bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use
Authors: Damle Bharat , Varma Manthena V. , Wood Nolan 
Published: August 2011

ABSTRACT
In clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor metabolizers of CYP2C19. The study consisted of 4-day voriconazole-only and 5-day voriconazole-plus-fluconazole treatments, separated by a 14-day washout. Voriconazole pharmacokinetics were determined by noncompartmental analyses. A physiologically based pharmacokinetic model was developed in Simcyp (Simcyp Ltd., Sheffield, United Kingdom) to predict the magnitude of drug interaction should antifungal therapy be switched from fluconazole to voriconazole, following various simulated lag times for the switch. In CYP2C19 extensive metabolizers, fluconazole increased the maximum plasma concentration and the area under the plasma concentration-time curve (AUC) of voriconazole by 57% and 178%, respectively. In poor metabolizers, however, voriconazole pharmacokinetics were unaffected by fluconazole. The simulations based on pharmacokinetic modeling predicted that if voriconazole was started 6, 12, 24, or 36 h after the last dose of fluconazole, the voriconazole AUC ratios (sequential therapy versus voriconazole only) after the first dose would be 1.51, 1.41, 1.28, and 1.14, respectively. This suggests that the remaining systemic fluconazole would result in a marked drug interaction with voriconazole for ≥24 h. Although no safety issues were observed during coadministration, concomitant use of fluconazole and voriconazole is not recommended. Frequent monitoring for voriconazole-related adverse events is advisable if voriconazole is used sequentially after fluconazole.
Interrogation of Related Clinical Pan-Azole-Resistant Aspergillus fumigatus Strains: G138C, Y431C, and G434C Single Nucleotide Polymorphisms in
cyp51A
, Upregulation of
cyp51A
, and Integration and Activation of Transposon
Atf1
in the
cyp51A
Promoter
Authors: Albarrag Ahmed M. , Anderson Michael J. , Howard Susan J. , Robson Geoff D. , Warn Peter A. , Sanglard Dominique , Denning David W. 
Published: August 2011

ABSTRACT

Multiple
Aspergillus fumigatus
isolates from a patient with two aspergillomas complicating chronic pulmonary aspergillosis were pan-azole resistant. Microsatellite typing was identical for all isolates despite major phenotypic and some growth rate differences. Three different
cyp51A
mutations were found (G138C, Y431C, and G434C), of which the first two were demonstrated by heterologous expression in a hypersusceptible
Saccharomyces cerevisiae
strain to be at least partly responsible for elevated MICs.
cyp51A
and
cyp51B
gene duplication was excluded, but increased expression of
cyp51A
was demonstrated in three isolates selected for additional study (7-to 13-fold increases). In the isolate with the greatest
cyp51A
expression, an
Aft1
transposon was found inserted 370 bp upstream of the start codon of the
cyp51A
gene, an integration location never previously demonstrated in
Aspergillus
. Two transcription start sites were identified at 49 and 136 bp upstream of the start codon. The role of the
Aft1
transposon, if any, in modulating
cyp51A
expression remains to be established. Increased mRNA expression of the transporters
AfuMDR1
and
AfuMDR4
also was demonstrated in some isolates, which could contribute to azole resistance or simply represent a stress response. The diversity of confirmed and possible azole resistance mechanisms demonstrated in a single series of isogenic isolates is remarkable, indicating the ability of
A. fumigatus
to adapt in the clinical setting.
Mortality in Hematologic Malignancy and Hematopoietic Stem Cell Transplant Patients with Mucormycosis, 2001 to 2009
Authors: Hammond Sarah P. , Baden Lindsey R. , Marty Francisco M. 
Published: August 2011

ABSTRACT

Mortality due to mucormycosis is high. We assessed clinical characteristics and mortality among stem cell transplant and hematologic malignancy patients diagnosed with mucormycosis from 2001 to 2009. Thirty patients were diagnosed with probable or proven mucormycosis during the study. Twenty-six were diagnosed premortem, and most were treated with liposomal amphotericin B single-agent antifungal therapy initially. While the initial antifungal and surgical treatment approach remained stable throughout the study period, 6-week mortality significantly declined over time (67% in 2001 to 2003 versus 45% in 2004 to 2006 versus 20% in 2007 to 2009 [
P
= 0.04]), as did 12-week mortality (78% in 2001 to 2003 versus 55% in 2004 to 2006 versus 20% in 2007 to 2009 [
P
= 0.01]).
Nelfinavir and Its Active Metabolite, Hydroxy-
t
-Butylamidenelfinavir (M8), Are Transferred in Small Quantities to Breast Milk and Do Not Reach Biologically Significant Concentrations in Breast-Feeding Infants Whose Mothers Are Taking Nelfinavir
Authors: Weidle Paul J. , Zeh Clement , Martin Amy , Lando Richard , Angira Frank , Osoga Joseph , Ogindo Paul , Girde Sonali , Minniear Timothy D. , Thomas Timothy K. 
Published: August 2011

ABSTRACT
Antiretroviral drugs cross from maternal plasma to breast milk and from breast milk to the infant in different concentrations. We measured concentrations of nelfinavir and its active metabolite (M8) in maternal plasma and breast milk from women and in dried blood spots collected from their infants at delivery and postnatal weeks 2, 6, 14, and 24 in the Kisumu Breastfeeding Study, Kisumu, Kenya. Nelfinavir-based antiretroviral regimens given to mothers as prevention of mother-to-child HIV transmission (PMTCT) do not expose the breast-feeding infant to biologically significant concentrations of nelfinavir or M8.
Filarial Lymphatic Pathology Reflects Augmented Toll-Like Receptor-Mediated, Mitogen-Activated Protein Kinase-Mediated Proinflammatory Cytokine Production
Authors: Babu Subash , Anuradha R. , Kumar N. Pavan , George P. Jovvian , Kumaraswami V. , Nutman Thomas B. 
Published: August 2011

ABSTRACT
Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined cytokine responses to different Toll ligands in patients with chronic lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic-normal (EN) individuals. TLR2, -7, and -9 ligands induced significantly elevated production of Th1 and other proinflammatory cytokines in CP patients in comparison to both INF and EN patients. TLR adaptor expression was not significantly different among the groups; however, both TLR2 and TLR9 ligands induced significantly higher levels of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinases (MAPK) as well as increased activation of NF-κB in CP individuals. Pharmacologic inhibition of both ERK1/2 and p38 MAP kinase pathways resulted in significantly diminished production of proinflammatory cytokines in CP individuals. Our data, therefore, strongly suggest an important role for TLR2- and TLR9-mediated proinflammatory cytokine induction and activation of both the MAPK and NF-κB pathways in the development of pathology in human lymphatic filariasis.
LuxS Mediates Iron-Dependent Biofilm Formation, Competence, and Fratricide in Streptococcus pneumoniae
Authors: Trappetti Claudia , Potter Adam J. , Paton Adrienne W. , Oggioni Marco R. , Paton James C. 
Published: August 2011

ABSTRACT

During infection,
Streptococcus pneumoniae
exists mainly in sessile biofilms rather than in planktonic form, except during sepsis. The capacity to form biofilms is believed to be important for nasopharyngeal colonization as well as disease pathogenesis, but relatively little is known about the regulation of this process. Here, we investigated the effect of exogenous iron [Fe(III)] as well as the role of
luxS
(encoding S-ribosylhomocysteine lyase) on biofilm formation by
S. pneumoniae
D39. Fe(III) strongly enhanced biofilm formation at concentrations of ≥50 μM, while Fe(III) chelation with deferoxamine was inhibitory. Importantly, Fe(III) also upregulated the expression of
luxS
in wild-type D39. A
luxS
-deficient mutant (D39
luxS
) failed to form a biofilm, even with Fe(III) supplementation, whereas a derivative overexpressing
luxS
(D39
luxS
+) exhibited enhanced biofilm formation capacity and could form a biofilm without added Fe(III). D39
luxS
exhibited reduced expression of the major Fe(III) transporter PiuA, and the cellular [Fe(III)] was significantly lower than that in D39; in contrast, D39
luxS
+ had a significantly higher cellular [Fe(III)] than the wild type. The release of extracellular DNA, which is an important component of the biofilm matrix, also was directly related to
luxS
expression. Similarly, genetic competence, as measured by transformation frequency as well as the expression of competence genes
comD
,
comX
,
comW
,
cglA
, and
dltA
and the murein hydrolase
cbpD
, which is associated with fratricide-dependent DNA release, all were directly related to
luxS
expression levels and were further upregulated by Fe(III). Moreover, mutagenesis of
cbpD
blocked biofilm formation. We propose that competence, fratricide, and biofilm formation are closely linked in pneumococci, and that
luxS
is a central regulator of these processes. We also propose that the stimulatory effects of Fe(III) on all of these parameters are due to the upregulation of
luxS
expression, and that LuxS provides for a positive Fe(III)-dependent amplification loop by increasing iron uptake.
Sediment transport processes in an ancient mud-dominated succession: a comparison of processes operating in marine offshore settings and anoxic basinal environments
Authors: Ghadeer Samer G. , Macquaker Joe H.S. 
Published: August 2011

Abstract:
Few studies describe and compare the transport mechanisms operating to disperse mud in different parts of basins. Instead, the physical processes operating to disperse mud in offshore environments, where storm and tidal processes are interpreted to dominate, are generally considered in isolation from those occurring in basinal settings where changes in bottom-water anoxia and suspension settling from buoyant plumes are mostly interpreted to dominate. Using microtextural, mineralogical and geochemical data derived from the analyses of 151 thin sections obtained from the Lower Jurassic mudstone-dominated succession exposed on the coast of NE England, we investigate how varying sediment dispersal mechanisms, bioturbation and early diagenesis operated to produce the lithofacies variability observed. In particular, we consider the processes of sediment delivery while bottom waters were interpreted to be euxinic. Analyses of these samples reveal that the succession is highly variable at millimetre to centimetre scales. Six main lithofacies were observed: (1) sand- and clay-bearing, silt-rich mudstones; (2) silt-bearing, clay-rich mudstones; (3) clay-rich mudstones; (4) clay-, calcareous nannoplankton-, and organic carbon-bearing mudstones; (5) fine-grained muddy sandstones; (6) cement-rich mudstones. These units are organized typically into stacked successions of sharp-based, normally graded, thin (<10 mm) beds. Single beds exhibit a variety of sedimentary structures. Specifically tempestites, wave-enhanced sediment gravity flows of fluid mud, ripples and gutter casts are common in the coarser-grained mudstone facies. In contrast, thin siltstone lags, compacted ripples and organo-mineralic aggregates are common in the finer grained mudstone facies and those with significant primary production-derived components. Bioturbation is common throughout. These data indicate that sediment was transported by density flows and traction currents operating at the sediment–water interface in all parts of the studied succession. Bioturbation has overprinted depositional fabrics in the majority of samples. The extent to which persistent bottom-water anoxia and low-energy suspension settling influenced lithofacies variability in the basinal parts of the succession has been overstated; these environments were more dynamic than most researchers have previously concluded.
Geochemical evolution of Dalradian metavolcanic rocks: implications for the break-up of the Rodinia supercontinent
Authors: Fettes D.J. , Macdonald R. , Fitton J.G. , Stephenson D. , Cooper M.R. 
Published: August 2011

Abstract:

Neoproterozoic basaltic magmatism in the Dalradian Supergroup of Scotland and Ireland was associated with the break-up of the Rodinia supercontinent. Magmas were erupted in rift-related basins along a strike length of at least 700 km and during a time period of
c
. 80 Ma. New major and trace element analyses of metabasalts from several formations are presented to trace the variations in magma compositions in time and space. The primary magmas resulted from variable degrees of mixing of melts derived from mantle sources similar to those of normal and enriched mid-ocean ridge basalts; some younger lavas also show evidence of contamination with continental crust. In contrast to speculations about magmatism elsewhere in Rodinia, the evidence here suggests that there was no involvement of a mantle plume in basalt generation. For example, the Scottish promontory of Laurentia drifted rapidly southwards through
c
. 25° over the duration of the magmatism, with no evidence of significant elevation above sea level, as might be expected from involvement of a plume. Generation of the primary magmas might have taken place predominantly through decompression melting in depleted upper mantle containing enriched streaks and blobs. Both the Dalradian lithostratigraphy and the metabasaltic compositions are consistent with extreme lithospheric stretching and possibly rupture during the earliest phase of magmatism, whereas generation of later magmatism appears to have been associated with major fault systems, possibly on a foundering continental margin.

Supplementary material:

Chemical analyses of Dalradian metavolcanic rocks (major elements recalculated to 100%, anhydrous) are available at
www.geolsoc.org.uk/SUP18468
.
A record of continental collision and regional sediment flux for the Cretaceous and Palaeogene core of SE Asia: implications for early Cenozoic palaeogeography
Authors: Clements Benjamin , Hall Robert 
Published: August 2011

Abstract:

Palaeogene sedimentary rocks exposed in West Java were derived from local volcanic sources and central Sundaland, the continental core of SE Asia. Detrital zircons from seven sandstone samples contain U–Pb age populations with ages of 50–80 Ma, 74–145 Ma, 202–298 Ma, 480–653 Ma and 723–1290 Ma. Late Cretaceous and Palaeogene zircons in Middle Eocene forearc sandstones are interpreted as derived from two spatially and temporally discrete volcanic arcs located in Java and Sulawesi respectively. In contrast, all other populations have a Sundaland provenance. Most Permian–Triassic zircons were derived from granites of this age in the SE Asian Tin Belt. Mid-Cretaceous zircons in all Upper Eocene and Lower Oligocene formations were derived from the Schwaner Mountains of SW Borneo. The differences in zircon populations reflect changing Sundaland sources with time. In the Middle Eocene, sediment was derived mainly from the Tin Belt. From the Late Eocene onwards a Borneo source became more important. Older zircon ages are from SE Asia basement that once formed part of Gondwana. Zircons also record the timing of microcontinental collision at the Java margin (
c
. 80 Ma) that halted Cretaceous subduction and probably resulted in the elevation of large parts of continental SE Asia.

Supplementary material:

Methods, sample locality list, tables for U–Pb zircon age measurements, point count data and heavy mineral assemblages, sandstone petrographic descriptions and palaeocurrent data are available at
www.geolsoc.org.uk/SUP18489
.
Jeannette M. Wing @ PCAST; Barbara Liskov keynote
Authors: Wing Jeannette M. , Barr Valerie 
Published: August 2011

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Communications
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Jeannette M. Wing discusses her PCAST presentation about the importance of computer science and its impact. Valerie Barr shares highlights from Barbara Liskov's keynote at Grace Hopper.
Reducing the effort of bug report triage
Authors: Anvik John , Murphy Gail C. 
Published: August 2011

A key collaborative hub for many software development projects is the bug report repository. Although its use can improve the software development process in a number of ways, reports added to the repository need to be triaged. A triager determines if a report is meaningful. Meaningful reports are then organized for integration into the project's development process.
To assist triagers with their work, this article presents a machine learning approach to create recommenders that assist with a variety of decisions aimed at streamlining the development process. The recommenders created with this approach are accurate; for instance, recommenders for which developer to assign a report that we have created using this approach have a precision between 70% and 98% over five open source projects. As the configuration of a recommender for a particular project can require substantial effort and be time consuming, we also present an approach to assist the configuration of such recommenders that significantly lowers the cost of putting a recommender in place for a project. We show that recommenders for which developer should fix a bug can be quickly configured with this approach and that the configured recommenders are within 15% precision of hand-tuned developer recommenders.
miR-31 Is a Broad Regulator of β1-Integrin Expression and Function in Cancer Cells
Authors: Augoff Katarzyna , Das Mitali , Bialkowska Katarzyna , McCue Brian , Plow Edward F. , Sossey-Alaoui Khalid 
Published: August 2011

Abstract
Integrins are adhesion receptors involved in bidirectional signaling that are crucial for various cellular responses during normal homeostasis and pathologic conditions such as cancer progression and metastasis. Aberrant expression of noncoding microRNAs (miRNA) has been implicated in the deregulation of integrin expression and activity, leading to the development and progression of cancer tumors, including their acquisition of the metastatic phenotype. miR-31 is a key regulator of several critical genes involved in the invasion-metastasis cascade in cancer. Using diverse cell-based, genetic, biochemical, flow cytometry, and functional analyses, we report that miR-31 is a master regulator of integrins as it targets multiple α subunit partners (α2, α5, and αV) of β1 integrins and also β3 integrins. We found that expression of miR-31 in cancer cells resulted in a significant repression of these integrin subunits both at the mRNA and protein levels. Loss of expression of α2, α5, αV, and β3 was a direct consequence of miR-31 targeting conserved seed sequences in the 3′ untranslated region of these integrin subunits leading to their posttranscriptional repression, which was reflected in their diminished surface expression in live cells. The biological consequence of decreased the cell surface of these integrins was a significant inhibition of cell spreading in a ligand-dependent manner. Although different reports have shown that a single integrin can be regulated by several miRNAs, here we show that a single miRNA, miR-31, is able to specifically target several integrin subunits to regulate key aspects of cancer cell invasion and metastasis. Mol Cancer Res; 9(11); 1500–8. ©2011 AACR.
Delayed Postconditioning in the Mouse Heart In Vivo
Authors: Roubille François , Franck-Miclo Alicia , Covinhes Aurélie , Lafont Chrystel , Cransac Frédéric , Combes Stéphane , Vincent Anne , Fontanaud Pierre , Sportouch-Dukhan Catherine , Redt-Clouet Christelle , Nargeot Joël , Piot Christophe , Barrère-Lemaire Stéphanie 
Published: August 2011

Background—
Reperfusion during acute myocardial infarction remains the best treatment for reducing infarct size. Postconditioning, applied at the onset of reperfusion, reduces myocardial infarction both in animals and humans. The objective of this study was to identify the time delay to apply postconditioning at reperfusion, allowing preservation of cardioprotection in the mouse myocardium. This is a major issue in the management of acute myocardial infarction patients.

Methods and Results—

Mice were subjected to 40 minutes of ischemia and 60 minutes of reperfusion (IR
60′
). Postconditioning protocols corresponding to repetitive ischemia (3 cycles of 1 minute of ischemia and 1 minute of reperfusion) were applied during early reperfusion at various time durations (Δt) after reopening of the coronary artery (Δt=10 seconds, 1, 5, 10, 15, 20, 30, and 45 minutes; PostC
Δt
). Infarct size/area at risk was reduced by 71% in PostC
Δ1
compared with IR
60′
mice (
P
=5×10
−6
). There was a linear correlation (
r
2
=0.91) between infarct size and Δt, indicating that the cardioprotective effect of delayed postconditioning was progressively attenuated when Δt time increased. The protective effect of PostC
Δ1
and PostC
Δ15
was still effective when the duration of reperfusion was prolonged to 24 hours (IR
24 hours
; PostC
Δ1
and PostC
Δ15
versus IR
24 hours
,
P
=0.001). Similar results were obtained for internucleosomal DNA fragmentation and lactate dehydrogenase release.

Conclusions—
This study in our in vivo mouse model of myocardial IR shows for the first time that delaying the intervention of postconditioning to 30 minutes does not abrogate the cardioprotective effect of postconditioning. This finding provides evidence that the time window of protection afforded by postconditioning may be larger than initially reported.