bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overton's Rule Helps To Estimate the Penetration of Anti-Infectives into Patients' Cerebrospinal Fluid
Authors: Djukic Marija , Munz Martin , Sörgel Fritz , Holzgrabe Ulrike , Eiffert Helmut , Nau Roland 
Published: November 2011

ABSTRACT

In 1900, Ernst Overton found that the entry of anilin dyes through the cell membranes of living cells depended on the lipophilicity of the dyes. The brain is surrounded by barriers consisting of lipid layers that possess several inward and outward active transport systems. In the absence of meningeal inflammation, the cerebrospinal fluid (CSF) penetration of anti-infectives in humans estimated by the ratio of the area under the concentration-time curve (AUC) in CSF (AUC
CSF
) to that in serum (AUC
CSF
/AUC
S
) correlated positively with the lipid-water partition coefficient at pH 7.0 (log
D
) (Spearman's rank correlation coefficient

r
S

= 0.40;
P
= 0.01) and negatively with the molecular mass (MM) (

r
S

= −0.33;
P
= 0.04). The ratio of AUC
CSF
to the AUC of the fraction in serum that was not bound (AUC
CSF
/AUC
S,free
) strongly correlated with log
D
(

r
S

= 0.67;
P
< 0.0001). In the presence of meningeal inflammation, AUC
CSF
/AUC
S
also correlated positively with log
D
(

r
S

= 0.46;
P
= 0.002) and negatively with the MM (

r
S

= −0.37;
P
= 0.01). The correlation of AUC
CSF
/AUC
S,free
with log
D
(

r
S

= 0.66;
P
< 0.0001) was as strong as in the absence of meningeal inflammation. Despite these clear correlations, Overton's rule was able to explain only part of the differences in CSF penetration of the individual compounds. The site of CSF withdrawal (lumbar versus ventricular CSF), age of the patients, underlying diseases, active transport, and alterations in the pharmacokinetics by comedications also appeared to strongly influence the CSF penetration of the drugs studied.
Influence of
NAT2
Polymorphisms on Sulfamethoxazole Pharmacokinetics in Renal Transplant Recipients
Authors: Kagaya Hideaki , Miura Masatomo , Niioka Takenori , Saito Mitsuru , Numakura Kazuyuki , Habuchi Tomonori , Satoh Shigeru 
Published: November 2011

ABSTRACT

The sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis against
Pneumocystis
pneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact of
N
-acetyltransferase 2 (
NAT2
) and
CYP2C9
polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX-trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC
0-24
) for 15 recipients with the
NAT2
slow acetylator genotype (
NAT2*5/*6
, -*
6/*6
, -
*6/*7
, and -
*7/*7
) was significantly greater than that for 56 recipients with the
NAT2
rapid acetylator genotype (homozygous for
NAT2*4
) (766.4 ± 432.3 versus 537.2 ± 257.5 μg-h/ml, respectively;
P
= 0.0430), whereas there were no significant differences in the SMX AUC
0-24
between the
CYP2C9*1/*1
and -
*1/*3
groups. In a multiple regression analysis, the SMX AUC
0-24
was associated with
NAT2
slow acetylator polymorphisms (
P
= 0.0095) and with creatinine clearance (
P
= 0.0499). Hepatic dysfunction in
NAT2
slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected by
NAT2
polymorphisms and renal dysfunction. Although standard SMX administration to patients with
NAT2
slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects.
Occidiofungin's Chemical Stability and
In Vitro
Potency against Candida Species
Authors: Ellis Dayna , Gosai Jiten , Emrick Charles , Heintz Rachel , Romans Lanette , Gordon Donna , Lu Shi-En , Austin Frank , Smith Leif 
Published: November 2011

ABSTRACT

Occidiofungin is a cyclic glyco-lipopeptide produced by
Burkholderia contaminans
. MICs against
Candida
species were between 0.5 and 2.0 μg/ml. Occidiofungin retains its
in vitro
potency in the presence of 5% and 50% human serum with a minimal lethal concentration (MLC) of 2 and 4 μg/ml, respectively. Time-kill and postantifungal effect (PAFE) experiments of occidiofungin against
Candida albicans
were performed. The results demonstrate that occidiofungin is fungicidal. Occidiofungin was also found to be a very stable molecule. It is resistant to extreme temperatures and pH and maintains its activity following exposure to gastric proteases.
Possible Inhibitory Molecular Mechanism of Farnesol on the Development of Fluconazole Resistance in Candida albicans Biofilm
Authors: Yu Li-hua , Wei Xin , Ma Ming , Chen Xiao-jun , Xu Shuang-bo 
Published: November 2011

ABSTRACT

Candida albicans
biofilm infections are usually treated with azole antifungals such as fluconazole. However, the development of resistance to this drug in
C. albicans
biofilms is very common, especially in immunocompromised individuals. The upregulation of the sterol biosynthetic pathway gene
ERG
and the efflux pump genes
CDR
and
MDR
may contribute to this azole tolerance in
Candida
species. We hypothesize that farnesol, an endogenous quorum sensing molecule with possible antimicrobial properties which is also the precursor of ergosterols in
C. albicans
, may interfere with the development of fluconazole resistance in
C. albicans
biofilms. To test this hypothesis, MICs were compared and morphology changes were observed by confocal laser scanning microscopy (CLSM) for farnesol-treated and -untreated and fluconazole-resistant groups. The expression of possible target genes (
ERG11
,
ERG25
,
ERG6
,
ERG5
,
ERG3
,
ERG1
,
MDR1
,
CDR1
, and
CDR2
) in biofilms was analyzed by reverse transcription-PCR (RT-PCR) and quantitative PCR (qPCR) to investigate the molecular mechanisms of the inhibitory effects of farnesol. The results showed a decreased MIC of fluconazole and thinner biofilms for the farnesol-treated group, indicating that farnesol inhibited the development of fluconazole resistance. The sterol biosynthetic pathway may contribute to the inhibitory effects of farnesol, as the transcription levels of the
ERG11
,
ERG25
,
ERG6
,
ERG3
, and
ERG1
genes decreased in the farnesol-treated group.
In Vivo
Activity of Aryl Ozonides against Schistosoma Species
Authors: Keiser Jennifer , Ingram Katrin , Vargas Mireille , Chollet Jacques , Wang Xiaofang , Dong Yuxiang , Vennerstrom Jonathan L. 
Published: November 2011

ABSTRACT

We evaluated the
in vivo
antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult
Schistosoma mansoni
, with total and female worm burden reductions of 80 and 90% (
P
< 0.05), respectively. Furthermore, treatment of
S. haematobium
-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound.
In Vitro
Evaluation of the Activities of the Novel Anticytomegalovirus Compound AIC246 (Letermovir) against Herpesviruses and Other Human Pathogenic Viruses
Authors: Marschall Manfred , Stamminger Thomas , Urban Andreas , Wildum Steffen , Ruebsamen-Schaeff Helga , Zimmermann Holger , Lischka Peter 
Published: November 2011

ABSTRACT
AIC246 (letermovir) is a potent anticytomegalovirus drug in clinical development. Here, we report a consistent antiviral efficacy of AIC246 against human cytomegalovirus laboratory strains, clinical isolates, and virus variants resistant to approved drugs. Furthermore, we describe a remarkable selectivity of AIC246 for human cytomegaloviruses compared to that of other alpha-, beta-, or gammaherpesviruses or nonrelated pathogenic viruses, including adeno-, hepadna-, retro-, orthomyxo-, and flaviviruses. Our data confirm and support an excellent and selective anticytomegaloviral activity of AIC246.
Synergistic Interaction between Candida albicans and Commensal Oral Streptococci in a Novel
In Vitro
Mucosal Model
Authors: Diaz Patricia I. , Xie Zhihong , Sobue Takanori , Thompson Angela , Biyikoglu Basak , Ricker Austin , Ikonomou Laertis , Dongari-Bagtzoglou Anna 
Published: November 2011

ABSTRACT

Candida albicans
is a commensal colonizer of the gastrointestinal tract of humans, where it coexists with highly diverse bacterial communities. It is not clear whether this interaction limits or promotes the potential of
C. albicans
to become an opportunistic pathogen. Here we investigate the interaction between
C. albicans
and three species of streptococci from the viridans group, which are ubiquitous and abundant oral commensal bacteria. The ability of
C. albicans
to form biofilms with
Streptococcus oralis
,
Streptococcus sanguinis
, or
Streptococcus gordonii
was investigated using flow cell devices that allow abiotic biofilm formation under salivary flow. In addition, we designed a novel flow cell system that allows mucosal biofilm formation under conditions that mimic the environment in the oral and esophageal mucosae. It was observed that
C. albicans
and streptococci formed a synergistic partnership where
C. albicans
promoted the ability of streptococci to form biofilms on abiotic surfaces or on the surface of an oral mucosa analogue. The increased ability of streptococci to form biofilms in the presence of
C. albicans
could not be explained by a growth-stimulatory effect since the streptococci were unaffected in their growth in planktonic coculture with
C. albicans
. Conversely, the presence of streptococci increased the ability of
C. albicans
to invade organotypic models of the oral and esophageal mucosae under conditions of salivary flow. Moreover, characterization of mucosal invasion by the biofilm microorganisms suggested that the esophageal mucosa is more permissive to invasion than the oral mucosa. In summary,
C. albicans
and commensal oral streptococci display a synergistic interaction with implications for the pathogenic potential of
C. albicans
in the upper gastrointestinal tract.
Establishment of a Real-Time, Quantitative, and Reproducible Mouse Model of Staphylococcus Osteomyelitis Using Bioluminescence Imaging
Authors: Funao Haruki , Ishii Ken , Nagai Shigenori , Sasaki Aya , Hoshikawa Tomoyuki , Aizawa Mamoru , Okada Yasunori , Chiba Kazuhiro , Koyasu Shigeo , Toyama Yoshiaki , Matsumoto Morio 
Published: November 2011

ABSTRACTOsteomyelitis remains a serious problem in the orthopedic field. There are only a few animal models in which the quantity and distribution of bacteria can be reproducibly traced. Here, we established a real-time quantitative mouse model of osteomyelitis using bioluminescence imaging (BLI) without sacrificing the animals. A bioluminescent strain ofStaphylococcus aureuswas inoculated into the femurs of mice. The bacterial photon intensity (PI) was then sequentially measured by BLI. Serological and histological analyses of the mice were performed. The mean PI peaked at 3 days, and stable signals were maintained for over 3 months after inoculation. The serum levels of interleukin-6, interleukin-1β, and C-reactive protein were significantly higher in the infected mice than in the control mice on day 7. The serum monocyte chemotactic protein 1 level was also significantly higher in the infected group at 12 h than in the control group. A significantly higher proportion of granulocytes was detected in the peripheral blood of the infected group after day 7. Additionally, both acute and chronic histological manifestations were observed in the infected group. This model is useful for elucidating the pathophysiology of both acute and chronic osteomyelitis and to assess the effects of novel antibiotics or antibacterial implants.
Improved Left Ventricular Mass Quantification With Partial Voxel Interpolation
Authors: Codella Noel C.F. , Lee Hae Yeoun , Fieno David S. , Chen Debbie W. , Hurtado-Rua Sandra , Kochar Minisha , Finn John Paul , Judd Robert , Goyal Parag , Schenendorf Jesse , Cham Matthew D. , Devereux Richard B. , Prince Martin , Wang Yi , Weinsaft Jonathan W. 
Published: November 2011

Background—
Cardiac magnetic resonance (CMR) typically quantifies LV mass (LVM) by means of manual planimetry (MP), but this approach is time-consuming and does not account for partial voxel components— myocardium admixed with blood in a single voxel. Automated segmentation (AS) can account for partial voxels, but this has not been used for LVM quantification. This study used automated CMR segmentation to test the influence of partial voxels on quantification of LVM.

Methods and Results—

LVM was quantified by AS and MP in 126 consecutive patients and 10 laboratory animals undergoing CMR. AS yielded both partial voxel (AS
PV
) and full voxel (AS
FV
) measurements. Methods were independently compared with LVM quantified on echocardiography (echo) and an ex vivo standard of LVM at necropsy. AS quantified LVM in all patients, yielding a 12-fold decrease in processing time versus MP (0:21±0:04 versus 4:18±1:02 minutes;
P
<0.001). AS
FV
mass (136±35 g) was slightly lower than MP (139±35; Δ=3±9 g,
P
<0.001). Both methods yielded similar proportions of patients with LV remodeling (
P
=0.73) and hypertrophy (
P
=1.00). Regarding partial voxel segmentation, AS
PV
yielded higher LVM (159±38 g) than MP (Δ=20±10 g) and AS
FV
(Δ=23±6 g, both
P
<0.001), corresponding to relative increases of 14% and 17%. In multivariable analysis, magnitude of difference between AS
PV
and AS
FV
correlated with larger voxel size (partial
r
=0.37,
P
<0.001) even after controlling for LV chamber volume (
r
=0.28,
P
=0.002) and total LVM (
r
=0.19,
P
=0.03). Among patients, AS
PV
yielded better agreement with echo (Δ=20±25 g) than did AS
FV
(Δ=43±24 g) or MP (Δ=40±22 g, both
P
<0.001). Among laboratory animals, AS
PV
and ex vivo results were similar (Δ=1±3 g,
P
=0.3), whereas AS
FV
(6±3 g,
P
<0.001) and MP (4±5 g,
P
=0.02) yielded small but significant differences with LVM at necropsy.

Conclusions—
Automated segmentation of myocardial partial voxels yields a 14–17% increase in LVM versus full voxel segmentation, with increased differences correlated with lower spatial resolution. Partial voxel segmentation yields improved CMR agreement with echo and necropsy-verified LVM.
The Diagnostic Value of Physical Examination and Additional Testing in Primary Care Patients With Suspected Heart Failure
Authors: Kelder Johannes C. , Cramer Maarten J. , van Wijngaarden Jan , van Tooren Rob , Mosterd Arend , Moons Karel G.M. , Lammers Jan W. , Cowie Martin R. , Grobbee Diederick E. , Hoes Arno W. 
Published: November 2011

Background—
Early diagnosis of nonacute heart failure is crucial because prompt initiation of evidence-based treatment can prevent or slow down further progression. To diagnose new-onset heart failure in primary care is challenging.

Methods and Results—

This is a cross-sectional diagnostic accuracy study with external validation. Seven hundred twenty-one consecutive patients suspected of new-onset heart failure underwent standardized diagnostic work-up including chest x-ray, spirometry, ECG, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, and echocardiography in specially equipped outpatient diagnostic heart failure clinics. The presence of heart failure was determined by an outcome panel using the initial clinical data and 6-month follow-up data, blinded to biomarker data. Of the 721 patients, 207 (28.7%) had heart failure. The combination of 3 items from history (age, coronary artery disease, and loop diuretic use) plus 6 from physical examination (pulse rate and regularity, displaced apex beat, rales, heart murmur, and increased jugular vein pressure) showed independent diagnostic value (c-statistic 0.83). NT-proBNP was the most powerful supplementary diagnostic test, increasing the c-statistic to 0.86 and resulting in net reclassification improvement of 69% (
P
<0.0001). A simplified diagnostic rule was applied to 2 external validation datasets, resulting in c- statistics of 0.95 and 0.88, confirming the results.

Conclusions—
In this study, we estimated the quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients, which may help to improve clinical decision making. The largest additional quantitative diagnostic contribution to those elements was provided by measurement of NT-proBNP. For daily practice, a diagnostic rule was derived that may be useful to quantify the probability of heart failure in patients with new symptoms suggestive of heart failure.
Survival After Open Versus Endovascular Thoracic Aortic Aneurysm Repair in an Observational Study of the Medicare Population
Authors: Goodney Philip P. , Travis Lori , Lucas F. Lee , Fillinger Mark F. , Goodman David C. , Cronenwett Jack L. , Stone David H. 
Published: November 2011

Background—
The goal of this study was to describe short- and long-term survival of patients with descending thoracic aortic aneurysms (TAAs) after open and endovascular repair (TEVAR).

Methods and Results—

Using Medicare claims from 1998 to 2007, we analyzed patients who underwent repair of intact and ruptured TAA, identified from a combination of procedural and diagnostic
International Classification of Disease
, ninth revision, codes. Our main outcome measure was mortality, defined as perioperative mortality (death occurring before hospital discharge or within 30 days), and 5-year survival, from life-table analysis. We examined outcomes across repair type (open repair or TEVAR) in crude, adjusted (for age, sex, race, procedure year, and Charlson comorbidity score), and propensity-matched cohorts. Overall, we studied 12 573 Medicare patients who underwent open repair and 2732 patients who underwent TEVAR. Perioperative mortality was lower in patients undergoing TEVAR compared with open repair for both intact (6.1% versus 7.1%;
P
=0.07) and ruptured (28% versus 46%;
P
<0.0001) TAA. However, patients with intact TAA selected for TEVAR had significantly worse survival than open patients at 1 year (87% for open, 82% for TEVAR;
P
=0.001) and 5 years (72% for open; 62% for TEVAR;
P
=0.001). Furthermore, in adjusted and propensity-matched cohorts, patients selected for TEVAR had worse 5-year survival than patients selected for open repair.

Conclusions—
Although perioperative mortality is lower with TEVAR, Medicare patients selected for TEVAR have worse long-term survival than patients selected for open repair. The results of this observational study suggest that higher-risk patients are being offered TEVAR and that some do not benefit on the basis of long-term survival. Future work is needed to identify TEVAR candidates unlikely to benefit from repair.
Immune Activation Resulting From NKG2D/Ligand Interaction Promotes Atherosclerosis
Authors: Xia Mingcan , Guerra Nadia , Sukhova Galina K. , Yang Kangkang , Miller Carla K. , Shi Guo-Ping , Raulet David H. , Xiong Na 
Published: November 2011

Background—
The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood.

Methods and Results—
Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E–deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions.

Conclusions—
The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.
Pacific Shallow Meridional Overturning Circulation in a Warming Climate
Authors: Wang Daiwei , Cane Mark A. 
Published: November 2011

Abstract
By analyzing a set of the Coupled Model Intercomparison Project phase 3 (CMIP3) climate model projections of the twenty-first century, it is found that the shallow meridional overturning of the Pacific subtropical cells (STCs) show contrasting trends between two hemispheres in a warming climate. The strength of STCs and equivalently the STC surface-layer transport tend to be weakening (strengthening) in the Northern (Southern) Hemisphere as a response to large-scale surface wind changes over the tropical Pacific. The STC pycnocline transport convergence into the equatorial Pacific Ocean from higher latitudes shows a robust weakening in the twenty-first century. This weakening is mainly through interior pathways consistent with the relaxation of the zonal pycnocline tilt, whereas the transport change through western boundary pathways is small and not consistent across models. It is found that the change of the western boundary pycnocline transport is strongly affected by the shoaling of the pycnocline base. In addition, there is a robust weakening of the Indonesian Throughflow (ITF) transport in a warming climate. In the multimodel ensemble mean, the response to greenhouse warming of the upper-ocean mass balance associated with the STCs is such that the weakening of the equatorward pycnocline transport convergence is balanced by a weakening of the poleward surface-layer transport divergence and the ITF transport of similar amounts.