bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of antibiotic prescribing patterns in patients receiving sustained low-efficiency dialysis: opportunities for pharmacists
Authors: Harris Laura E , Reaves Anne B , Krauss Amy G , Griner Justin , Hudson Joanna Q 
Published: July 2012

Abstract

Objectives
Sustained low-efficiency dialysis (SLED) is a ‘hybrid’ form of continuous renal replacement therapy; however, there is very limited information on drug disposition during this procedure. Individuals requiring SLED are often critically ill and require antibiotics. The study aim was to evaluate antibiotic orders for patients requiring SLED compared to literature-based recommendations. We also evaluated whether doses were administered as prescribed and assessed clinical and microbiologic cure.

Methods
A retrospective review was performed over a 2-year period for patients who received concurrent SLED and antibiotic therapy. Demographic data, prescribed antibiotic dosing regimens and doses delivered as prescribed were determined for 10 antibiotics: cefepime (C), daptomycin (Da), doripenem (D), gentamicin (G), imipenem-cilastatin (I), linezolid (L), meropenem (M), piperacillin-tazobactam (P), tobramycin (T) and vancomycin (V). Dosing regimens were compared to recommendations from the literature where available. The incidence of clinical and microbiologic cure was also evaluated.

Results
A total of 87 patients met inclusion criteria: mean age 54 ± 14 years, 60% male, 58% white. Prescribed doses were evidence-based for 37% of Da, 97% of L, 15% of M and 7% of V orders. The majority of discrepancies were due to under-dosing. There were 129 (11%) antibiotic doses missed. Of the 13 patients who met criteria for assessment of clinical and microbiologic cure, 10 achieved a microbiologic cure and none reached clinical cure.

Conclusions
Prescribed antibiotic dosing regimens varied substantially and under-dosing was common. There is a need to further define appropriate dosing regimens for antibiotics administered during SLED and determine how pharmacists may help to ensure appropriate therapy.
Computing isogenies between abelian varieties
Authors: Lubicz David , Robert Damien 
Published: July 2012

AbstractWe describe an efficient algorithm for the computation of separable isogenies between abelian varieties represented in the coordinate system given by algebraic theta functions. Let A be an abelian variety of dimension g defined over a field of odd characteristic. Our algorithm comprises two principal steps. First, given a theta null point for A and a subgroup K isotropic for the Weil pairing, we explain how to compute the theta null point corresponding to the quotient abelian variety A/K. Then, from the knowledge of a theta null point of A/K, we present an algorithm to obtain a rational expression for an isogeny from A to A/K. The algorithm that results from combining these two steps can be viewed as a higher-dimensional analog of the well-known algorithm of Vélu for computing isogenies between elliptic curves. In the case where K is isomorphic to (ℤ/ℓℤ)g for ℓ∈ℕ*, the overall time complexity of this algorithm is equivalent to O(log ℓ) additions in A and a constant number of ℓth root extractions in the base field of A. In order to improve the efficiency of our algorithms, we introduce a compressed representation that allows us to encode a point of level 4ℓ of a g-dimensional abelian variety using only g(g+1)/2⋅4g coordinates. We also give formulas for computing the Weil and commutator pairings given input points in theta coordinates.
ATP‐mediated vasodilatation occurs via activation of inwardly rectifying potassium channels in humans
Authors: Crecelius Anne R. , Kirby Brett S. , Luckasen Gary J. , Larson Dennis G. , Dinenno Frank A. 
Published: July 2012

Key points
ATP is a substance in the blood vessels that can cause vasodilatation and increase blood flow and oxygen delivery in humans.
The exact signalling pathways that ATP stimulates to cause vasodilatation are not well known.
We show that a large portion of ATP‐mediated vasodilatation occurs through the activation of inwardly rectifying potassium channels (Kir).
Our results lend insight into the vasodilator mechanisms of ATP, a substance that is important for vascular control.
Further, our results may stimulate additional investigations in humans regarding the activation of Kir channels and subsequent vascular hyperpolarization during other physiologically relevant conditions.
Abstract  Circulating ATP possesses unique vasomotor properties in humans and has been hypothesized to play a role in vascular control under a variety of physiological conditions. However, the primary downstream signalling mechanisms underlying ATP‐mediated vasodilatation remain unclear. The purpose of the present experiment was to determine whether ATP‐mediated vasodilatation is independent of nitric oxide (NO) and prostaglandin (PG) synthesis and occurs primarily via the activation of Na+/K+‐ATPase and inwardly rectifying potassium (KIR) channels in humans. In all protocols, young healthy adults were studied and forearm vascular conductance (FVC) was calculated from forearm blood flow (measured via venous occlusion plethysmography) and intra‐arterial blood pressure to quantify local vasodilatation. Vasodilator responses (%ΔFVC) during intra‐arterial ATP infusions were unchanged following combined inhibition of NO and PGs (n= 8; P > 0.05) whereas the responses to KCl were greater (P < 0.05). Combined infusion of ouabain (to inhibit Na+/K+‐ATPase) and barium chloride (BaCl2; to inhibit KIR channels) abolished KCl‐mediated vasodilatation (n= 6; %ΔFVC = 134 ± 13 vs. 4 ± 5%; P < 0.05), demonstrating effective blockade of direct vascular hyperpolarization. The vasodilator responses to three different doses of ATP were inhibited on average 56 ± 5% (n= 16) following combined ouabain plus BaCl2 infusion. In follow‐up studies, BaCl2 alone inhibited the vasodilator responses to ATP on average 51 ± 3% (n= 6), which was not different than that observed for combined ouabain plus BaCl2 administration. Our novel results indicate that the primary mechanism of ATP‐mediated vasodilatation is vascular hyperpolarization via activation of KIR channels. These observations translate in vitro findings to humans in vivo and may help explain the unique vasomotor properties of intravascular ATP in the human circulation.
Bicarbonate‐dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu‐3
Authors: Shan Jiajie , Liao Jie , Huang Junwei , Robert Renaud , Palmer Melissa L. , Fahrenkrug Scott C. , O’Grady Scott M. , Hanrahan John W. 
Published: July 2012

Key points
The mechanisms of anion and fluid transport by airway submucosal glands are not well understood and may differ from those in surface epithelium.
The Calu‐3 cell line is often used as a model for submucosal gland serous cells and has cAMP‐stimulated fluid secretion; however, it does not actively transport chloride under short‐circuit conditions.
In this study we show that fluid secretion requires chloride, bicarbonate and sodium, that chloride is the predominant anion in Calu‐3 secretions, and that a large fraction of the basolateral chloride loading during cAMP stimulation occurs by Cl−/HCO3− exchange.
The results suggest a novel cellular model for anion and fluid secretion by Calu‐3 and submucosal gland acinar cells
Abstract  Anion and fluid secretion are both defective in cystic fibrosis (CF); however, the transport mechanisms are not well understood. In this study, Cl− and HCO3− secretion was measured using genetically matched CF transmembrane conductance regulator (CFTR)‐deficient and CFTR‐expressing cell lines derived from the human airway epithelial cell line Calu‐3. Forskolin stimulated the short‐circuit current (Isc) across voltage‐clamped monolayers, and also increased the equivalent short‐circuit current (Ieq) calculated under open‐circuit conditions. Isc was equivalent to the HCO3− net flux measured using the pH‐stat technique, whereas Ieq was the sum of the Cl− and HCO3− net fluxes. Ieq and HCO3− fluxes were increased by bafilomycin and ZnCl2, suggesting that some secreted HCO3− is neutralized by parallel electrogenic H+ secretion. Ieq and fluid secretion were dependent on the presence of both Na+ and HCO3−. The carbonic anhydrase inhibitor acetazolamide abolished forskolin stimulation of Ieq and HCO3− secretion, suggesting that HCO3− transport under these conditions requires catalysed synthesis of carbonic acid. Cl− was the predominant anion in secretions under all conditions studied and thus drives most of the fluid transport. Nevertheless, 50–70% of Cl− and fluid transport was bumetanide‐insensitive, suggesting basolateral Cl− loading by a sodium–potassium–chloride cotransporter 1 (NKCC1)‐independent mechanism. Imposing a transepithelial HCO3− gradient across basolaterally permeabilized Calu‐3 cells sustained a forskolin‐stimulated current, which was sensitive to CFTR inhibitors and drastically reduced in CFTR‐deficient cells. Net HCO3− secretion was increased by bilateral Cl− removal and therefore did not require apical Cl−/HCO3− exchange. The results suggest a model in which most HCO3− is recycled basolaterally by exchange with Cl−, and the resulting HCO3−‐dependent Cl− transport provides an osmotic driving force for fluid secretion.
Mature Pseudomonas aeruginosa Biofilms Prevail Compared to Young Biofilms in the Presence of Ceftazidime
Authors: Bowler Laura L. , Zhanel George G. , Ball T. Blake , Saward Laura L. 
Published: July 2012

ABSTRACT

Phenotypic tolerances to antibiotics of mature and young
Pseudomonas aeruginosa
PAO1 biofilms and released planktonic bacteria were compared for four antibiotics. Resistance levels were similar for gentamicin and ciprofloxacin but differed for ceftazidime and meropenem. β-Lactamase mapping showed that, after 5 h of ceftazidime exposure, mature biofilms produced more β-lactamase than young biofilms, facilitating the growth of released planktonic bacteria. This shows the importance of early treatment and choice of antibiotics for
P. aeruginosa
biofilm infections.
A Whole-Cell Phenotypic Screening Platform for Identifying Methylerythritol Phosphate Pathway-Selective Inhibitors as Novel Antibacterial Agents
Authors: Testa Charles A. , Johnson L. Jeffrey 
Published: July 2012

ABSTRACT

Isoprenoid biosynthesis is essential for survival of all living organisms. More than 50,000 unique isoprenoids occur naturally, with each constructed from two simple five-carbon precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Two pathways for the biosynthesis of IPP and DMAPP are found in nature. Humans exclusively use the mevalonate (MVA) pathway, while most bacteria, including all Gram-negative and many Gram-positive species, use the unrelated methylerythritol phosphate (MEP) pathway. Here we report the development of a novel, whole-cell phenotypic screening platform to identify compounds that selectively inhibit the MEP pathway. Strains of
Salmonella enterica
serovar Typhimurium were engineered to have separately inducible MEP (native) and MVA (nonnative) pathways. These strains, RMC26 and CT31-7d, were then used to differentiate MVA pathway- and MEP pathway-specific perturbation. Compounds that inhibit MEP pathway-dependent bacterial growth but leave MVA-dependent growth unaffected represent MEP pathway-selective antibacterials. This screening platform offers three significant results. First, the compound is antibacterial and is therefore cell permeant, enabling access to the intracellular target. Second, the compound inhibits one or more MEP pathway enzymes. Third, the MVA pathway is unaffected, suggesting selectivity for targeting the bacterial versus host pathway. The cell lines also display increased sensitivity to two reported MEP pathway-specific inhibitors, further biasing the platform toward inhibitors selective for the MEP pathway. We demonstrate development of a robust, high-throughput screening platform that combines phenotypic and target-based screening that can identify MEP pathway-selective antibacterials simply by monitoring optical density as the readout for cell growth/inhibition.
Polyclonal Mucosa-Associated Invariant T Cells Have Unique Innate Functions in Bacterial Infection
Authors: Chua Wei-Jen , Truscott Steven M. , Eickhoff Christopher S. , Blazevic Azra , Hoft Daniel F. , Hansen Ted H. 
Published: July 2012

ABSTRACTMucosa-associated invariant T (MAIT) cells are a unique population of αβ T cells in mammals that reside preferentially in mucosal tissues and express an invariant Vα paired with limited Vβ T-cell receptor (TCR) chains. Furthermore, MAIT cell development is dependent upon the expression of the evolutionarily conserved major histocompatibility complex (MHC) class Ib molecule MR1. Usingin vitroassays, recent studies have shown that mouse and human MAIT cells are activated by antigen-presenting cells (APCs) infected with diverse microbes, including numerous bacterial strains and yeasts, but not viral pathogens. However, whether MAIT cells play an important, and perhaps unique, role in controlling microbial infection has remained unclear. To probe MAIT cell function, we show here that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth ofMycobacterium bovisBCG in macrophages (MΦ) in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ. Surprisingly, however, the cognate recognition of MR1 by MAIT cells on the infected MΦ was found to play only a minor role in MAIT cell effector function. We also report that MAIT cell-deficient mice had higher bacterial loads at early times after infection compared to wild-type (WT) mice, demonstrating that MAIT cells play a unique role among innate lymphocytes in protective immunity against bacterial infection.
Identification of Genes That Contribute to the Pathogenesis of Invasive Pneumococcal Disease by
In Vivo
Transcriptomic Analysis
Authors: Ogunniyi Abiodun D. , Mahdi Layla K. , Trappetti Claudia , Verhoeven Nadine , Mermans Daphne , Van der Hoek Mark B. , Plumptre Charles D. , Paton James C. 
Published: July 2012

ABSTRACT

Streptococcus pneumoniae
(the pneumococcus) continues to be responsible for a high level of global morbidity and mortality resulting from pneumonia, bacteremia, meningitis, and otitis media. Here we have used a novel technique involving niche-specific, genome-wide
in vivo
transcriptomic analyses to identify genes upregulated in distinct niches during pathogenesis after intranasal infection of mice with serotype 4 or 6A pneumococci. The analyses yielded 28 common, significantly upregulated genes in the lungs relative to those in the nasopharynx and 25 significantly upregulated genes in the blood relative to those in the lungs in both strains, some of which were previously unrecognized. The role of five upregulated genes from either the lungs or the blood in pneumococcal pathogenesis and virulence was then evaluated by targeted mutagenesis. One of the mutants (Δ
malX
) was significantly attenuated for virulence in the lungs, two (Δ
aliA
and Δ
ilvH
) were significantly attenuated for virulence in the blood relative to the wild type, and two others (Δ
cbiO
and Δ
piuA
) were completely avirulent in a mouse intranasal challenge model. We also show that the products of
aliA
,
malX
, and
piuA
are promising candidates for incorporation into multicomponent protein-based pneumococcal vaccines currently under development. Importantly, we suggest that this new approach is a viable complement to existing strategies for the discovery of genes critical to the distinct stages of invasive pneumococcal disease and potentially has broad application for novel protein antigen discovery in other pathogens such as
S. pyogenes
,
Haemophilus influenzae
type b, and
Neisseria meningitidis
.
The Meningococcal Minor Pilin PilX Is Responsible for Type IV Pilus Conformational Changes Associated with Signaling to Endothelial Cells
Authors: Brissac Terry , Mikaty Guillain , Duménil Guillaume , Coureuil Mathieu , Nassif Xavier 
Published: July 2012

ABSTRACT

Neisseria meningitidis
crosses the blood-brain barrier (BBB) following the activation of the β2-adrenergic receptor by the type IV pili (TFP). Two components of the type IV pili recruit the β2-adrenergic receptor, the major pilin PilE and the minor pilin PilV. Here, we report that a strain deleted of PilX, one of the three minor pilins, is defective in endothelial cell signaling. The signaling role of PilX was abolished when pili were not retractable. Purified PilX was unable to recruit the β2-adrenergic receptor, thus suggesting that PilX was playing an indirect role in endothelial cell signaling. Considering the recent finding that type IV pili can transition into a new conformation (N. Biais, D. L. Higashi, J. Brujic, M. So, and M. P. Sheetz, Proc. Natl. Acad. Sci. U. S. A. 107:11358–11363, 2010), we hypothesized that PilX was responsible for a structural modification of the fiber and allowed hidden epitopes to be exposed. To confirm this hypothesis, we showed that a monoclonal antibody which recognizes a linear epitope of PilE bound fibers only when bacteria adhered to endothelial cells. On the other hand, this effect was not observed in PilX-deleted pili. A deletion of a region of PilX exposed on the surface of the fiber had phenotypical consequences identical to those of a PilX deletion. These data support a model in which surface-exposed motifs of PilX use forces generated by pilus retraction to promote conformational changes required for TFP-mediated signaling.
Candida albicans and Bacterial Microbiota Interactions in the Cecum during Recolonization following Broad-Spectrum Antibiotic Therapy
Authors: Mason Katie L. , Erb Downward John R. , Mason Kelly D. , Falkowski Nicole R. , Eaton Kathryn A. , Kao John Y. , Young Vincent B. , Huffnagle Gary B. 
Published: July 2012

ABSTRACT

Candida albicans
is a normal member of the gastrointestinal (GI) tract microbiota of healthy humans, but during host immunosuppression or alterations in the bacterial microbiota,
C. albicans
can disseminate and cause life-threatening illness. The bacterial microbiome of the GI tract, including lactic acid bacteria (LAB), plays a vital role in preventing fungal invasion. However, little is known about the role of
C. albicans
in shaping the bacterial microbiota during antibiotic recovery. We investigated the fungal burdens in the GI tracts of germfree mice and mice with a disturbed microbiome to demonstrate the role of the microbiota in preventing
C. albicans
colonization. Histological analysis demonstrated that colonization with
C. albicans
during antibiotic treatment does not trigger overt inflammation in the murine cecum. Bacterial diversity is reduced long term following cefoperazone treatment, but the presence of
C. albicans
during antibiotic recovery promoted the recovery of bacterial diversity. Cefoperazone diminishes
Bacteroidetes
populations long term in the ceca of mice, but the presence of
C. albicans
during cefoperazone recovery promoted
Bacteroidetes
population recovery. However, the presence of
C. albicans
resulted in a long-term reduction in
Lactobacillus
spp. and promoted
Enterococcus faecalis
populations. Previous studies have focused on the ability of bacteria to alter
C. albicans
; this study addresses the ability of
C. albicans
to alter the bacterial microbiota during nonpathogenic colonization.
Climate and ground temperature relations at sites across the continuous and discontinuous permafrost zones, northern Canada1This article is one of a series of papers published in this CJES Special Issue on the theme of Fundamental and applied research on permafrost in Canada.2Earth Science Sector (ESS) Contribution 20110128.
Authors: Throop Jennifer , Lewkowicz Antoni G. , Smith Sharon L. 
Published: July 2012

Climate – ground temperature relations are examined under a range of conditions for 10 sites across northern Canada. The sites are located between 60°N and 83°N and at elevations of 40 to 1840 m above sea level. They encompass various environmental and climatic conditions, with permafrost temperatures that range from just below 0 to –15 °C. The substrates range from bedrock to fine-grained sediment with high ice content, and vegetation types include coniferous forests in the Mackenzie Valley, shrub tundra at high elevation in the southern Yukon Territory, and polar desert in the High Arctic. Permafrost conditions at all of these sites are determined primarily by air temperature, followed by snow and substrate conditions. The apparent thermal diffusivity is relatively high at colder sites and in bedrock and is lower at sites in sediment with high ice content. Snow has a greater influence on air–ground temperature relations at sites where mean annual air temperatures and active-layer moisture contents are relatively high, leading to physically significant latent heat effects and a slower freeze-back of the active layer.
Lake- and channel-bottom temperatures in the Mackenzie Delta, Northwest Territories1This article is one of a series of papers published in this CJES Special Issue on the theme of Fundamental and applied research on permafrost in Canada.2Polar Continental Shelf Project Contribution 03511.
Authors: Ensom T.P. , Burn C.R. , Kokelj S.V. 
Published: July 2012

Temperature loggers were placed in 17 lakes and 13 channels throughout the Mackenzie Delta to determine the annual mean bottom temperature ([Formula: see text]) and its spatial and temporal variation for June 2009 – June 2010. The lakes were classified as perched or connected, depending on the duration of their connection to the channel hydrologic system. Average [Formula: see text] values for nine perched lakes, five channels, and eight connected lakes distributed throughout the Mackenzie Delta were 5.5, 4.6, and 3.4 °C, respectively. The range of [Formula: see text] among all instrumented water bodies in the Delta was 4.0 °C. Over the year, bottom temperatures ranged from >20 °C in midsummer to –5 °C in midwinter, with relative stability between freeze-up in mid-October and breakup at the beginning of June. Channel, perched, and connected lake [Formula: see text], and mean annual near-surface ground temperatures of –4 °C in alluvial sedge wetlands and –2.25 °C in forest, were used to estimate that about 60% of Delta lakes and nearly the entire channel network maintain through-taliks.
Factors influencing permafrost temperatures across tree line in the uplands east of the Mackenzie Delta, 2004–20101This article is one of a series of papers published in this CJES Special Issue on the theme of Fundamental and applied research on permafrost in Canada.2Polar Continental Shelf Contribution 03611.
Authors: Palmer M.J. , Burn C.R. , Kokelj S.V. 
Published: July 2012

Air and near-surface ground temperatures, late-winter snow conditions, and characteristics of the vegetation cover and soil were measured across the forest–tundra transition in the uplands east of the Mackenzie Delta, Northwest Territories, in 2004–2010. Mean late-winter snow depth decreased northward from 73 cm in the subarctic boreal forest near Inuvik to 22 cm in low-shrub tundra. Annual near-surface ground temperatures decreased northward by 0.1–0.3 °C/km near the northern limit of trees, in association with an abrupt change in snow depth. The rate decreased to 0.01–0.06 °C/km in the tundra. The freezing season is twice as long as the thawing season in the region, so measured differences in the regional ground thermal regime were dominated by the contrast in winter surface conditions between forest and tundra.