bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stored blood transfusion induces transient pulmonary arterial hypertension without impairing coagulation in an ovine model of nontraumatic haemorrhage
Authors: Fung Y. L. , Tung J. P. , Foley S. R. , Simonova G. , Thom O. , Staib A. , Collier J. , Dunster K. R. , Solano C. , Shekar K. , Chew M. S. , Fraser J. F. 
Published: March 2013

Background and ObjectivesTransfusion of blood products in particular older products is associated with patient morbidity. Previously, we demonstrated a higher incidence of acute lung injury in lipopolysaccharide‐treated sheep transfused with stored blood products. As transfusion following haemorrhage is more common, we aimed to determine whether a ‘first hit’ of isolated haemorrhage would precipitate similar detrimental effects following transfusion and also disrupt haemostasis.Materials and MethodsAnaesthetized sheep had 33% of their total blood volume collected into Leukotrap bags (Pall Medical), which were processed into packed red blood cells and cross‐matched for transfusion into other sheep. After 30 mins, the sheep were resuscitated with either: fresh (<5 days old) or stored (35–42 days old) ovine blood followed by 4% albumin to replacement volume, albumin alone or normal saline alone and monitored for 4 h.ResultsThe first hit of haemorrhage precipitated substantial decreases in mean arterial pressure however haemostasis was preserved. Transfusion of stored ovine blood induced (1) transient pulmonary arterial hypertension but no oedema and (2) reduced fibrinogen levels more than fresh blood, but neither induced coagulopathy. Thus, transfusion of stored blood affected pulmonary function even in the absence of overt organ injury.ConclusionThe fact that stored blood transfusions: (1) did not induce acute lung injury in contrast to previous lipopolysaccharide‐primed animal models identifies the ‘first hit’ as an important determinant of the severity of transfusion‐mediated injury; (2) impaired pulmonary dynamics verifies the sensitivity and vulnerability of the pulmonary system to injury.
The evaporative requirement for heat balance determines whole‐body sweat rate during exercise under conditions permitting full evaporation
Authors: Gagnon Daniel , Jay Ollie , Kenny Glen P. 
Published: March 2013

Key points
A relative exercise intensity (%) protocol is often used to compare absolute whole‐body sweat rates (WBSRs) during exercise between participants of different aerobic capacity.
Under conditions permitting full evaporation, heat balance theory suggests that exercise intensity should be fixed to elicit the same rate of evaporation required for heat balance (Ereq).
Whole‐body direct calorimetry was employed to measure WBSRs throughout 90 min of exercise across a range of air temperatures and rates of metabolic heat production.
Irrespective of ambient temperature and metabolic heat production, Ereq alone described ∼90% of all variability in WBSR during steady‐state and non‐steady‐state exercise, whereas <2% of variation was independently described by %.
To perform an unbiased comparison of WBSRs (but not necessarily core temperature) between different individuals/groups under conditions allowing full evaporation, future studies should consider using a fixed Ereq irrespective of the % incurred.
Abstract  Although the requirements for heat dissipation during exercise are determined by the necessity for heat balance, few studies have considered them when examining sweat production and its potential modulators. Rather, the majority of studies have used an experimental protocol based on a fixed percentage of maximum oxygen uptake (%). Using multiple regression analysis, we examined the independent contribution of the evaporative requirement for heat balance (Ereq) and % to whole‐body sweat rate (WBSR) during exercise. We hypothesised that WBSR would be determined by Ereq and not by %. A total of 23 males performed two separate experiments during which they exercised for 90 min at different rates of metabolic heat production (200, 350, 500 W) at a fixed air temperature (30°C, n= 8), or at a fixed rate of metabolic heat production (290 W) at different air temperatures (30, 35, 40°C, n= 15 and 45°C, n= 7). Whole‐body evaporative heat loss was measured by direct calorimetry and used to calculate absolute WBSR in grams per minute. The conditions employed resulted in a wide range of Ereq (131–487 W) and % (15–55%). The individual variation in non‐steady‐state (0–30 min) and steady‐state (30–90 min) WBSR correlated significantly with Ereq (P < 0.001). In contrast, % correlated negatively with the residual variation in WBSR not explained by Ereq, and marginally increased (∼2%) the amount of total variability in WBSR described by Ereq alone (non‐steady state: R2= 0.885; steady state: R2= 0.930). These data provide clear evidence that absolute WBSR during exercise is determined by Ereq, not by %. Future studies should therefore use an experimental protocol which ensures a fixed Ereq when examining absolute WBSR between individuals, irrespective of potential differences in relative exercise intensity.
Mutational Activation of the AmgRS Two-Component System in Aminoglycoside-Resistant Pseudomonas aeruginosa
Authors: Lau Calvin Ho-Fung , Fraud Sebastien , Jones Marcus , Peterson Scott N. , Poole Keith 
Published: March 2013

ABSTRACT

The
amgRS
operon encodes a presumed membrane stress-responsive two-component system linked to intrinsic aminoglycoside resistance in
Pseudomonas aeruginosa
. Genome sequencing of a lab isolate showing modest pan-aminoglycoside resistance, strain K2979, revealed a number of mutations, including a substitution in
amgS
that produced an R182C change in the AmgS sensor kinase product of this gene. Introduction of this mutation into an otherwise wild-type strain recapitulated the resistance phenotype, while correcting the mutation in the resistant mutant abrogated the resistant phenotype, confirming that the
amgS
mutation is responsible for the aminoglycoside resistance of strain K2979. The
amgS
R182
mutation promoted an AmgR-dependent, 2- to 3-fold increase in expression of the AmgRS target genes
htpX
and PA5528, mirroring the impact of aminoglycoside exposure of wild-type cells on
htpX
and PA5528 expression. This suggests that
amgS
R182
is a gain-of-function mutation that activates AmgS and the AmgRS two-component system in promoting modest resistance to aminoglycosides. Screening of several pan-aminoglycoside-resistant clinical isolates of
P. aeruginosa
revealed three that showed elevated
htpX
and PA5528 expression and harbored single amino acid-altering mutations in
amgS
(V121G or D106N) and no mutations in
amgR
. Introduction of the
amgS
V121G
mutation into wild-type
P. aeruginosa
generated a resistance phenotype reminiscent of the
amgS
R182
mutant and produced a 2- to 3-fold increase in
htpX
and PA5528 expression, confirming that it, too, is a gain-of-function aminoglycoside resistance-promoting mutation. These results highlight the contribution of
amgS
mutations and activation of the AmgRS two-component system to acquired aminoglycoside resistance in lab and clinical isolates of
P. aeruginosa
.
Randomized Dose-Ranging Study of the 14-Day Early Bactericidal Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive Pulmonary Tuberculosis
Authors: Diacon Andreas H. , Dawson Rodney , Von Groote-Bidlingmaier Florian , Symons Gregory , Venter Amour , Donald Peter R. , Conradie Almari , Erondu Ngozi , Ginsberg Ann M. , Egizi Erica , Winter Helen , Becker Piet , Mendel Carl M. 
Published: March 2013

ABSTRACT

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log
10
CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (
P
= 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (
P
= 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.
Polymyxin Resistance of
Pseudomonas aeruginosa phoQ
Mutants Is Dependent on Additional Two-Component Regulatory Systems
Authors: Gutu Alina D. , Sgambati Nicole , Strasbourger Pnina , Brannon Mark K. , Jacobs Michael A. , Haugen Eric , Kaul Rajinder K. , Johansen Helle Krogh , Høiby Niels , Moskowitz Samuel M. 
Published: March 2013

ABSTRACT

Pseudomonas aeruginosa
can develop resistance to polymyxin as a consequence of mutations in the PhoPQ regulatory system, mediated by covalent lipid A modification. Transposon mutagenesis of a polymyxin-resistant
phoQ
mutant defined 41 novel loci required for resistance, including two regulatory systems, ColRS and CprRS. Deletion of the
colRS
genes, individually or in tandem, abrogated the polymyxin resistance of a Δ
phoQ
mutant, as did individual or tandem deletion of
cprRS
. Individual deletion of
colR
or
colS
in a Δ
phoQ
mutant also suppressed 4-amino-
l
-arabinose addition to lipid A, consistent with the known role of this modification in polymyxin resistance. Surprisingly, tandem deletion of
colRS
or
cprRS
in the Δ
phoQ
mutant or individual deletion of
cprR
or
cprS
failed to suppress 4-amino-
l
-arabinose addition to lipid A, indicating that this modification alone is not sufficient for PhoPQ-mediated polymyxin resistance in
P. aeruginosa
. Episomal expression of
colRS
or
cprRS
in tandem or of
cprR
individually complemented the Pm resistance phenotype in the Δ
phoQ
mutant, while episomal expression of
colR
,
colS
, or
cprS
individually did not. Highly polymyxin-resistant
phoQ
mutants of
P. aeruginosa
isolated from polymyxin-treated cystic fibrosis patients harbored mutant alleles of
colRS
and
cprS
; when expressed in a Δ
phoQ
background, these mutant alleles enhanced polymyxin resistance. These results define ColRS and CprRS as two-component systems regulating polymyxin resistance in
P. aeruginosa
, indicate that addition of 4-amino-
l
-arabinose to lipid A is not the only PhoPQ-regulated biochemical mechanism required for resistance, and demonstrate that
colRS
and
cprS
mutations can contribute to high-level clinical resistance.
Effect of Farnesol on Growth, Ergosterol Biosynthesis, and Cell Permeability in Coccidioides posadasii
Authors: Brilhante Raimunda Sâmia Nogueira , de Lima Rita Amanda Chaves , Caetano Erica Pacheco , Leite João Jaime Giffoni , Castelo-Branco Débora de Souza Collares Maia , Ribeiro Joyce Fonteles , Bandeira Tereza de Jesus Pinheiro Gomes , Cordeiro Rossana de Aguiar , Monteiro André Jalles , Sidrim José Júlio Costa , Rocha Marcos Fábio Gadelha 
Published: March 2013

ABSTRACT

Coccidioidomycosis is a systemic mycosis caused by the dimorphic fungi
Coccidioides
spp. The treatment for chronic and/or disseminated coccidioidomycosis can be prolonged and complicated. Therefore, the search for new drugs is necessary. Farnesol is a precursor in the sterol biosynthesis pathway that has been shown to present antifungal activity. Thus, the objective of this study was to evaluate the
in vitro
antifungal activity of farnesol alone and in combination with antifungal agents against clinical and environmental strains of
Coccidioides posadasii
as well as to determine their effect on the synthesis of ergosterol and on cell permeability. This study employed the broth macrodilution method to determine the MIC of farnesol against 18 strains of
C. posadasii
. Quantification of ergosterol was performed with 10 strains of
C. posadasii
after exposure to subinhibitory concentrations of farnesol. Finally, the activity of farnesol was evaluated in the presence of osmotic stress, induced by the addition of NaCl to the culture medium, during the susceptibility tests. The results showed that farnesol exhibited low MICs (ranging from 0.00171 to 0.01369 mg/liter) against all tested strains. The combination of farnesol with the antifungals showed synergistic effects (fractional inhibitory concentration index [FICI] ≤ 0.5). As for the ergosterol quantification, it was observed that exposure to subinhibitory concentrations of farnesol decreased the amount of ergosterol extracted from the fungal cells. Furthermore, farnesol also showed lower MIC values when the strains were subjected to osmotic stress, indicating the action of this compound on the fungal membrane. Thus, due to the high
in vitro
antifungal activity, this work brings perspectives for the performance of
in vivo
studies to further elucidate the effects of farnesol on the host cells.
Adherence Profiles and Therapeutic Responses of Treatment-Naive HIV-Infected Patients Starting Boosted Atazanavir-Based Therapy in the ANRS 134-COPHAR 3 Trial
Authors: Parienti Jean-Jacques , Barrail-Tran Aurélie , Duval Xavier , Nembot Georges , Descamps Diane , Vigan Marie , Vrijens Bernard , Panhard Xavière , Taburet Anne-Marie , Mentré France , Goujard Cécile 
Published: March 2013

ABSTRACTThe adherence profile of HIV-infected patients predicts the therapeutic outcome, in particular during the early phase of antiretroviral therapy (ART). We conducted a prospective observational multicenter trial monitoring adherence and virological and immunological parameters over the initial 6 months of treatment. Thirty-five subjects were starting a treatment regimen including atazanavir, ritonavir, and emtricitabine-tenofovir. Adherence was assessed using self-completed questionnaires, announced pill counts, and the medication event monitoring system (MEMS) for each drug. Three MEMS measures were defined: the percentages of doses taken, days with the correct dosing, and doses taken on time (±3 h). Dynamic virological suppression (DVS) was defined as a reduction in the plasma HIV-RNA level of >1 log10per month or <40 copies/ml. The cumulative treatment time was 5,526 days. A high level of adherence was observed. The MEMS-defined adherence for correct dosing (−0.68% per 4-week period,P< 0.03) and timing compliance (−1.60% per 4-week period,P< 0.003) decreased significantly over time. The MEMS-defined adherence data were concordant with the pill counts during the trial but not with the data from the questionnaires. The median [range] percentages of doses taken (100% [50 to 102]), days with the correct dosing (95% [41 to 100]), and doses taken on time (86% [32 to 100]) were significantly associated with DVS in separate models. Among these three measures, the percentage of doses taken on time had the greatest ability to predict DVS. Timing compliance should be supported to optimize DVS during the early phase of treatment by once-daily boosted protease inhibitor-based ART. (This study has been registered at ClinicalTrials.gov under registration no. NCT00528060.)
A Lactotransferrin Single Nucleotide Polymorphism Demonstrates Biological Activity That Can Reduce Susceptibility to Caries
Authors: Fine Daniel H. , Toruner Gokce A. , Velliyagounder Kabilan , Sampathkumar Vandana , Godboley Dipti , Furgang David 
Published: March 2013

ABSTRACT

Streptococcus mutans
is prominently linked to dental caries. Saliva's influence on caries is incompletely understood. Our goal was to identify a salivary protein with anti-
S. mutans
activity, characterize its genotype, and determine genotypic variants associated with
S. mutans
activity and reduced caries. An
S. mutans
affinity column was used to isolate active moieties from saliva obtained from a subject with minimal caries. The bound and eluted protein was identified as lactotransferrin (LTF) by matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) analysis and confirmed by Western blotting with LTF antibody. A single nucleotide polymorphism (SNP) that produced a shift from arginine (R) to lysine (K) at amino acid position 47 in the LTF antimicrobial region (rs: 1126478) killed
S. mutans
in vitro
. Saliva from a subject with moderate caries and with the LTF “wild-type” R form at position 47 had no such activity. A pilot genetic study (
n
= 30) showed that KK subjects were more likely to have anti-
S. mutans
activity than RR subjects (
P
= 0.001; relative risk = 3.6; 95% confidence interval [95% CI] = 1.5 to 11.13). Pretreatment of KK saliva with antibody to LTF reduced
S. mutans
killing in a dose-dependent manner (
P
= 0.02). KK subjects were less likely to have caries (
P
= 0.02). A synthetic 11-mer LTF/K peptide killed
S. mutans
and other caries-related bacteria, while the LTF/R peptide had no effect (
P
= 0.01). Our results provide functional evidence that the LTF/K variant results in both anti-
S. mutans
activity and reduced decay. We suggest that the LTF/K variant can influence oral microbial ecology in general and caries-provoking microbes specifically.
Replication and Distribution of Toxoplasma gondii in the Small Intestine after Oral Infection with Tissue Cysts
Authors: Gregg Beth , Taylor Betsy C. , John Beena , Tait-Wojno Elia D. , Girgis Natasha M. , Miller Natalie , Wagage Sagie , Roos David S. , Hunter Christopher A. 
Published: March 2013

ABSTRACTNatural infection byToxoplasma gondiioccurs via oral ingestion of tissue cysts that rupture in the small intestine, releasing zoites that infect locally before disseminating throughout the host. The studies presented here used fluorescent parasites combined with flow cytometry and multiphoton microscopy techniques to understand the events associated with parasite replication in the mucosa. At 3 days postinfection with tissue cysts, parasites were localized in small foci and flow cytometry revealed parasites present in macrophages, neutrophils, and monocytes in the lamina propria. By day 6 postinfection, there were large foci of replicating parasites; however, foci unexpectedly varied in the number of villi involved and were associated with the presence of viable tachyzoites within the intestinal lumen. Consistent with the flow cytometry data, neutrophils and monocytes in the lamina propria were preferentially associated with parasite plaques. In contrast, dendritic cells comprised a small fraction of the infected immune cell population and were localized at the periphery of parasite plaques. Together, these findings reveal the formation of localized sites of parasite replication and inflammation early during infection and suggest that sustained replication ofT. gondiiin the gut may be a function of pathogen luminal spread.
The Formins FMNL1 and mDia1 Regulate Coiling Phagocytosis of Borrelia burgdorferi by Primary Human Macrophages
Authors: Naj Xenia , Hoffmann Ann-Kathrin , Himmel Mirko , Linder Stefan 
Published: March 2013

ABSTRACT

Spirochetes of the
Borrelia burgdorferi
sensu lato
complex are the causative agent of Lyme borreliosis, a tick-borne infectious disease primarily affecting the skin, nervous system, and joints. During infection, macrophages and dendritic cells are the first immune cells to encounter invading borreliae. Phagocytosis and intracellular processing of
Borrelia
by these cells is thus decisive for the eventual outcome of infection. Phagocytic uptake of
Borrelia
by macrophages proceeds preferentially through coiling phagocytosis, which is characterized by actin-rich unilateral pseudopods that capture and enwrap spirochetes. Actin-dependent growth of these pseudopods necessitates
de novo
nucleation of actin filaments, which is regulated by actin-nucleating factors such as Arp2/3 complex. Here, we demonstrate that, in addition, also actin-regulatory proteins of the formin family are important for uptake of borreliae by primary human macrophages. Using immunofluorescence, live-cell imaging, and ratiometric analysis, we find specific enrichment of the formins FMNL1 and mDia1 at macrophage pseudopods that are in contact with borreliae. Consistently, small interfering RNA (siRNA)-mediated knockdown of FMNL1 or mDia1 leads to decreased formation of
Borrelia
-induced pseudopods and to decreased internalization of borreliae by macrophage
s
. Our results suggest that macrophage coiling phagocytosis is a complex process involving several actin nucleation/regulatory factors. They also point specifically to the formins mDia1 and FMNL1 as novel regulators of spirochete uptake by human immune cells.
Rodents' rights: patients or pet food?
Authors: Richards Isobel 
Published: March 2013

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved. In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Rodents’ rights: patients or provisions?', was submitted by a reader and is discussed by Isobel Richards. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Vaccinations and the Animal Welfare Act’, which was published in the February issue of In Practice, appears on page 159.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas.
Forecasting large explosions at Bezymianny Volcano using thermal satellite data
Authors: van Manen S. M. , Blake S. , Dehn J. , Valcic L. 
Published: March 2013

Abstract
Large volcanic explosions pose a severe risk to life and cargo by injecting ash into local and international air traffic routes. Prior to exploding, Bezymianny (Kamchatka) commonly shows an increase in lava extrusion rate, which can be detected by satellites as an increase in thermal radiance. Here we present the first method of forecasting explosive eruptions based solely on satellite data. A pattern recognition algorithm using Advanced Very High Resolution Radiometer (AVHRR) data has been developed based on known precursory trends of increasing radiance prior to 19 explosions at Bezymianny Volcano in 1993–2008. The algorithm retrospectively forecasts 89% of the explosions (100% of the explosions that show precursory increases in thermal radiance), with 71% of alerts issued in the 30 days beforehand. The method also provides the probability of an explosion occurring within a given number of days after an alert is triggered by the algorithm. When applied to independent data, the algorithm correctly provided alerts before the 16 December 2009, 31 May 2010 and 13 April 2011 explosions.