bluuebunny/crossref_metadata_2025 huggingface dataset:
Pacemaker Implantation and Need for Ventricular Pacing during Follow‐Up after Transcatheter Aortic Valve Implantation
Authors: RAMAZZINA CAROLA , KNECHT SVEN , JEGER RABAN , KAISER CHRISTOPH , SCHAER BEAT , OSSWALD STEFAN , STICHERLING CHRISTIAN , KÜHNE MICHAEL
Published: September 2014

Background

To categorize indications of permanent pacemaker (PPM) implantation after transcatheter aortic valve implantation (TAVI), to determine predictors for conduction disturbances and to quantify the need for ventricular pacing during follow‐up.

Method

We studied 97 patients (median age 83 years, 58% female) undergoing TAVI using the Medtronic CoreValve Revalving System (MCRS; Medtronic Inc., Minneapolis, MN, USA) or Edwards‐Sapien Valve (Edwards Lifesciences, Irvine, CA, USA). During follow‐up, no need for ventricular pacing was defined as <1% ventricular pacing and intrinsic 1:1 atrioventricular (AV) conduction.

Results

In the 35 patients (36.1%) undergoing PPM implantation three indication categories were identified: (1) high‐grade AV block (Mobitz 2 or higher), (2) new‐onset left bundle branch block (LBBB) with a prolonged PR interval, and (3) new‐onset LBBB. The only independent predictors of high‐grade AV block were the use of MCRS (odds ratio [OR] 79.25; 95% confidence interval [CI] 4.57–1373.31) and the presence of preprocedural right bundle branch block (OR 81.95; 95% 95% CI 8.72–770.46). Whereas high‐grade AV block resolved only in 17% of cases, none of the patients receiving a PPM due to LBBB with or without PR prolongation required ventricular pacing during follow‐up.

Conclusion

Our findings justify early PPM implantation in patients with high‐grade AV block and may suggest a more conservative approach to PPM implantation in patients with new‐onset LBBB after TAVI.
Effect of Cardiac Rehabilitation in Patients with ICD: Are Gender Differences Present? Results from the COPE‐ICD Trial
Authors: CHRISTENSEN ANNE VINGGAARD , ZWISLER ANN‐DORTHE , SVENDSEN JESPER HASTRUP , PEDERSEN PREBEN ULRICH , BLUNK LOUISE , THYGESEN LAU CASPAR , BERG SELINA KIKKENBORG
Published: September 2014

Background

The COPE‐ICD (Copenhagen Outpatient ProgrammE‐implantable cardioverter defibrillator) trial studied comprehensive cardiac rehabilitation for patients with ICDs. The purpose of this paper was to explore: (1) gender differences in self‐rated health and quality of life (QoL) at hospital discharge after ICD implantation, (2) gender differences in effect of cardiac rehabilitation, and (3) predictors of effect of cardiac rehabilitation.

Methods

Patients with first‐time ICD implantation were randomized to comprehensive cardiac rehabilitation versus usual care. Gender differences in self‐rated health and QoL and effect of rehabilitation were tested using t‐tests. Predictors of effect of rehabilitation were tested using logistic regression.

Results

A total of 196 patients (mean age 58 ± 13 years; 155 men, 41 women) were included. At hospital discharge, significant differences were found in physical component scale, mental component scale, social functioning, physical functioning, bodily pain, vitality, mental health, and QoL with men having higher scores. Among men only, significant differences were found in VO2 (rehabilitation: 20.9 mL/min/kg [standard deviation (SD) 8.1] vs 23.4 mL/min/kg [SD 9.5] and usual care: 22.1 mL/min/kg [SD 8.1] vs 21.8 mL/min/kg [SD 8.3], P = 0.01), total exercise time (rehabilitation: 587.0 seconds [SD 249.6] vs 650.7 seconds [SD 279.8] and usual care: 613.8 seconds [SD 264.7] vs 606.1 seconds [SD 277.3], P = 0.01), and the mental component scale (rehabilitation: 47.7 points [SD 10.1] vs 54.8 points [7.1] and usual care: 48.1 points [SD 10.9] vs 51.9 points [SD 9.6], P = 0.05).

Conclusions

After ICD implantation, significant gender differences were found in physical health, mental health, and QoL. Effects of rehabilitation were found among men only and gender predicted effect of rehabilitation on the mental component scale.
The Impact of Changing Antiseptic Skin Preparation Agent used for Cardiac Implantable Electronic Device (CIED) Procedures on the Risk of Infection
Authors: QINTAR MOHAMMED , ZARDKOOHI OMEED , HAMMADAH MUHAMMAD , HSU AMY , WAZNI OUSSAMA , WILKOFF BRUCE L. , TARAKJI KHALDOUN G.
Published: September 2014

Background

Cardiac implantable electronic device (CIED) infection is a major complication that is associated with increased morbidity and mortality. Recent data suggested a relationship between the antiseptic agent used for skin preparation at time of CIED procedure and risk for infection.

Methods

On April 30, 2011, we changed the antiseptic agent used for skin preparation at our tertiary care facility from chlorhexidine‐alcohol to povidone‐iodine for all CIED procedures. We retrospectively reviewed records of all patients who underwent CIED procedure 1 year before and after the change. CIED infection was defined as pocket or endovascular systemic infection that required removal within 1 year of the index procedure. We examined if the change affected the risk of CIED infection.

Results

A total of 2,792 patients underwent 2,840 CIED procedures; 1,748 (61.5%) had implantable cardioverter defibrillator procedures and 1,092 (38.4%) had permanent pacemaker procedures. Chlorhexidine‐alcohol agent was used in 1,450 (51.1%) procedures, and povidone‐iodine agent was used in 1,390 (48.9%). After 1 year of follow‐up, 31 patients (1.09%) developed CIED infection that required system removal. The 1‐year infection rate was 1.1% among both antiseptic agent groups and there were no significant differences in the infection presentations among both groups (P = 0.950). Multivariate Cox proportional hazards regression model showed that risk factors for infection within 1 year included age, diabetes, and African American race.

Conclusion

In one large cohort of patients undergoing CIED procedures, the antiseptic agent used for skin preparation (chlorhexidine‐alcohol vs povidone‐iodine) was not associated with increased risk of developing CIED infection.
Sevoflurane anesthesia and brain perfusion
Authors: Rhondali Ossam , Pouyau Agnès , Mahr Aurélie , Juhel Simon , De Queiroz Mathilde , Rhzioual‐Berrada Khalid , Mathews Sylvain , Chassard Dominique
Published: September 2014

Objective/Aim

To assess the impact of sevoflurane and anesthesia‐induced hypotension on brain perfusion in children younger than 6 months.

Background

Safe lower limit of blood pressure during anesthesia in infant is unclear, and inadequate anesthesia can lead to hypotension, hypocapnia, and low cerebral perfusion. Insufficient cerebral perfusion in infant during anesthesia is an important factor of neurological morbidity. In two previous studies, we assessed the impact of sevoflurane anesthesia on cerebral blood flow (CBF) by transcranial Doppler (TCD) and on brain oxygenation by NIRS, in children ≤2 years. As knowledge about consequences of anesthesia‐induced hypotension on cerebral perfusion in children ≤6 months is scarce, we conducted a retrospective analysis to compare the data of CBF and brain oxygenation, in this specific population.

Methods

We performed a retrospective analysis of data collected from our two previous studies. Baseline values of TCD or NIRS were recorded and then during sevoflurane anesthesia. From a database of 338 patients, we excluded all patients older than 6 months. Then, we compared physiological variables of TCD and NIRS population to ensure that the two groups were comparable. We compared rSO2c and TCD measurements variation according to MAP value during sevoflurane anesthesia, using anova and Student–Newman–Keuls for posthoc analysis.

Results

One hundred and eighty patients were included in the analysis. TCD and NIRS groups were comparable. CBF velocities (CBFV) or rSO2c reflects a good cerebral perfusion when MAP is above 45 mmHg. When MAP is between 35 and 45 mmHg, CBFV variation reflects a reduction of CBF, but rSO2c increase is the consequence of a still positive balance between CMRO2 and O2 supply. Below 35 mmHg of MAP during anesthesia, CBFV decrease and rSO2c variation from baseline is low. For each category of MAP and for the two groups, etCo2 and expired fraction of sevoflurane (FeSevo) were comparable (anova P > 0.05).

Conclusion

In a healthy infant without dehydration, with normal PaCO2 and hemoglobin value, scheduled for short procedures, MAP is a good proxy of cerebral perfusion as we found that CBF assessed by CBFV and rSO2c decreased proportionally with cerebral perfusion pressure. During 1 MAC sevoflurane anesthesia, maintaining MAP beyond 35 mmHg during anesthesia is probably safe and sufficient. But when MAP decreases below 35 mmHg, CBF decreases and rSO2c variation from baseline is low despite CMRO2 reduction. In this situation, cerebral metabolic reserve is low and further changes of systemic conditions may be poorly tolerated by the brain.
Procalcitonin as a marker of respiratory disorder in neonates
Authors: Ochi Fumihiro , Higaki Takashi , Ohta Masaaki , Yamauchi Toshifumi , Tezuka Mari , Chisaka Toshiyuki , Moritani Tomozo , Tauchi Hisamichi , Ishii Eiichi
Published: September 2014

Background

Serum procalcitonin (PCT) increases in various respiratory disorders such as acute respiratory distress syndrome. Elevated PCT is also observed in healthy neonates. In this study, we investigated whether PCT is a good marker of respiratory disorder in neonates.

Methods

A total of 155 neonates with or without respiratory disorder, were eligible for the study. PCT was measured on electrochemiluminescence immunoassay. Each neonate was allocated to the non‐respiratory disorder (control) group (n = 95), or a respiratory disorder group (n = 60). PCT was compared between the groups, and association with other markers, including C‐reactive protein (CRP) and white blood cell (WBC) count, was analyzed.

Results

Of the 60 neonates in the respiratory disorder group, 39, 10, five, one, two, two, and one neonates had transient tachypnea of the newborn, respiratory distress syndrome, air leak syndrome, meconium aspiration syndrome, 18‐trisomy, neonatal asphyxia, and congenital diaphragmatic hernia, respectively. Mean PCT, CRP and WBC count in the respiratory disorder group were 9.01 ng/mL, 0.26 mg/dL, and 16 100 cells/μL, respectively. The area under the curve obtained for PCT in distinguishing between the respiratory disorder and control groups was 0.85 (sensitivity, 66.7%; specificity, 93.0%; optimum cut‐off, 3.73 ng/mL), that for CRP was 0.72 (sensitivity, 75.0%; specificity, 64.6%; optimum cut‐off, 0.14 mg/dL), and for WBC it was 0.44 (sensitivity, 60.0%; specificity, 29.6%; optimum cut‐off, 15 000 cells/μL).

Conclusions

PCT is more susceptible, as a diagnostic parameter of infection, to the effect of respiratory disturbance than CRP and WBC.
Evidence for two predominant viral lineages, recombination and subpopulation structure in begomoviruses associated with yellow vein mosaic disease of okra in India
Authors: Venkataravanappa V. , Prasanna H. C. , Lakshminarayana Reddy C. N. , Krishna Reddy M.
Published: September 2014

Yellow vein mosaic disease (YVMD) caused by whitefly‐transmitted begomoviruses is an economically significant viral disease of okra. In this study, a survey of begomoviruses associated with YVMD was carried out in eight states and two union territories of India. A total of 92 full‐length DNA‐A components were sequenced and characterized. Sequence comparisons and population structure analysis revealed the existence of four begomovirus species. Two novel species were detected with several recombinationally derived genome fragments that probably originated from begomoviruses known to infect malvaceous and non‐malvaceous hosts. Among the four species, Bhendi yellow vein Maharastra virus (BYVMaV) and Bhendi yellow vein Madurai virus (BYVMV) were found to be predominant in okra, with BYVMV having a pan‐India distribution. There was evidence for a high degree of genetic variability and subpopulation structure within these four species. Neutrality tests suggested the occurrence of purifying selection acting upon these populations. The results of the current study have uncovered the diversity and genetic structure of okra‐infecting begomoviruses in India and generated potentially useful information for developing management strategies for YVMD.
Litter Fall Dynamics of Restored Mangroves (Rhizophora mucronata Lamk. and Sonneratia alba Sm.) in Kenya
Authors: Wang'ondu Virginia W. , Bosire Jared O. , Kairo James G. , Kinyamario Jenesio I. , Mwaura Francis B. , Dahdouh‐Guebas Farid , Koedam Nico
Published: September 2014

Mangrove forests are active carbon sinks and important for nutrient cycling in coastal ecosystems. Restoration of degraded mangrove habitats enhances return of ecosystem goods and services, including carbon sequestration. Our objective was to assess the restoration of primary productivity of reforested mangrove stands in comparison with natural reference stands in Gazi Bay, Kenya. Litter fall data were collected in nine Rhizophora mucronata and Sonneratia alba monospecific stands by use of litter traps over 2 years. Litter was emptied monthly, dried, sorted, and weighed. The reforested and natural stands showed seasonality patterns only in the production of reproductive material. Leaves constituted the highest percentage to total litter fall. Litter productivity rates for the R. mucronata stands were not significantly different and ranged from 6.61–10.15 to 8.36–11.02 t ha−1 yr−1 for the restored and natural stands, respectively. The productivity of 5 years R. mucronata stands reached 5.22 t ha−1 yr−1 and was significantly different from other stands. Litter productivity rates for S. alba stands was 7.77–7.85 for the restored stands and 10.15 t ha−1 yr−1 for the natural stand but differences were not significant. Our results indicate that plantations of at least 11 years have attained litter productivity rates comparable to the natural forests. This suggests that productivity of replanted mangroves is likely to reach complete recovery by this age under the prevailing environmental conditions.
Suicide Prevention in Australian Aboriginal Communities: A Review of Past and Present Programs
Authors: Ridani Rebecca , Shand Fiona L. , Christensen Helen , McKay Kathryn , Tighe Joe , Burns Jane , Hunter Ernest
Published: September 2014

A review of Aboriginal suicide prevention programs were conducted to highlight promising projects and strategies. A content analysis of gray literature was conducted to identify interventions reported to have an impact in reducing suicidal rates and behaviors. Most programs targeted the whole community and were delivered through workshops, cultural activities, or creative outlets. Curriculums included suicide risk and protective factors, warning signs, and mental health. Many programs were poorly documented and evaluations did not include suicidal outcomes. Most evaluations considered process variables. Results from available outcome evaluations suggest that employing a whole of community approach and focusing on connectedness, belongingness and cultural heritage may be of benefit. Despite the challenges, there is a clear need to evaluate outcomes if prevention is to be progressed.
Changing Behaviours, Improving Outcomes? Governing Healthy Lifestyles Through Social Marketing
Authors: Crawshaw Paul
Published: September 2014

Recent public health policy and practice in the UK and beyond has promoted behavioural and lifestyle change as key methods for health improvement and the reduction of inequalities. These methods contrast with more upstream and structural interventions intended to address environmental and material determinants of health. A current exemplar of this approach is the use of social marketing. These changes represent a shift from the social to the individual as the target of public health interventions and raise a number of critical questions for health social scientists concerned not only with health improvement but also equity and social justice. Further, they can be identified as part of broader social and economic shifts that posit the individual as responsible for the management of their own bodies and selves in late modern societies characterised by ‘government at a distance’ and the repeal of welfare. This paper offers a review of shifting paradigms of public health and considers the implications of newer modes of health governance such as social marketing and their role as a modern form of health governance.
Short‐beam Shear Method for Assessment of Stress–Strain Curves for Fibre‐reinforced Polymer Matrix Composite Materials
Authors: Makeev A. , He Y. , Schreier H.
Published: September 2014

This work presents a thorough description of a short‐beam shear (SBS) test method coupled with digital image correlation (DIC) for the measurement of shear stress–strain curves of polymer matrix composites. The method provides a time‐ and cost‐effective alternative to established methods, and the authors hope this work can serve as a starting point for discussions on the developments of new standards for the characterisation of shear stress–strain curves for composites. The experimental set‐up, including several modifications to the American Society of Testing and Materials current standard configuration, is described. Implementation of the DIC technique to obtain accurate surface strain in the SBS specimens is also presented. Accuracy of beam theory‐based shear stress calculation is assessed using a non‐linear finite element model (FEM). A simple means to improve the accuracy of the closed‐form shear stress approximation is provided. Glass/epoxy and carbon/epoxy composite material systems are used to demonstrate the developed method. Strain surveys are conducted to compare the experimentally generated and FEM‐computed strain fields and verify the accuracy of the shear stress–strain curves. Shear stress–strain response generated from SBS tests is also compared with V‐notched beam test results for further verification.
Systemic delivery of siRNA in pumpkin by a plant PHLOEM SMALL RNA‐BINDING PROTEIN 1–ribonucleoprotein complex
Authors: Ham Byung‐Kook , Li Gang , Jia Weitao , Leary Julie A. , Lucas William J.
Published: September 2014

In plants, the vascular system, specifically the phloem, functions in delivery of small RNA (sRNA) to exert epigenetic control over developmental and defense‐related processes. Although the importance of systemic sRNA delivery has been established, information is currently lacking concerning the nature of the protein machinery involved in this process. Here, we show that a PHLOEM SMALL‐RNA BINDING PROTEIN 1 (PSRP1) serves as the basis for formation of an sRNA ribonucleoprotein complex (sRNPC) that delivers sRNA (primarily 24 nt) to sink organs. Assembly of this complex is facilitated through PSRP1 phosphorylation by a phloem‐localized protein kinase, PSRPK1. During long‐distance transport, PSRP1–sRNPC is stable against phloem phosphatase activity. Within target tissues, phosphatase activity results in disassembly of PSRP1–sRNPC, a process that is probably required for unloading cargo sRNA into surrounding cells. These findings provide an insight into the mechanism involved in delivery of sRNA associated with systemic gene silencing in plants.
ADC texture—An imaging biomarker for high‐grade glioma?
Authors: Brynolfsson Patrik , Nilsson David , Henriksson Roger , Hauksson Jón , Karlsson Mikael , Garpebring Anders , Birgander Richard , Trygg Johan , Nyholm Tufve , Asklund Thomas
Published: September 2014

Purpose:

Survival for high‐grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion‐weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers.

Methods:

Twenty‐three consecutive high‐grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1‐weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray‐level co‐occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression.

Results:

The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001.

Conclusions:

By combining PCA and texture analysis, ADC texture characteristics were identified, which seems to hold pretreatment prognostic information, independent of known prognostic factors such as age, stage, and surgical procedure. These findings encourage further studies with a larger patient cohort.
The Teacher Benefits From Giving Autonomy Support During Physical Education Instruction
Authors: Cheon Sung Hyeon , Reeve Johnmarshall , Yu Tae Ho , Jang Hue Ryen
Published: September 2014

Recognizing that students benefit when they receive autonomy-supportive teaching, the current study tested the parallel hypothesis that teachers themselves would benefit from giving autonomy support. Twenty-seven elementary, middle, and high school physical education teachers (20 males, 7 females) were randomly assigned either to participate in an autonomy-supportive intervention program (experimental group) or to teach their physical education course with their existing style (control group) within a three-wave longitudinal research design. Manipulation checks showed that the intervention was successful, as students perceived and raters scored teachers in the experimental group as displaying a more autonomy-supportive and less controlling motivating style. In the main analyses, ANCOVA-based repeated-measures analyses showed large and consistent benefits for teachers in the experimental group, including greater teaching motivation (psychological need satisfaction, autonomous motivation, and intrinsic goals), teaching skill (teaching efficacy), and teaching well-being (vitality, job satisfaction, and lesser emotional and physical exhaustion). These findings show that giving autonomy support benefits teachers in much the same way that receiving it benefits their students.
Cognitive Fatigue Effects on Physical Performance During Running
Authors: MacMahon Clare , Schücker Linda , Hagemann Norbert , Strauss Bernd
Published: September 2014

This study investigated the effect of cognitive fatigue on physical performance in a paced running task. Experienced runners (n = 20) performed two 3,000-m runs on an indoor track, once after cognitive fatigue, and once under nonfatigued conditions. Completion times were significantly slower in the cognitive fatigue condition (M = 12:11,88 min, SD = 0:54,26), compared with the control condition (M = 11:58,56 min, SD = 0:48,39), F(1, 19) = 8.58, p = .009, eta2p = .31. There were no differences in heart rate, t(17) = 0.13, p > .05, blood lactate levels, t(19) = 1.19, p > .05, or ratings of perceived exertion F(1, 19) = .001, p 3 .05. While previous research has examined the impact of cognitive tasks on physical tasks, this is the first study to examine a self-paced physical task, showing that cognitive activity indeed contributes significantly to overall performance. Specifically, cognitive fatigue increased the perception of exertion, leading to lesser performance on the running task.
Impact of Antibiotics with Various Target Sites on the Metabolome of Staphylococcus aureus
Authors: Dörries Kirsten , Schlueter Rabea , Lalk Michael
Published: September 2014

In this study, global intra- and extracellular metabolic profiles were exploited to investigate the impact of antibiotic compounds with different cellular targets on the metabolome of
Staphylococcus aureus
HG001. Primary metabolism was largely covered, yet uncommon staphylococcal metabolites were detected in the cytosol of
S. aureus
, including sedoheptulose-1,7-bisphosphate and the UDP-MurNAc-pentapeptide with an alanine-seryl residue. By comparing the metabolic profiles of unstressed and stressed staphylococcal cells in a time-dependent manner, we found far-ranging effects within the metabolome. For each antibiotic compound, accumulation as well as depletion of metabolites was detected, often comprising whole biosynthetic pathways, such as central carbon and amino acid metabolism and peptidoglycan, purine, and pyrimidine synthesis. Ciprofloxacin altered the pool of (deoxy)nucleotides as well as peptidoglycan precursors, thus linking stalled DNA and cell wall synthesis. Erythromycin tended to increase the amounts of intermediates of the pentose phosphate pathway and lysine. Fosfomycin inhibited the first enzymatic step of peptidoglycan synthesis, which was followed by decreased levels of peptidoglycan precursors but enhanced levels of substrates such as UDP-GlcNAc and alanine-alanine. In contrast, vancomycin and ampicillin inhibited the last stage of peptidoglycan construction on the outer cell surface. As a result, the amounts of UDP-MurNAc-peptides drastically increased, resulting in morphological alterations in the septal region and in an overall decrease in central metabolite levels. Moreover, each antibiotic affected intracellular levels of tricarboxylic acid cycle intermediates.
In Vivo
Efficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates
Authors: MacVane Shawn H. , Crandon Jared L. , Nichols Wright W. , Nicolau David P.
Published: September 2014

Ceftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of the
in vivo
efficacy of the combination against these targeted ceftazidime- and carbapenem-resistant
Enterobacteriaceae
. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam against
Enterobacteriaceae
exhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinical
Enterobacteriaceae
isolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log
10
CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against the
Enterobacteriaceae
isolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [
f
T
>MIC
] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (
f
T
>MIC
of 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistant
Enterobacteriaceae
.
HIV-1 Group O Integrase Displays Lower Enzymatic Efficiency and Higher Susceptibility to Raltegravir than HIV-1 Group M Subtype B Integrase
Authors: Depatureaux Agnès , Quashie Peter K. , Mesplède Thibault , Han Yingshan , Koubi Hannah , Plantier Jean-Christophe , Oliveira Maureen , Moisi Daniela , Brenner Bluma , Wainberg Mark A.
Published: September 2014

HIV-1 group O (HIV-O) is a rare HIV-1 variant characterized by a high number of polymorphisms, especially in the integrase coding region. As HIV-O integrase enzymes have not previously been studied, our aim was to assess the impact of HIV-O integrase polymorphisms on enzyme function and susceptibility to integrase inhibitors. Accordingly, we cloned and purified integrase proteins from each of HIV-1 group O clades A and B, an HIV-O divergent strain, and HIV-1 group M (HIV-M, subtype B), used as a reference. To assess enzymatic function of HIV-O integrase, we carried out strand transfer and 3′ processing assays with various concentrations of substrate (DNA target and long terminal repeats [LTR], respectively) and characterized these enzymes for susceptibility to integrase strand transfer inhibitors (INSTIs) in cell-free assays and in tissue culture, in the absence or presence of various concentrations of several INSTIs. The inhibition constant (Ki) and 50% effective concentration (EC50) values were calculated for HIV-O integrases and HIV-O viruses, respectively, and compared with those of HIV-M. The results showed that HIV-O integrase displayed lower activity in strand transfer assays than did HIV-M enzyme, whereas 3′ processing activities were similar to those of HIV-M. HIV-O integrases were more susceptible to raltegravir (RAL) in competitive inhibition assays and in tissue culture than were HIV-M enzymes and viruses, respectively. Molecular modeling suggests that two key polymorphic residues that are close to the integrase catalytic site, 74I and 153A, may play a role in these differences.
Inflammation Is Associated with Voriconazole Trough Concentrations
Authors: van Wanrooy Marjolijn J. P. , Span Lambert F. R. , Rodgers Michael G. G. , van den Heuvel Edwin R. , Uges Donald R. A. , van der Werf Tjip S. , Kosterink Jos G. W. , Alffenaar Jan-Willem C.
Published: September 2014

Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. Inflammation may be a contributing factor, as inflammatory stimuli can change the activities and expression levels of cytochrome P450 isoenzymes. We explored the correlation between inflammation, reflected by C-reactive protein (CRP) concentrations, and voriconazole trough concentrations. A retrospective chart review of patients with at least one steady-state voriconazole trough concentration and a CRP concentration measured on the same day was performed. A total of 128 patients were included. A significantly (
P
< 0.001) higher voriconazole trough concentration was observed in patients with severe inflammation (6.2 mg/liter; interquartile range [IQR], 3.4 to 8.7 mg/liter;
n
= 20) than in patients with moderate inflammation (3.4 mg/liter; IQR, 1.6 to 5.4 mg/liter;
n
= 60) and in patients with no to mild inflammation (1.6 mg/liter; IQR, 0.8 to 3.0 mg/liter;
n
= 48). The patients in all three groups received similar voriconazole doses based on mg/kg body weight (
P
= 0.368). Linear regression analyses, both unadjusted and adjusted for covariates of gender, age, dose, route of administration, liver enzymes, and interacting coadministered medications, showed a significant association between voriconazole and CRP concentration (
P
< 0.001). For every 1-mg/liter increase in the CRP concentration, the voriconazole trough concentration increased by 0.015 mg/liter (unadjusted 95% confidence interval [CI], 0.011 to 0.020 mg/liter; adjusted 95% CI, 0.011 to 0.019 mg/liter). Inflammation, reflected by the C-reactive protein concentration, is associated with voriconazole trough concentrations. Further research is necessary to assess if taking the inflammatory status of a patient into account is helpful in therapeutic drug monitoring of voriconazole to maintain concentrations in the therapeutic window, thereby possibly preventing suboptimal treatment or adverse events.
Effect of Ceftriaxone on the Outcome of Murine Pyelonephritis Caused by Extended-Spectrum-β-Lactamase-Producing Escherichia coli
Authors: Tratselas A. , Simitsopoulou M. , Giannakopoulou A. , Dori I. , Saoulidis S. , Kollios K. , Papaioannidou P. , Pournaras S. , Roilides E.
Published: September 2014

Urinary tract infections (UTIs) due to extended-spectrum-β-lactamase (ESBL)-producing
Enterobacteriaceae
in children are becoming more frequent, and they are commonly treated initially with a second- or third-generation cephalosporin. We developed a murine model of ascending UTI caused by ESBL-producing
Escherichia coli
. Using this model, we investigated the renal bacterial burden, interleukin-6 (IL-6) expression, and histopathological alterations caused by ESBL- and non-ESBL-producing bacteria after 1, 2, or 6 days with or without ceftriaxone therapy. The renal bacterial burden, IL-6 concentration, and histological inflammatory lesions were not significantly different between mice infected with ESBL- and non-ESBL-producing bacteria without treatment at any of the time points examined. Following ceftriaxone administration, the bacterial burden was eliminated in the kidneys of mice infected with ESBL- and non-ESBL-producing bacteria on the 6th postinfection day. The histological analysis demonstrated that among mice treated with ceftriaxone, those infected with ESBL-producing bacteria had more profound renal alterations than those infected with non-ESBL-producing bacteria on the 6th day (
P
< 0.001). In comparison, microbiological outcomes did not differ significantly between mice infected with ESBL- and non-ESBL-producing bacteria at any of the time points examined. The effectiveness of ceftriaxone in mice with UTIs due to ESBL-producing
E. coli
may have therapeutic implications; it is, however, hampered by limited activity on the histopathological lesions, a finding that needs further investigation.
Cellular Requirements for Systemic Control of Salmonella enterica Serovar Typhimurium Infections in Mice
Authors: Kupz Andreas , Bedoui Sammy , Strugnell Richard A.
Published: September 2014

The rational design of vaccines requires an understanding of the contributions of individual immune cell subsets to immunity. With this understanding, targeted vaccine delivery approaches and adjuvants can be developed to maximize vaccine efficiency and to minimize side effects (S. H. E. Kaufmann et al., Immunity 33:555–577, 2010; T. Ben-Yedidia and R. Arnon, Hum. Vaccines 1:95–101, 2005). We have addressed the contributions of different immune cell subsets and their ability to contribute to the control and clearance of the facultative intracellular pathogenSalmonella entericaserovar Typhimurium (S. Typhimurium) in a murine model. Using a systematic and reproducible model of experimental attenuatedS. Typhimurium infection, we show that distinct lymphocyte deficiencies lead to one of four different infection outcomes: clearance, chronic infection, early death, or late death. Our study demonstrates a high level of functional redundancy in the ability of different lymphocyte subsets to provide interferon gamma (IFN-γ), a critical cytokine inSalmonellaimmunity. Whereas early control of the infection was entirely dependent on IFN-γ but not on any particular lymphocyte subset, clearance of the infection critically required CD4+T cells but appeared to be independent of IFN-γ. These data reinforce the idea of a bimodal immune response againstSalmonella: an early T cell-independent but IFN-γ-dependent phase and a late T cell-dependent phase that may be IFN-γ independent.
Antigenic Variation of TprK Facilitates Development of Secondary Syphilis
Authors: Reid Tara B. , Molini Barbara J. , Fernandez Mark C. , Lukehart Sheila A.
Published: September 2014

Although primary syphilis lesions heal spontaneously, the infection is chronic, with subsequent clinical stages. Healing of the primary chancre occurs as antibodies against outer membrane antigens facilitate opsonophagocytosis of the bacteria by activated macrophages. TprK is an outer membrane protein that undergoes antigenic variation at 7 variable regions, and variants are selected by immune pressure. We hypothesized that individual TprK variants escape immune clearance and seed new disseminated lesions to cause secondary syphilis. As in human syphilis, infected rabbits may develop disseminated secondary skin lesions. This study explores the nature of secondary syphilis, specifically, the contribution of antigenic variation to the development of secondary lesions. Our data from the rabbit model show that the odds of secondary lesions containing predominately TprK variant treponemes is 3.3 times higher than the odds of finding TprK variants in disseminated primary lesions (odds ratio [OR] = 3.3 [95% confidence interval {CI}, 0.98 to 11.0];P= 0.055) and that 96% of TprK variant secondary lesions are likely seeded by single treponemes. Analysis of antibody responses demonstrates significantly higher antibody titers totprKvariable region sequences found in the inoculum compared to reactivity totprKvariant sequences found in newly arising secondary lesions. This suggests thattprKvariants escape the initial immune response raised against the V regions expressed in the inoculum. These data further support a role for TprK in immune evasion and suggest that the ability of TprK variants to persist despite a robust immune response is instrumental in the development of later stages of syphilis.
Enhanced Virulence of the Escherichia coli O157:H7 Spinach-Associated Outbreak Strain in Two Animal Models Is Associated with Higher Levels of Stx2 Production after Induction with Ciprofloxacin
Authors: Zangari T. , Melton-Celsa A. R. , Panda A. , Smith M. A. , Tatarov I. , De Tolla L. , O'Brien A. D.
Published: September 2014

Shiga toxin (Stx)-producing
Escherichia coli
(STEC) causes hemorrhagic colitis and the hemolytic-uremic syndrome (HUS). STEC strains may produce Stx1a and/or Stx2a or variants of either toxin. A 2006 spinach-associated outbreak of STEC O157:H7 resulted in higher hospitalization and HUS rates than previous STEC outbreaks. The spinach isolate, strain K3995, contains both
stx
2a
and
stx
2c
. We hypothesized that the enhanced virulence of K3995 reflects the combination of
stx
2
alleles (carried on lysogenic phages) and/or the amount of Stx2 made by that strain. We compared the virulence of K3995 to those of other O157:H7 isolates and an isogenic Stx2 mutant in rabbits and mice. We also measured the relative levels of Stx2 produced from those strains with or without induction of the
stx
-carrying phage. Some rabbits infected with K3995 exhibited intestinal pathology and succumbed to infection, while none of those infected with O157:H7 strain 2812 (Stx1a
+
Stx2a
+
) died or showed pathological signs. Rabbits infected with the isogenic Stx2a mutant K3995
stx
2a
::
cat
were not colonized as well as those infected with K3995 and exhibited no signs of disease. In the streptomycin-treated mouse model, more animals infected with K3995 died than did those infected with O157:H7 strain 86-24 (Stx2a
+
). Additionally, K3995 produced higher levels of total Stx2 and toxin phage DNA in cultures after phage induction than did 86-24. Our results demonstrate the greater virulence of K3995 compared to other O157:H7 strains in rabbits and mice. We conclude that this enhanced virulence is linked to higher levels of Stx2 expression as a consequence of increased phage induction.
Fasciola hepatica Fatty Acid Binding Protein Induces the Alternative Activation of Human Macrophages
Authors: Figueroa-Santiago Olgary , Espino Ana M.
Published: September 2014

The liver fluke
Fasciola hepatica
is a highly evolved parasite that uses sophisticated mechanisms to evade the host immune response. The immunosuppressive capabilities of the parasite have been associated with antigens secreted through the parasite's tegument, called excretory-secretory products (ESPs). Proteomic studies have identified the fatty acid binding protein (FABP) as one of molecules present in the parasite ESPs. Although FABP has been investigated for potential use in the development of vaccines against fascioliasis, its direct interaction with cells of immune system has not been studied. In this study, FABP was purified in native form from soluble extracts of
F. hepatica
adult flukes using a combination of molecular sieving chromatography and preparative isoelectric focusing. The immunological effect of the purified protein, termed Fh12, was assayed
in vitro
using monocyte-derived macrophages (MDM) obtained from healthy human donors. Results from the assay indicate that Fh12 produced a significantly increased arginase expression and activity and induced the expression of chitinase-3-like protein (CHI3L1). The assay also showed that Fh12 downregulated the production of nitric oxide (NO) and the expression of nitric oxide synthase (NOS2). This indicates that Fh12 induced the production of alternatively activated macrophages (AAMϕ). The results also demonstrated the ability of Fh12 to downregulate the secretion of the proinflammatory and inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and IL-1βB, even after stimulation with lipopolysaccharide (LPS), as well as its ability to stimulate the overexpression of IL-10. These results suggest a potent anti-inflammatory role for Fh12, which could occur via targeting of Toll-like receptor 4 (TLR4).
Sporulation during Growth in a Gut Isolate of Bacillus subtilis
Authors: Serra Cláudia R. , Earl Ashlee M. , Barbosa Teresa M. , Kolter Roberto , Henriques Adriano O.
Published: September 2014

Sporulation by
Bacillus subtilis
is a cell density-dependent response to nutrient deprivation. Central to the decision of entering sporulation is a phosphorelay, through which sensor kinases promote phosphorylation of Spo0A. The phosphorelay integrates both positive and negative signals, ensuring that sporulation, a time- and energy-consuming process that may bring an ecological cost, is only triggered should other adaptations fail. Here we report that a gastrointestinal isolate of
B. subtilis
sporulates with high efficiency during growth, bypassing the cell density, nutritional, and other signals that normally make sporulation a post-exponential-phase response. Sporulation during growth occurs because Spo0A is more active per cell and in a higher fraction of the population than in a laboratory strain. This in turn, is primarily caused by the absence from the gut strain of the genes
rapE
and
rapK
, coding for two aspartyl phosphatases that negatively modulate the flow of phosphoryl groups to Spo0A. We show, in line with recent results, that activation of Spo0A through the phosphorelay is the limiting step for sporulation initiation in the gut strain. Our results further suggest that the phosphorelay is tuned to favor sporulation during growth in gastrointestinal
B. subtilis
isolates, presumably as a form of survival and/or propagation in the gut environment.
Role of Lipase from Community-Associated Methicillin-Resistant Staphylococcus aureus Strain USA300 in Hydrolyzing Triglycerides into Growth-Inhibitory Free Fatty Acids
Authors: Cadieux Brigitte , Vijayakumaran Vithooshan , Bernards Mark A. , McGavin Martin J. , Heinrichs David E.
Published: September 2014

Part of the human host innate immune response involves the secretion of bactericidal lipids on the skin and delivery of triglycerides into abscesses to control invading pathogens. Two

S
taphylococcus
a
ureus

l
ipases, named SAL1 and SAL2, were identified in the community-associated methicillin-resistant
S. aureus
strain USA300, which, presumably, are produced and function to degrade triglycerides to release free fatty acids. We show that the SAL2 lipase is one of the most abundant proteins secreted by USA300 and is proteolytically processed from the 72-kDa proSAL2 to the 44-kDa mature SAL2 by the metalloprotease aureolysin. We show that spent culture supernatants had lipase activity on both short- and long-chain fatty acid substrates and that deletion of
gehB
, encoding SAL2, resulted in the complete loss of these activities. With the use of gas chromatography-mass spectrometry, we show that SAL2 hydrolyzed trilinolein to linoleic acid, a fatty acid with known antistaphylococcal properties. When added to cultures of USA300, trilinolein and, to a lesser extent, triolein inhibited growth in a SAL2-dependent manner. This effect was shown to be due to the enzymatic activity of SAL2 on these triglycerides, since the catalytically inactive SAL2 Ser412Ala mutant was incapable of hydrolyzing the triglycerides or yielding delayed growth in their presence. Overall, these results reveal that SAL2 hydrolyzes triglycerides of both short- and long-chain fatty acids and that the released free fatty acids have the potential to cause significant delays in growth, depending on the chemical nature of the free fatty acid.
Associations between dairy intake and metabolic risk parameters in a healthy French-Canadian population
Authors: Da Silva Marine S. , Julien Pierre , Couture Patrick , Lemieux Simone , Vohl Marie-Claude , Rudkowska Iwona
Published: September 2014

Observational studies support that dairy product intake is associated with a reduced risk of developing type 2 diabetes; however, several clinical studies report conflicting results on the association between dairy product consumption and metabolic parameters. The aim of this study was to determine associations between dairy product consumption and metabolic profile. Dietary data, using a validated food frequency questionnaire, and fasting blood samples were collected from 233 French Canadians. Plasma phospholipid (PL) fatty acids (FA) concentrations were determined by gas chromatography. Subjects consumed 2.5 ± 1.4 portions of dairy products daily, including 1.6 ± 1.3 portions of low-fat (LF) and 0.90 ± 0.70 portions of high-fat (HF) dairy products. Trans-palmitoleic acid level in plasma PL was related to HF dairy consumption (r = 0.15; p = 0.04). Total (r = –0.21; p = 0.001) and LF dairy (r = –0.20; p = 0.003) intakes were inversely correlated with fasting plasma glucose level. Total dairy intake was inversely associated to systolic blood pressure (r = –0.17; p = 0.008) and diastolic blood pressure (r = –0.14; p = 0.03). LF dairy intake was also inversely correlated with systolic blood pressure (r = –0.17; p = 0.009). Total dairy intake was correlated with plasma C-reactive protein (CRP) (r = 0.15; p = 0.03). No association was found between HF dairy consumption and the risk factors studied. In conclusion, dairy intake is inversely associated with glycaemia and blood pressure; yet, it may modify CRP levels. Moreover, trans-palmitoleic FA levels in plasma PL may be potentially used to assess full-fat dairy consumption.