resistantStaphylococcus aureus(MRSA) skin and soft tissue infections (SSTI). We performed a retrospective cohort study of 276 patients who presented with 282 episodes of MRSA SSTI to the emergency room or outpatient clinic at two tertiary medical centers between October 2002 and February 2007. The median percentage of patients infected with MRSA strains that were susceptible to tetracycline was 95%. Time zero was defined as the time of the first incision and drainage procedure or, if none was performed, the time of the first positive wound culture. The median patient age was 48 years. Abscesses constituted the majority of clinical presentations (75%), followed by furuncles or carbuncles (13%) and cellulitis originating from a purulent focus of infection (12%). A total of 225 patients (80%) underwent incision and drainage. Doxycycline or minocycline was administered in 90 episodes (32%); the other 192 SSTI were treated with β-lactams. Treatment failure, defined as the need for a second incision and drainage procedure and/or admission to the hospital within at least 2 days after time zero, was diagnosed in 28 episodes (10%) at a median of 3 days after time zero. On logistic regression analysis, receipt of a β-lactam agent was the only clinical characteristic associated with treatment failure (adjusted odds ratio, 3.94; 95% confidence interval, 1.28 to 12.15;P= 0.02). The expanded-spectrum tetracyclines appear to be a reasonable oral treatment option for patients with community onset MRSA SSTI in areas where MRSA strains are susceptible to the tetracyclines.
Differential Fungicidal Activities of Amphotericin B and Voriconazole against
Aspergillus
Species Determined by Microbroth Methodology
Authors: Meletiadis Joseph , Antachopoulos Charalampos , Stergiopoulou Theodouli , Pournaras Spyros , Roilides Emmanuel , Walsh Thomas J. 
Published: June 2007

ABSTRACT

Antifungal agents may differ in their fungicidal activities against
Aspergillus
spp. In order to compare the fungicidal activities of voriconazole and amphotericin B against 40 isolates of
Aspergillus fumigatus
,
A. flavus
, and
A. terreus
, we developed a new microbroth colorimetric method for assessing fungicidal activities and determining minimal fungicidal concentrations (MFCs). This methodology follows the antifungal susceptibility testing reference method M-38A for MIC determination. After drug removal and addition of fresh medium, growth of viable conidia adhering to the bottoms of the microtitration wells was assessed by a colorimetric assay of metabolic activity after 24 h of incubation. The new method was faster (six times), reproducible (92 to 97%), and in agreement with culture-based MFCs (91 to 100%). Differential fungicidal activities of voriconazole and amphotericin B were found among the three
Aspergillus
species, with
A. fumigatus
and
A. flavus
having the lowest (1 and 2 mg/liter, respectively) and
A. terreus
the highest (>16 mg/liter) median amphotericin B MFCs;
A. flavus
had a lower median voriconazole MFC (4 mg/liter) than the other species (>8 mg/liter;
P
< 0.05). Amphotericin B was fungicidal (MFC/MIC ≤ 4) against all
A. fumigatus
and
A. flavus
isolates but no
A. terreus
isolates, whereas voriconazole was fungicidal against 82% of
A. flavus
isolates and fungistatic (MFC/MIC > 4) against 94% of
A. fumigatus
and 84% of
A. terreus
isolates. The new methodology revealed a concentration-dependent sigmoid pattern of fungicidal effects, indicating that fungicidal activity is not an all-or-nothing phenomenon and that some degree of fungicidal action can be found even for agents considered fungistatic based on the MFC/MIC ratio.
Safety and Pharmacokinetics of Bevirimat (PA-457), a Novel Inhibitor of Human Immunodeficiency Virus Maturation, in Healthy Volunteers
Authors: Martin David E. , Blum Robert , Wilton John , Doto Judy , Galbraith Hal , Burgess Gina L. , Smith Philip C. , Ballow Charles 
Published: June 2007

ABSTRACT

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (
n
= 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (
n
= 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.
Colistin Methanesulfonate against Multidrug-Resistant
Acinetobacter baumannii
in an In Vitro Pharmacodynamic Model
Authors: Kroeger Lisa A. , Hovde Laurie B. , Mitropoulos Isaac F. , Schafer Jeremy , Rotschafer John C. 
Published: June 2007

ABSTRACT

Using an in vitro pharmacodynamic model, a multidrug-resistant strain of
Acinetobacter baumannii
was exposed to colistin methanesulfonate alone and in combination with ceftazidime. Pre- and postexposure colistin sulfate MICs were determined. A single daily dose of colistin methanesulfonate combined with continuous-infusion ceftazidime prevented regrowth and postexposure MIC increases.
In Vivo Efficacy of Moxifloxacin Compared with Cloxacillin and Vancomycin in a
Staphylococcus aureus
Rabbit Arthritis Experimental Model
Authors: Grossi Olivier , Caillon Jocelyne , Arvieux Cedric , Jacqueline Cedric , Bugnon Denis , Potel Gilles , Hamel Antoine 
Published: June 2007

ABSTRACT

We investigated the efficacies of moxifloxacin, cloxacillin, and vancomycin in a rabbit model of
Staphylococcus aureus
arthritis. No significant difference between therapeutic regimens was observed after a 7-day treatment. Oral moxifloxacin could be a suitable alternative to standard parenteral therapy for
S. aureus
arthritis.
Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-Exposure Relationships Using Monte Carlo Simulation
Authors: Vinks Alexander A. , van Rossem Ronald N. , Mathôt Ron A. A. , Heijerman Harry G. M. , Mouton Johan W. 
Published: June 2007

ABSTRACT

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including
Pseudomonas aeruginosa
. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (
f
T>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 ± 17.1 versus 76.2 ± 7.4 ml/min in healthy subjects;
P
< 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 ± 0.17 h [mean ± the standard deviation]) and volume of distribution (0.20 ± 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a
f
T>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of ≤4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.
Concentration-Effect Relationship of Ceftazidime Explains Why the Time above the MIC Is 40 Percent for a Static Effect In Vivo
Authors: Mouton Johan W. , Punt Nieko , Vinks Alexander A. 
Published: June 2007

ABSTRACT
Growth-kill dynamics were characterized in vitro, and the parameter estimates were used to simulate bacterial growth and kill in vivo using both mouse and human pharmacokinetics. The parameter estimates obtained in vitro predicted a time above the MIC of between 35 and 38% for a static effect in mice after 24 h of treatment.
Molecular Characterization of
Staphylococcus aureus
Isolates from a 2005 Clinical Trial of Uncomplicated Skin and Skin Structure Infections
Authors: Jones Ronald N. , Nilius Angela M. , Akinlade Bolanle K. , Deshpande Lalitagauri M. , Notario Gerard F. 
Published: June 2007

ABSTRACT

A clinical trial of uncomplicated skin and skin structure infections (39 locations in 19 states) observed that community-associated or community-onset methicillin-resistant
Staphylococcus aureus
(CO-MRSA) represented 23% of all pathogens at baseline culture and 53% of 190
S. aureus
isolates. CO-MRSA strains typically were Panton-Valentine leukocidin (PVL) positive (95%), contained staphylococcal cassette chromosome
mec
type IVa (99%), were USA300 or USA400 clones (92%), and exhibited minimal coresistances (macrolides and/or fluoroquinolones). Clinical results remained identical (89% cures) regardless of the antimicrobial used or CO-MRSA molecular patterns, PVL production, or antimicrobial susceptibility profiles.
Identification and Characterization of Small Molecules That Inhibit Intracellular Toxin Transport
Authors: Saenz Jose B. , Doggett Teresa A. , Haslam David B. 
Published: June 2007

ABSTRACT

Shiga toxin (Stx), cholera toxin (Ctx), and the plant toxin ricin are among several toxins that reach their intracellular destinations via a complex route. Following endocytosis, these toxins travel in a retrograde direction through the endosomal system to the
trans
-Golgi network, Golgi apparatus, and endoplasmic reticulum (ER). There the toxins are transported across the ER membrane to the cytosol, where they carry out their toxic effects. Transport via the ER from the cell surface to the cytosol is apparently unique to pathogenic toxins, raising the possibility that various stages in the transport pathway can be therapeutically targeted. We have applied a luciferase-based high-throughput screen to a chemical library of small-molecule compounds in order to identify inhibitors of Stx. We report two novel compounds that protect against Stx and ricin inhibition of protein synthesis, and we demonstrate that these compounds reversibly inhibit bacterial transport at various stages in the endocytic pathway. One compound (compound 75) inhibited transport at an early stage of Stx and Ctx transport and also provided protection against diphtheria toxin, which enters the cytosol from early endosomes. In contrast, compound 134 inhibited transport from recycling endosomes through the Golgi apparatus and protected only against toxins that access the ER. Small-molecule compounds such as these will provide insight into the mechanism of toxin transport and lead to the identification of compounds with therapeutic potential against toxins routed through the ER.
Transcriptional Regulation of the Heme Binding Protein Gene Family of
Bartonella quintana
Is Accomplished by a Novel Promoter Element and Iron Response Regulator
Authors: Battisti James M. , Smitherman Laura S. , Sappington Kate N. , Parrow Nermi L. , Raghavan Rahul , Minnick Michael F. 
Published: June 2007

ABSTRACT

We previously identified a five-member family of hemin-binding proteins (Hbp's) of
Bartonella quintana
that bind hemin on the outer surface but share no homology with known bacterial heme receptors. Subsequently, we demonstrated that expression of the
hbp
family is significantly influenced by oxygen, heme, and temperature conditions encountered by the pathogen in the human host and the body louse vector; e.g., we observed a dramatic (>100-fold) increase in
hbpC
transcript levels in response to the “louse-like” temperature of 30°C. The goal of the present study was to identify a transcription factor(s) involved in the coordinated and differential regulation of the
hbp
family. First, we used quantitative real-time PCR (qRT-PCR) to show that the same environmental conditions generate parallels in the transcript profiles of four candidate transcriptional regulators (Irr, Fur, RirA, and BatR) described in the order
Rhizobiales
, with the greatest overall change in the transcription of
irr
(a >5-fold decrease) at a “louse-like” temperature, suggesting that Irr may function as an
hbpC
repressor. Second, a
B. quintana
strain hyperexpressing Irr was constructed; it exhibits a “bloodstream-like”
hbp
transcript profile in the absence of an environmental stimulus (i.e.,
hbpC
is repressed and
hbpA
,
hbpD
, and
hbpE
mRNAs are relatively abundant). Furthermore, when this strain is grown at a “louse-like” temperature, an inversion of the transcript profile occurs, where derepression of
hbpC
and repression of
hbpA
,
hbpD
, and
hbpE
are readily evident, strongly suggesting that Irr and temperature influence
hbp
family expression. Third, electrophoretic mobility shift analyses show that recombinant Irr binds specifically to the
hbpC
promoter region at a sequence that is highly conserved in
Bartonella hbp
genes, which we designated the
hbp
family box, or “H-box.” Fourth, we used the H-box to search the
B. quintana
genome and discovered a number of intriguing open reading frames, e.g., five members of a six-member family of cohemolysin autotransporters. Finally, qRT-PCR data regarding the effects of Fur and RirA overexpression on the
hbp
family are provided; they show that Fur's effect on the
hbp
family is relatively minor but RirA generates a “bloodstream-like”
hbp
transcript profile in the absence of an environmental stimulus, as observed for the Irr-hyperexpressing strain.
SalY of theStreptococcus pyogenesLantibiotic Locus Is Required for Full Virulence and Intracellular Survival in Macrophages
Authors: Phelps Hilary A. , Neely Melody N. 
Published: June 2007

ABSTRACTStreptococcus pyogenesutilizes numerous mechanisms for evading the host immune response but has only recently been found to survive in the intracellular environment. In this study, we demonstrate the requirement of a putative ABC transporter permease for intracellular survival in macrophages. The highly attenuatedS. pyogenesmutant, SalY, was identified from a transposon mutagenesis screen, with over 200-fold attenuation in virulence in a zebrafish invasive-disease model. Sequencing of the region surrounding the insertion identified a locus that is highly conserved in otherS. pyogenesgenomes and is homologous to an operon involved in lantibiotic production. In vitro analysis demonstrated that the SalY mutant is deficient in intracellular survival in murine macrophages, a phenotype also observed in zebrafish macrophages in vivo. Macrophage crude cell lysates added to bacterial cultures resulted in the death of the SalY mutant but only growth inhibition of the wild-type strain. Specific depletion of zebrafish macrophages in vivo restored the ability of the SalY mutant to cause disease to wild-type levels. The SalY-infected, macrophage-depleted zebrafish exhibit large lesions and invasive dissemination at a rate and level similar to those of the wild type. In contrast, an M protein mutant with a degree of attenuation similar to that of the SalY mutant did not regain full virulence by in vivo depletion of macrophages. The putative SalY ABC transporter may be an example of the ability ofS. pyogenesto adapt and evolve new survival strategies that allow dissemination and growth in previously uninhabitable sites.