bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci
Authors: Smith Jordan R. , Yim Juwon , Raut Animesh , Rybak Michael J. 
Published: February 2016

ABSTRACT

Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistant
Staphylococcus aureus
(MRSA).
In vitro
data suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistant
Enterococcus faecalis
, and vancomycin-resistant
Enterococcus faecium
. Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log
10
-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 μg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 μg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 μg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (
P
< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted.
Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy
Authors: Huurneman Luc J. , Neely Michael , Veringa Anette , Docobo Pérez Fernando , Ramos-Martin Virginia , Tissing Wim J. , Alffenaar Jan-Willem C. , Hope William 
Published: February 2016

ABSTRACT

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC
50
) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC
50
)/15.4 predicted terminal galactomannan (
P
= 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (
P
= 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival.
Evaluation of the Efficacy of ME1111 in the Topical Treatment of Dermatophytosis in a Guinea Pig Model
Authors: Long L. , Hager C. , Ghannoum M. 
Published: February 2016

ABSTRACT

The treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, the
in vivo
efficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused by
Trichophyton mentagrophytes
using a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with a
P
value of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding.
Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen
Authors: McCormack Ryan , Bahnan Wael , Shrestha Niraj , Boucher Justin , Barreto Marcella , Barrera Carlos M. , Dauer Edward A. , Freitag Nancy E. , Khan Wasif N. , Podack Eckhard R. , Schesser Kurt 
Published: February 2016

ABSTRACT

The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1,
Mpeg1
), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogen
Listeria monocytogenes
. Within a few hours of systemic infection, the massive proliferation of
L. monocytogenes
in
Perforin
-2
−/−
mice leads to a rapid appearance of acute disease symptoms. We go on to show in cultured
Perforin
-2
−/−
cells that the vacuole-to-cytosol transitioning of
L. monocytogenes
is greatly accelerated. Unexpectedly, we found that in
Perforin
-2
−/−
macrophages,
Listeria
-containing vacuoles quickly (≤15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation of
L. monocytogenes
to its replicative niche in the cytosol. This hypothesis was supported by our finding that a
L. monocytogenes
strain expressing virulence factors at a constitutively high level replicated equally well in
Perforin
-2
+/+
and
Perforin
-2
−/−
macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification of
Listeria
-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.
Minicells, Back in Fashion
Authors: Farley Madeline M. , Hu Bo , Margolin William , Liu Jun 
Published: February 2016

ABSTRACT

Cryo-electron tomography (cryo-ET) has emerged as a leading technique for three-dimensional visualization of large macromolecular complexes and their conformational changes in their native cellular environment. However, the resolution and potential applications of cryo-ET are fundamentally limited by specimen thickness, preventing high-resolution
in situ
visualization of macromolecular structures in many bacteria (such as
Escherichia coli
and
Salmonella enterica
). Minicells, which were discovered nearly 50 years ago, have recently been exploited as model systems to visualize molecular machines
in situ
, due to their smaller size and other unique properties. In this review, we discuss strategies for producing minicells and highlight their use in the study of chemotactic signaling, protein secretion, and DNA translocation. In combination with powerful genetic tools and advanced imaging techniques, minicells provide a springboard for in-depth structural studies of bacterial macromolecular complexes
in situ
and therefore offer a unique approach for gaining novel structural insights into many important processes in microbiology.
Sulfide Consumption in Sulfurimonas denitrificans and Heterologous Expression of Its Three Sulfide-Quinone Reductase Homologs
Authors: Han Yuchen , Perner Mirjam 
Published: February 2016

ABSTRACTSulfurimonas denitrificansis a sulfur-oxidizing epsilonproteobacterium. It has been reported to grow with sulfide and to harbor genes that encode sulfide-quinone reductases (SQRs) (catalyze sulfide oxidation). However, the actual sulfide concentrations at whichS. denitrificansgrows and whether its SQRs are functional remain enigmatic. Here, we illustrate the sulfide concentrations at whichS. denitrificansexhibits good growth, namely, 0.18 mM to roughly 1.7 mM. Around 2.23 mM, sulfide appears to inhibit growth.S. denitrificansharbors three SQR homolog genes on its genome (Suden_2082 for type II SQR, Suden_1879 for type III SQR, and Suden_619 for type IV SQR). They are all transcribed inS. denitrificans. According to our experiments, they appear to be loosely bound to the membrane. Each individualS. denitrificansSQR was heterologously expressed in theRhodobacter capsulatusSB1003sqrdeletion mutant, and all exhibited SQR activities individually. This suggests that all of these three genes encode functional SQRs. This study also provides the first experimental evidence of a functional bacterial type III SQR.IMPORTANCEAlthough the epsilonproteobacteriumSulfurimonas denitrificanshas been described as using many reduced sulfur compounds as electron donors, there is little knowledge about its growth with sulfide. In many bacteria, the sulfide-quinone reductase (SQR) is responsible for catalyzing sulfide oxidation.S. denitrificanshas an array of different types ofsqrgenes on its genome and so do several other sulfur-oxidizingEpsilonproteobacteria. However, whether these SQRs are functional has remained unknown. Here, we shed light on sulfide metabolism inS. denitrificans. Our study provides the first experimental evidence of active epsilonproteobacterial SQRs and also gives the first report of a functional bacterial type III SQR.
Different Functions of Phylogenetically Distinct Bacterial Complex I Isozymes
Authors: Spero Melanie A. , Brickner Joshua R. , Mollet Jordan T. , Pisithkul Tippapha , Amador-Noguez Daniel , Donohue Timothy J. 
Published: February 2016

ABSTRACT

NADH:quinone oxidoreductase (complex I) is a bioenergetic enzyme that transfers electrons from NADH to quinone, conserving the energy of this reaction by contributing to the proton motive force. While the importance of NADH oxidation to mitochondrial aerobic respiration is well documented, the contribution of complex I to bacterial electron transport chains has been tested in only a few species. Here, we analyze the function of two phylogenetically distinct complex I isozymes in
Rhodobacter sphaeroides
, an alphaproteobacterium that contains well-characterized electron transport chains. We found that
R. sphaeroides
complex I activity is important for aerobic respiration and required for anaerobic dimethyl sulfoxide (DMSO) respiration (in the absence of light), photoautotrophic growth, and photoheterotrophic growth (in the absence of an external electron acceptor). Our data also provide insight into the functions of the phylogenetically distinct
R. sphaeroides
complex I enzymes (complex I
A
and complex I
E
) in maintaining a cellular redox state during photoheterotrophic growth. We propose that the function of each isozyme during photoheterotrophic growth is either NADH synthesis (complex I
A
) or NADH oxidation (complex I
E
). The canonical alphaproteobacterial complex I isozyme (complex I
A
) was also shown to be important for routing electrons to nitrogenase-mediated H
2
production, while the horizontally acquired enzyme (complex I
E
) was dispensable in this process. Unlike the singular role of complex I in mitochondria, we predict that the phylogenetically distinct complex I enzymes found across bacterial species have evolved to enhance the functions of their respective electron transport chains.

IMPORTANCE
Cells use a proton motive force (PMF), NADH, and ATP to support numerous processes. In mitochondria, complex I uses NADH oxidation to generate a PMF, which can drive ATP synthesis. This study analyzed the function of complex I in bacteria, which contain more-diverse and more-flexible electron transport chains than mitochondria. We tested complex I function in
Rhodobacter sphaeroides
, a bacterium predicted to encode two phylogenetically distinct complex I isozymes.
R. sphaeroides
cells lacking both isozymes had growth defects during all tested modes of growth, illustrating the important function of this enzyme under diverse conditions. We conclude that the two isozymes are not functionally redundant and predict that phylogenetically distinct complex I enzymes have evolved to support the diverse lifestyles of bacteria.
Randomised controlled trial of topical kanuka honey for the treatment of acne
Authors: Semprini Alex , Braithwaite Irene , Corin Andrew , Sheahan Davitt , Tofield Christopher , Helm Colin , Montgomery Barney , Fingleton James , Weatherall Mark , Beasley Richard 
Published: February 2016

ObjectiveTo investigate the efficacy of Honevo, a topical 90% medical-grade kanuka honey, and 10% glycerine (honey product) as a treatment for facial acne.DesignRandomised controlled trial with single blind assessment of primary outcome variable.SettingOutpatient primary care from 3 New Zealand localities.ParticipantsOf 136 participants aged between 16 and 40 years with a diagnosis of acne and baseline Investigator's Global Assessment (IGA) for acne score of ≥2.68, participants were randomised to each treatment arm.InterventionsAll participants applied Protex, a triclocarban-based antibacterial soap twice daily for 12 weeks. Participants randomised to the honey product treatment arm applied this directly after washing off the antibacterial soap, twice daily for 12 weeks.Outcome measuresThe primary outcome was ≥2 point decrease in IGA score from baseline at 12 weeks. Secondary outcomes included mean lesion counts and changes in subject-rated acne improvement and severity at weeks 4 and 12, and withdrawals for worsening acne.Results4/53 (7.6%) participants in the honey product group and 1/53 (1.9%) of participants in the control group had a ≥ 2 improvement in IGA score at week 12, compared with baseline, OR (95% CI) for improvement 4.2 (0.5 to 39.3), p=0.17. There were 15 and 14 participants who withdrew from the honey product group and control group, respectively.ConclusionsThis randomised controlled trial did not find evidence that addition of medical-grade kanuka honey in combination with 10% glycerine to standard antibacterial soap treatment is more effective than the use of antibacterial soap alone in the treatment of acne.Trial registration numberACTRN12614000003673; Results.
Secular trends in smoking during pregnancy according to income and ethnic group: four population-based perinatal surveys in a Brazilian city
Authors: Silveira Mariangela F , Matijasevich Alicia , Menezes Ana Maria B , Horta Bernardo L , Santos Ina S , Barros Aluisio J D , Barros Fernando C , Victora Cesar G 
Published: February 2016

ObjectivesTo assess socioeconomic and ethnic inequalities in smoking during pregnancy over three decades (1982–2011).SettingPopulation-based study in Pelotas City, Brazil.ParticipantsAll urban women giving birth in the city hospitals in 1982 (5909), 1993 (5223) and 2004 (4201), plus all urban and rural women delivering from January 2011 to April 2012 (6275).Primary outcomeSelf-reported smoking during pregnancy.ResultsThe prevalence of smoking during pregnancy fell from 35.7% in 1982 to 21.0% in 2011. In each survey, prevalence decreased with increasing income (p<0.001). In the poorest quintile, smoking fell by 27.4% in the period studied compared to 67.1% in the wealthiest quintile. In all surveys, prevalence was lower among white women than among those who classified themselves as black or brown (p<0.001). Over time, smoking declined by 50.0% among the former and 30.7% among the latter. Absolute and relative inequalities both increased over time.ConclusionsThe reduction in smoking during pregnancy was primarily due to a decline among white, high-income women. Further efforts are needed to reduce smoking among all population groups.
Does T wave inversion in lead aVL predict mid-segment left anterior descending lesions in acute coronary syndrome? A retrospective study
Authors: Nakanishi Nobuto , Goto Tadahiro , Ikeda Tomoya , Kasai Atsunobu 
Published: February 2016

ObjectivesLimited data are available regarding the predictive value of electrocardiographic T wave inversion in lead aVL for mid-segment left anterior descending (MLAD) lesions among patients with acute coronary syndrome (ACS).SettingRetrospective single-centre study, using a prospectively-collected coronary angiography database from January 2012 to December 2013.ParticipantsWe included consecutive adult patients with ACS who underwent urgent percutaneous coronary intervention (PCI) within 24 h after arriving at the hospital. We excluded patients who did not undergo an ECG before PCI, patients with proximal MLAD occlusion and patients diagnosed with vasospastic angina.Primary and secondary outcome measuresThe primary outcome was MLAD lesion >50%. The other outcome of interest was MLAD lesion as a cause of ACS. First, we evaluated the diagnostic values of T wave inversion in lead aVL regardless of other T wave changes for each outcome. Second, we evaluated the diagnostic values of isolated T wave inversion in lead aVL.ResultsOverall, 219 patients were eligible for the analysis. T wave inversion in lead aVL regardless of other T wave changes had a sensitivity of 32.9%, specificity of 48.2%, positive predictive value of 27.6% and negative predictive value of 54.5% for predicting MLAD lesions. Isolated T wave inversion in lead aVL had a sensitivity of 9.8%, specificity of 86.9%, positive predictive value of 30.8% and negative predictive value of 61.7% for predicting MLAD lesions. These diagnostic values did not change materially when focusing on patients with MLAD lesion as the cause.ConclusionsWhile T wave inversion in lead aVL regardless of other T wave changes had low diagnostic values for predicting MLAD lesions, isolated T wave inversion in lead aVL had a high specificity. Our inferences underscore the importance of a cautious interpretation of T wave inversion in lead aVL among patients with ACS.
Compression-only cardiopulmonary resuscitation in improving bystanders’ cardiopulmonary resuscitation performance: a literature review
Authors: Min Ko Rachel Jia , Wu Vivien Xi , Lim Swee Han , San Tam Wilson Wai , Liaw Sok Ying 
Published: February 2016

BackgroundCompression-only cardiopulmonary resuscitation (CPR) has been advocated as a preferable approach for bystanders in an out-of-hospital cardiac arrest (OHCA) event as it has been associated with an increased chance of survival. The elimination of mouth-to-mouth ventilation also addresses some of the barriers to performing CPR. The aim of this study is to undertake a literature review investigating the effectiveness of compression-only CPR in improving rescuers’ CPR performance when compared with standard CPR.MethodsA literature search was conducted in the following databases: Cumulative Index to Nursing and Allied Health Literature, Science Direct, Scopus and PubMed from January 2003 to January 2014, to include research studies that compared compression-only CPR with standard CPR on participants above the age of 21, and reported quality of CPR performance as the primary outcome.FindingsOf the 3004 articles retrieved, 16 met the inclusion criteria. The reviewed studies revealed that compression-only CPR requires a shorter time to initiate CPR and delivers a higher number of total compressions. The depth of compressions in compression-only CPR performed may be shallower than that of standard CPR due to greater rescuer fatigue. It therefore remains inconclusive if compression-only CPR can deliver a higher number of adequate compressions over extended periods of time. It is also unclear if simplified CPR can improve skill retention level in the long run.ConclusionsMore studies are needed to determine whether compression-only CPR can indeed help improve rescuers’ CPR performance. Future research efforts, together with resuscitation policy and practice implications, are needed to further improve rescuers’ CPR performance with the ultimate goal to enhance OHCA survival rates.
Cystine Deprivation Triggers Programmed Necrosis in VHL-Deficient Renal Cell Carcinomas
Authors: Tang Xiaohu , Wu Jianli , Ding Chien-Kuang , Lu Min , Keenan Melissa M. , Lin Chao-Chieh , Lin Chih-An , Wang Charles C. , George Daniel , Hsu David S. , Chi Jen-Tsan 
Published: February 2016

Abstract
Oncogenic transformation may reprogram tumor metabolism and render cancer cells addicted to extracellular nutrients. Deprivation of these nutrients may therefore represent a therapeutic opportunity, but predicting which nutrients cancer cells become addicted remains difficult. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear cell renal cancer cells (ccRCC), with or without VHL, upon the deprivation of individual amino acids. We found that cystine deprivation triggered rapid programmed necrosis in VHL-deficient cell lines and primary ccRCC tumor cells, but not in VHL-restored counterparts. Blocking cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status, suggesting that metabolic responses alone are not sufficient to explain the observed distinct fates of VHL-deficient and restored cells. Instead, we found that increased levels of TNFα associated with VHL loss forced VHL-deficient cells to rely on intact RIPK1 to inhibit apoptosis. However, the preexisting elevation in TNFα expression rendered VHL-deficient cells susceptible to necrosis triggered by cystine deprivation. We further determined that reciprocal amplification of the Src–p38 (MAPK14)–Noxa (PMAIP1) signaling and TNFα–RIP1/3 (RIPK1/RIPK3)–MLKL necrosis pathways potentiated cystine-deprived necrosis. Together, our findings reveal that cystine deprivation in VHL-deficient RCCs presents an attractive therapeutic opportunity that may bypass the apoptosis-evading mechanisms characteristic of drug-resistant tumor cells. Cancer Res; 76(7); 1892–903. ©2016 AACR.