bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Single-Dose Daptomycin in Patients with Suspected or Confirmed Neurological Infections
Authors: Kullar Ravina , Chin Judy N. , Edwards David J. , Parker Dennis , Coplin William M. , Rybak Michael J. 
Published: April 2011

ABSTRACT

There are currently few or no published data on the amount of cerebrospinal fluid (CSF) penetration of daptomycin in patients with suspected or documented neurosurgical infections. We conducted a prospective study, assessing the pharmacokinetics and CSF penetration of a single intravenous daptomycin dose administered at 10 mg/kg, based on total body weight (TBW), in six neurosurgical patients with indwelling external CSF shunts with suspected or documented meningitis or ventriculitis. Each patient had four blood and CSF samples drawn simultaneously at specific times after the end of infusion: 30 min, 6 h, 12 h, and 24 h. Pharmacokinetic parameters of daptomycin in serum were calculated using standard noncompartmental methods, and daptomycin was assayed using high-performance liquid chromatography (for serum) or liquid chromatography with mass spectrometry (for CSF). The mean (± standard deviation [SD]) maximum measured daptomycin concentrations were 93.7 ± 17.3 mg/liter in serum at 0.5 h postinfusion and 0.461 ± 0.51 mg/liter in CSF at 6 h postinfusion. The mean (± SD) daptomycin minimum concentrations were 13.8 ± 4.8 mg/liter in serum at 24 h postinfusion and 0.126 ± 0.12 mg/liter in CSF at 0.5 h postinfusion. The mean daptomycin penetration, determined by the area under the concentration-time curve in CSF (AUC
CSF
)/(AUC
serum
ratio), was 0.8%. Corrected for protein binding, the overall CSF penetration was 11.5%. Additional pharmacokinetic studies evaluating multiple and/or higher dosages of daptomycin are necessary in human subjects to better characterize the CSF penetration of daptomycin in neurosurgical patients.
Caspofungin Dose Escalation for Invasive Candidiasis Due to Resistant Candida albicans
Authors: Wiederhold Nathan P. , Najvar Laura K. , Bocanegra Rosie A. , Kirkpatrick William R. , Patterson Thomas F. 
Published: April 2011

ABSTRACT

Previous
in vivo
studies have reported caspofungin dose escalation to be effective against
Candida glabrata
with reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent species
Candida albicans
, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of three
C. albicans
isolates, including one susceptible and two resistant isolates with different
FKS1
hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (1→3)-β-
d
-glucan were measured. Significant differences in virulence were observed among the three
C. albicans
isolates, which translated into differences in responses to caspofungin. The most virulent of the resistant isolates studied (isolate 43001; Fks1p F641S) did not respond to caspofungin doses of up to 10 mg/kg of body weight, as there were no differences in survival (survival range, 0 to 12% with treatment), tissue burden, or (1→3)-β-
d
-glucan concentration compared to those for untreated controls. Higher doses of caspofungin did improve survival against the second resistant isolate (53264; Fks1p S645P) that demonstrated reduced virulence (5 and 10 mg/kg; 80% survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (1→3)-β-
d
-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistant
C. albicans
isolates, and this may be associated with the virulence of the strain.
Effect of Moxifloxacin Combined with Cefotaxime Compared to Cefotaxime-Gentamicin Combination on Prevention of White Matter Damage Associated with Escherichia coli Sepsis in Neonatal Rats
Authors: Le Saché Nolwenn , Baud Olivier , Pansiot Julien , Pham Hoa , Biran Valérie , Brunel-Meunier Nadège , Bidet Philippe , Kitzis Marie-Dominique , Gressens Pierre , Bingen Edouard , Charriaut-Marlangue Christiane , Bonacorsi Stéphane 
Published: April 2011

ABSTRACT

Relative to the cefotaxime-gentamicin combination, the moxifloxacin-cefotaxime combination significantly reduced microglial activation and immature oligodendrocyte cell death and delayed myelination in the developing white matter of neonatal rats with experimental
Escherichia coli
sepsis. These neuroprotective effects were not due to differences in
in vivo
bactericidal activities or in the systemic inflammatory responses and could be related to the intrinsic immunomodulatory properties of moxifloxacin. Molecular mechanisms underlying the neuroprotective effect of moxifloxacin remain to be elucidated.
Conservation of Ebp-Type Pilus Genes among Enterococci and Demonstration of Their Role in Adherence of Enterococcus faecalis to Human Platelets
Authors: Nallapareddy Sreedhar R. , Sillanpää Jouko , Mitchell Jennifer , Singh Kavindra V. , Chowdhury Shahreen A. , Weinstock George M. , Sullam Paul M. , Murray Barbara E. 
Published: April 2011

ABSTRACT

Ebp are
e
ndocarditis- and
b
iofilm-associated
p
ili of
Enterococcus faecalis
that are also important in experimental urinary tract infections (UTIs). Our analyses, using available genomes, found that the
ebp
locus is unique to enterococci. In
E. faecalis
, the
ebp
locus is very highly conserved and only 1/473
E. faecalis
isolates tested lacked
ebpABC
, while only 1.2% had the
bee
pilus locus. No other pilus-encoding operon was identified in 55 available genomes, indicating that the vast majority of
E. faecalis
strains (unlike
Enterococcus faecium
and streptococci) have a single pilus locus. Surface expression studies showed that Ebp pili were produced
in vitro
by 91/91 brain heart infusion (BHI) plus serum-grown
E. faecalis
isolates and that strain OG1RF expressed pili at even higher levels in rat endocarditis vegetations. However, Ebp expression was restricted to 30 to 72% of
E. faecalis
cells, consistent with a bistability mode of expression. We also evaluated
E. faecalis
interactions with human platelets and found that growth of
E. faecalis
in BHI plus serum significantly enhanced adherence to human platelets and that sortase deletion mutants (the Δ
srtA
, Δ
bps
, and Δ
bps
Δ
srtA
mutants) were markedly defective. Further studies identified that Ebp pili, but not the microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) Ace and Fss2, mediate adherence of
E. faecalis
to platelets. Taken together, our data show that the immunogenic (in human endocarditis patients) and commonly expressed Ebp pili, which are known to be important for experimental endocarditis, are highly conserved and mediate adherence to platelets, suggesting that Ebp pili may be a reasonable immunotherapeutic target for prevention or possibly treatment of endocarditis caused by this species.
Sialidase and Sialoglycoproteases Can Modulate Virulence in Porphyromonas gingivalis
Authors: Aruni Wilson , Vanterpool Elaine , Osbourne Devon , Roy Francis , Muthiah Arun , Dou Yuetan , Fletcher Hansel M. 
Published: April 2011

ABSTRACT

The
Porphyromonas gingivalis
recombinant VimA can interact with the gingipains and several other proteins, including a sialidase. Sialylation can be involved in protein maturation; however, its role in virulence regulation in
P. gingivalis
is unknown. The three sialidase-related proteins in
P. gingivalis
showed the characteristic sialidase Asp signature motif (SXDXGXTW) and other unique domains. To evaluate the roles of the associated genes, randomly chosen
P. gingivalis
isogenic mutants created by allelic exchange and designated FLL401 (
PG0778
::
ermF
), FLL402 (
PG1724
::
ermF
), and FLL403 (
PG0352
::
ermF-ermAM
) were characterized. Similar to the wild-type strain, FLL402 and FLL403 displayed a black-pigmented phenotype in contrast to FLL401, which was not black pigmented. Sialidase activity in
P. gingivalis
FLL401 was reduced by approximately 70% in comparison to those in FLL402 and FLL403, which were reduced by approximately 42% and 5%, respectively. Although there were no changes in the expression of the gingipain genes, their activities were reduced by 60 to 90% in all the isogenic mutants compared to that for the wild type. Immunoreactive bands representing the catalytic domains for RgpA, RgpB, and Kgp were present in FLL402 and FLL403 but were missing in FLL401. While adhesion was decreased, the capacity for invasion of epithelial cells by the isogenic mutants was increased by 11 to 16% over that of the wild-type strain. Isogenic mutants defective in
PG0778
and
PG0352
were more sensitive to hydrogen peroxide than the wild type. Taken together, these results suggest that the
P. gingivalis
sialidase activity may be involved in regulating gingipain activity and other virulence factors and may be important in the pathogenesis of this organism.
Essential Role of Factor B of the Alternative Complement Pathway in Complement Activation and Opsonophagocytosis during Acute Pneumococcal Otitis Media in Mice
Authors: Li Qian , Li Yong Xing , Stahl Gregory L. , Thurman Joshua M. , He Yujuan , Tong Hua Hua 
Published: April 2011

ABSTRACTWe recently reported that the complement system plays a pivotal role in innate immune defense againstStreptococcus pneumoniaeduring acute otitis media (OM) in mice. The current study was designed to determine which of the complement pathways are activated during acute pneumococcal OM and whether components of complement are expressed in the middle ear epithelium. Gene expression was determined by quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. We found thatS. pneumoniaeinduced increased gene expression of factor B of the alternative complement pathway and C3 in mouse middle ear epithelium. Activation of factor B and C3 in the middle ear lavage fluids was significantly greater than in simultaneously obtained serum samples as determined by Western blotting. Using mice deficient in complement C1qa, factor B, and factor B/C2, we found that complement C3 activation and opsonophagocytosis ofS. pneumoniaewere greatly attenuated in factor B- and factor B/C2-deficient mice. These findings support the concept that local complement activation is an important host innate immune response and that activation of the alternative complement pathway represents one of the innate immune defense mechanisms against pneumococcal infection during the early stage of acute OM.
Whose butt is it? tobacco industry research about smokers and cigarette butt waste: Table 1
Authors: Smith Elizabeth A , Novotny Thomas E 
Published: April 2011

BackgroundCigarette filters are made of non-biodegradable cellulose acetate. As much as 766 571 metric tons of butts wind up as litter worldwide per year. Numerous proposals have been made to prevent or mitigate cigarette butt pollution, but none has been effective; cigarette butts are consistently found to be the single most collected item in beach clean-ups and litter surveys.MethodsWe searched the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu) and http://tobaccodocuments.org using a snowball strategy beginning with keywords (eg, ‘filter’, ‘biodegradable’, ‘butts’). Data from approximately 680 documents, dated 1959–2006, were analysed using an interpretive approach.ResultsThe tobacco industry has feared being held responsible for cigarette litter for more than 20 years. Their efforts to avoid this responsibility included developing biodegradable filters, creating anti-litter campaigns, and distributing portable and permanent ashtrays. They concluded that biodegradable filters would probably encourage littering and would not be marketable, and that smokers were defensive about discarding their tobacco butts and not amenable to anti-litter efforts.ConclusionsTobacco control and environmental advocates should develop partnerships to compel the industry to take financial and practical responsibility for cigarette butt waste.
Marketing of menthol cigarettes and consumer perceptions: a review of tobacco industry documents
Authors: Anderson Stacey J 
Published: April 2011

ObjectiveTo examine tobacco industry marketing of menthol cigarettes and to determine what the tobacco industry knew about consumer perceptions of menthol.MethodsA snowball sampling design was used to systematically search the Legacy Tobacco Documents Library (LTDL) (http://legacy.library.ucsf.edu) between 28 February and 27 April 2010. Of the approximately 11 million documents available in the LTDL, the iterative searches returned tens of thousands of results from the major US tobacco companies and affiliated organisations. A collection of 953 documents from the 1930s to the first decade of the 21st century relevant to 1 or more of the research questions were qualitatively analysed, as follows: (1) are/were menthol cigarettes marketed with health reassurance messages? (2) What other messages come from menthol cigarette advertising? (3) How do smokers view menthol cigarettes? (4) Were menthol cigarettes marketed to specific populations?ResultsMenthol cigarettes were marketed as, and are perceived by consumers to be, healthier than non-menthol cigarettes. Menthol cigarettes are also marketed to specific social and demographic groups, including African–Americans, young people and women, and are perceived by consumers to signal social group belonging.ConclusionsThe tobacco industry knew consumers perceived menthol as healthier than non-menthol cigarettes, and this was the intent behind marketing. Marketing emphasising menthol attracts consumers who may not otherwise progress to regular smoking, including young, inexperienced users and those who find ‘regular’ cigarettes undesirable. Such marketing may also appeal to health-concerned smokers who might otherwise quit.
Menthol cigarettes and smoking cessation behaviour: a review of tobacco industry documents
Authors: Anderson Stacey J 
Published: April 2011

ObjectiveTo determine what the tobacco industry knew about menthol's relation to smoking cessation behaviour.MethodsA snowball sampling design was used to systematically search the Legacy Tobacco Documents Library (LTDL) (http://legacy.library.ucsf.edu) between 15 May to 1 August 2010. Of the approximately 11 million documents available in the LTDL, the iterative searches returned tens of thousands of results. A final collection of 509 documents relevant to 1 or more of the research questions were qualitatively analysed, as follows: (1) perceived sensory and taste rewards of menthol and potential relation to quitting; and (2) motivation to quit among menthol users.ResultsMenthol's cooling and anaesthetic effects mask the short-term negative physiological effects of smoking such as throat pain, burning and cough. This provides superficial physical relief as well as psychological assurance against concerns about the health dangers of smoking that would otherwise motivate smokers to quit. Menthol smokers, particularly women, perceive the minty aroma of menthol cigarettes to be more socially acceptable than non-menthol cigarettes.DiscussionConsumers believe menthol's sensory effects equate to health protections and that menthol cigarettes are more socially acceptable than non-menthol cigarettes. Menthol in cigarettes may encourage experimenters who find non-mentholated cigarettes too harsh, including young or inexperienced users, to progress to regular smoking rather than quitting, and may lessen the motivation to quit among established menthol smokers. The perception of menthol cigarettes as more socially acceptable lessens the impact of smoking denormalisation on quitting motivation. Menthol makes cigarettes easier and more palatable to smoke and less desirable to quit among established smokers. Fewer smokers quitting contributes to the incidence of tobacco-related diseases.
Health Problem Solving by Older Persons Using a Complex Government Web Site
Authors: Sharit Joseph , Hernandez Mario A. , Nair Sankaran N. , Kuhn Thomas , Czaja Sara J. 
Published: April 2011

A large number of health-related Web sites currently exist that offer consumers a wealth of information that can be used to enhance the quality of their lives. Much less attention has been given to Web sites that can support complex health-related problem solving, as opposed to more general information search activities, of user populations such as older adults. In this article, we expand on a prior usability study that examined the performance of 112 older adults who were asked to solve two problems using the U. S. government’s Medicare.gov Web site. The indications from that study were that older adults had difficulty carrying out these problem-solving tasks.
This article illustrates, in the context of a case study, the use of a structured methodology for obtaining insights into Web site design issues that could make it difficult for healthcare consumers such as older adults to solve health-related problems. Initially, a number of Web design guidelines that have been developed for older users are presented. The argument is made that such checklist-type guidelines, though essential, are difficult to apply to complex Web-based problem-solving activities. Following a review of research in the area of Web-based health information seeking and problem-solving by older adults, the description and implementation of a methodology for aiding designers in anticipating cognitive demands that older users might confront during their problem-solving activities is presented. Detailed analysis of task performance is then presented to demonstrate that very few of the study participants were able to successfully negotiate the solution to the problem. The use of the methodology for identifying a number user-Web site interaction issues and for proposing recommendations particularly relevant to older users, and ultimately for enhancing the accessibility of health Web sites, is highlighted. Finally, a detailed framework is presented that is intended for guiding designers in the application of this methodology.
Combining Histone Deacetylase Inhibitor Vorinostat with Aurora Kinase Inhibitors Enhances Lymphoma Cell Killing with Repression of c-Myc, hTERT, and microRNA Levels
Authors: Kretzner Leo , Scuto Anna , Dino Pamela M. , Kowolik Claudia M. , Wu Jun , Ventura Patrick , Jove Richard , Forman Stephen J. , Yen Yun , Kirschbaum Mark H. 
Published: April 2011

Abstract
MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G2–M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-XL and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorinostat or trichostatin A decreased MYC mRNA and protein as well as c-Myc-regulated microRNAs. MYC is a critical gene in these responses, as MYC knockdown combined with the expression of the c-Myc antagonist MXD1 raised cell sensitivity to the effects of either AKi. Thus, the HDACi vorinostat leads to both transcriptional and posttranscriptional changes to create a proapoptotic milieu, sensitizing cells to mitosis-specific agents such as AKis. Cancer Res; 71(11); 3912–20. ©2011 AACR.
A Requirement of STAT3 DNA Binding Precludes Th-1 Immunostimulatory Gene Expression by NF-κB in Tumors
Authors: Lee Heehyoung , Deng Jiehui , Xin Hong , Liu Yong , Pardoll Drew , Yu Hua 
Published: April 2011

Abstract
Both STAT3 and NF-κB are persistently activated in diverse cancers and promote tumor cell proliferation, survival, angiogenesis, and metastasis through transcriptional activation of multiple common genes. Paradoxically, STAT3 also suppresses many NF-κB–inducible genes involved in innate and adaptive antitumor immunity in spite of elevated levels of NF-κB in tumors. In this study, we show that expression of many NF-κB downstream target genes in tumors depends on STAT3 DNA binding. When STAT3 is elevated in tumor cells and tumor-infiltrating immune cells, persistently activated NF-κB interacts with STAT3 and preferentially binds to genes with STAT3-binding site(s) in promoters. A large number of NF-κB downstream genes associated with oncogenesis and chronic inflammation contain STAT3 DNA-binding site(s). However, in contrast, many genes frequently associated with antitumor immunity lack STAT3 DNA-binding site(s) and can only be activated by NF-κB when STAT3 is inhibited in tumors. The introduction of STAT3 DNA-binding sequences by site-specific mutagenesis in an immunostimulatory gene promoter allows its transcriptional activation by NF-κB in tumor cells. Furthermore, STAT3 facilitates NF-κB binding to genes that are important for tumor growth while inhibiting its binding to Th-1 immunostimulatory genes in growing tumors, including in tumor-infiltrating immune cells. The results of this study provide insight into how some of the oncogenic/inflammatory and Th-1 immunostimulatory genes are differentially regulated in cancer. Cancer Res; 71(11); 3772–80. ©2011 AACR.
Relationship Between Early Diastolic Dysfunction and Abnormal Microvolt T-Wave Alternans in Patients With Type 2 Diabetes
Authors: Bonapace Stefano , Targher Giovanni , Molon Giulio , Rossi Andrea , Costa Alessandro , Zenari Luciano , Bertolini Lorenzo , Cian Debora , Lanzoni Laura , Barbieri Enrico 
Published: April 2011

Background—
Abnormal microvolt T-wave alternans (MTWA), a marker of ventricular arrhythmic risk, is a highly prevalent condition in patients with type 2 diabetes mellitus (T2DM) and is correlated with glycemic control. However, there is uncertainty as to whether central or peripheral hemodynamic factors are associated with abnormal MTWA in T2DM individuals.

Methods and Results—

We studied 50 consecutive, well-controlled T2DM outpatients without a history of ischemic heart disease and with normal systolic function. All patients underwent a complete echocardiographic Doppler evaluation with spectral tissue Doppler analysis. MTWA analysis was performed noninvasively during submaximal exercise. Effective arterial elastance, arterial compliance, and heart rate variability were also measured. Compared with patients with MTWA negativity (n=38), those with MTWA abnormality (n=12, 24%) had significantly lower e′ (7.6±1.3 versus 9.1±1.7 cm/s;
P
<0.01), a′ (10.2±1.6 versus 12.7±1.9 cm/s;
P
<0.001) and s′ velocities (8.7±1.1 versus 10.2±1.5 cm/s;
P
=0.001) and higher indexed left ventricular mass (121.3±16.4 versus 107.5±16.5 g/m
2
;
P
=0.016), indexed left atrial volume (33.5±11.9 versus 23.6±5.6 mL/m
2
;
P
<0.001), and E/e′ ratio (8.8±1.4 versus 6.5±1.3;
P
<0.001). Multivariable logistic regression analysis revealed that higher E/e′ ratio was the only independent correlate of abnormal MTWA (adjusted odds ratio, 3.52; 95% confidence interval, 1.19 to 10.6;
P
=0.02) after controlling for glycemic control and other potential confounders.

Conclusions—
In this pilot study, we found that early diastolic dysfunction, as measured by tissue Doppler imaging, is independently associated with MTWA abnormality in T2DM individuals with normal systolic function. Further larger studies are needed to examine the reproducibility of these results.