bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly Virulent Non-O157 Enterohemorrhagic Escherichia coli (EHEC) Serotypes Reflect Similar Phylogenetic Lineages, Providing New Insights into the Evolution of EHEC
Authors: Eichhorn Inga , Heidemanns Katrin , Semmler Torsten , Kinnemann Bianca , Mellmann Alexander , Harmsen Dag , Anjum Muna F. , Schmidt Herbert , Fruth Angelika , Valentin-Weigand Peter , Heesemann Jürgen , Suerbaum Sebastian , Karch Helge , Wieler Lothar H.
Published: August 2015

Enterohemorrhagic
Escherichia coli
(EHEC) is the causative agent of bloody diarrhea and extraintestinal sequelae in humans, most importantly hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Besides the bacteriophage-encoded Shiga toxin gene (
stx
), EHEC harbors the locus of enterocyte effacement (LEE), which confers the ability to cause attaching and effacing lesions. Currently, the vast majority of EHEC infections are caused by strains belonging to five O serogroups (the “big five”), which, in addition to O157, the most important, comprise O26, O103, O111, and O145. We hypothesize that these four non-O157 EHEC serotypes differ in their phylogenies. To test this hypothesis, we used multilocus sequence typing (MLST) to analyze a large collection of 250 isolates of these four O serogroups, which were isolated from diseased as well as healthy humans and cattle between 1952 and 2009. The majority of the EHEC isolates of O serogroups O26 and O111 clustered into one sequence type complex, STC29. Isolates of O103 clustered mainly in STC20, and most isolates of O145 were found within STC32. In addition to these EHEC strains, STC29 also included
stx
-negative
E. coli
strains, termed atypical enteropathogenic
E. coli
(aEPEC), yet another intestinal pathogenic
E. coli
group. The finding that aEPEC and EHEC isolates of non-O157 O serogroups share the same phylogeny suggests an ongoing microevolutionary scenario in which the phage-encoded Shiga toxin gene
stx
is transferred between aEPEC and EHEC. As a consequence, aEPEC strains of STC29 can be regarded as post- or pre-EHEC isolates. Therefore, STC29 incorporates phylogenetic information useful for unraveling the evolution of EHEC.
Biosynthesis and Secretion of Indole-3-Acetic Acid and Its Morphological Effects on Tricholoma vaccinum-Spruce Ectomycorrhiza
Authors: Krause Katrin , Henke Catarina , Asiimwe Theodore , Ulbricht Andrea , Klemmer Sandra , Schachtschabel Doreen , Boland Wilhelm , Kothe Erika
Published: August 2015

Fungus-derived indole-3-acetic acid (IAA), which is involved in development of ectomycorrhiza, affects both partners, i.e., the tree and the fungus. The biosynthesis pathway, excretion from fungal hyphae, the induction of branching in fungal cultures, and enhanced Hartig net formation in mycorrhiza were shown. Gene expression studies, incorporation of labeled compounds into IAA, heterologous expression of a transporter, and bioinformatics were applied to study the effect of IAA on fungal morphogenesis and on ectomycorrhiza.
Tricholoma vaccinum
produces IAA from tryptophan via indole-3-pyruvate, with the last step of this biosynthetic pathway being catalyzed by an aldehyde dehydrogenase. The gene
ald1
was found to be highly expressed in ectomycorrhiza and induced by indole-3-acetaldehyde. The export of IAA from fungal cells is supported by the multidrug and toxic extrusion (MATE) transporter Mte1 found in
T. vaccinum
. The addition of IAA and its precursors induced elongated cells and hyphal ramification of mycorrhizal fungi; in contrast, in saprobic fungi such as
Schizophyllum commune
, IAA did not induce morphogenetic changes. Mycorrhiza responded by increasing its Hartig net formation. The IAA of fungal origin acts as a diffusible signal, influencing root colonization and increasing Hartig net formation in ectomycorrhiza.
Exploring Vertical Transmission of Bifidobacteria from Mother to Child
Authors: Milani Christian , Mancabelli Leonardo , Lugli Gabriele Andrea , Duranti Sabrina , Turroni Francesca , Ferrario Chiara , Mangifesta Marta , Viappiani Alice , Ferretti Pamela , Gorfer Valentina , Tett Adrian , Segata Nicola , van Sinderen Douwe , Ventura Marco
Published: August 2015

Passage through the birth canal and consequent exposure to the mother's microbiota is considered to represent the initiating event for microbial colonization of the gastrointestinal tract of the newborn. However, a precise evaluation of such suspected vertical microbiota transmission has yet to be performed. Here, we evaluated the microbiomes of four sample sets, each consisting of a mother's fecal and milk samples and the corresponding infant's fecal sample, by means of amplicon-based profiling supported by shotgun metagenomics data for two key samples. Notably, targeted genome reconstruction from microbiome data revealed vertical transmission of a
Bifidobacterium breve
strain and a
Bifidobacterium longum
subsp.
longum
strain from mother to infant, a notion confirmed by strain isolation and genome sequencing. Furthermore, PCR analyses targeting unique genes from these two strains highlighted their persistence in the infant gut at 6 months. Thus, this study demonstrates the existence of specific bifidobacterial strains that are common to mother and child and thus indicative of vertical transmission and that are maintained in the infant for at least relatively short time spans.
Burkholderia Diffusible Signal Factor Signals to Francisella novicida To Disperse Biofilm and Increase Siderophore Production
Authors: Dean Scott N. , Chung Myung-Chul , van Hoek Monique L.
Published: August 2015

In many bacteria, the ability to modulate biofilm production relies on specific signaling molecules that are either self-produced or made by neighboring microbes within the ecological niche. We analyzed the potential interspecies signaling effect of the
Burkholderia
diffusible signal factor (BDSF) on
Francisella novicida
, a model organism for
Francisella tularensis
, and demonstrated that BDSF both inhibits the formation and causes the dispersion of
Francisella
biofilm. Specificity was demonstrated for the
cis
versus the
trans
form of BDSF. Using transcriptome sequencing, quantitative reverse transcription-PCR, and activity assays, we found that BDSF altered the expression of many
F. novicida
genes, including genes involved in biofilm formation, such as chitinases. Using a chitinase inhibitor, the antibiofilm activity of BDSF was also shown to be chitinase dependent. In addition, BDSF caused an increase in RelA expression and increased levels of (p)ppGpp, leading to decreased biofilm production. These results support our observation that exposure of
F. novicida
to BDSF causes biofilm dispersal. Furthermore, BDSF upregulated the genes involved in iron acquisition (
figABCD
), increasing siderophore production. Thus, this study provides evidence for a potential role and mechanism of diffusible signal factor (DSF) signaling in the genus
Francisella
and suggests the possibility of interspecies signaling between
Francisella
and other bacteria. Overall, this study suggests that in response to the interspecies DSF signal,
F. novicida
can alter its gene expression and regulate its biofilm formation.
Geographical and Temporal Structures of Legionella pneumophila Sequence Types in Comunitat Valenciana (Spain), 1998 to 2013
Authors: Sánchez-Busó Leonor , Coscollà Mireia , Palero Ferran , Camaró María Luisa , Gimeno Ana , Moreno Pilar , Escribano Isabel , López Perezagua María Mar , Colomina Javier , Vanaclocha Herme , González-Candelas Fernando
Published: August 2015

Legionella pneumophila
is an accidental human pathogen associated with aerosol formation in water-related sources. High recombination rates make
Legionella
populations genetically diverse, and nearly 2,000 different sequence types (STs) have been described to date for this environmental pathogen. The spatial distribution of STs is extremely heterogeneous, with some variants being present worldwide and others being detected at only a local scale. Similarly, some STs have been associated with disease outbreaks, such as ST578 or ST23. Spain is among the European countries with the highest incidences of reported legionellosis cases, and specifically, Comunitat Valenciana (CV) is the second most affected area in the country. In this work, we aimed at studying the overall diversity of
Legionella pneumophila
populations found in the period from 1998 to 2013 in 79 localities encompassing 23 regions within CV. To do so, we performed sequence-based typing (SBT) on 1,088
L. pneumophila
strains detected in the area from both environmental and clinical sources. A comparison with the genetic structuring detected in a global data set that included 20 European and 7 non-European countries was performed. Our results reveal a level of diversity in CV that can be considered representative of the diversity found in other countries worldwide.
Nitrogen Cycling Potential of a Grassland Litter Microbial Community
Authors: Nelson Michaeline B. , Berlemont Renaud , Martiny Adam C. , Martiny Jennifer B. H.
Published: August 2015

Because microorganisms have different abilities to utilize nitrogen (N) through various assimilatory and dissimilatory pathways, microbial composition and diversity likely influence N cycling in an ecosystem. Terrestrial plant litter decomposition is often limited by N availability; however, little is known about the microorganisms involved in litter N cycling. In this study, we used metagenomics to characterize the potential N utilization of microbial communities in grassland plant litter. The frequencies of sequences associated with eight N cycling pathways differed by several orders of magnitude. Within a pathway, the distributions of these sequences among bacterial orders differed greatly. Many orders within the
Actinobacteria
and
Proteobacteria
appeared to be N cycling generalists, carrying genes from most (five or six) of the pathways. In contrast, orders from the
Bacteroidetes
were more specialized and carried genes for fewer (two or three) pathways. We also investigated how the abundance and composition of microbial N cycling genes differed over time and in response to two global change manipulations (drought and N addition). For many pathways, the abundance and composition of N cycling taxa differed over time, apparently reflecting precipitation patterns. In contrast to temporal variability, simulated global change had minor effects on N cycling potential. Overall, this study provides a blueprint for the genetic potential of N cycle processes in plant litter and a baseline for comparisons to other ecosystems.
ERG2
and
ERG24
Are Required for Normal Vacuolar Physiology as Well as Candida albicans Pathogenicity in a Murine Model of Disseminated but Not Vaginal Candidiasis
Authors: Luna-Tapia Arturo , Peters Brian M. , Eberle Karen E. , Kerns Morgan E. , Foster Timothy P. , Marrero Luis , Noverr Mairi C. , Fidel Paul L. , Palmer Glen E.
Published: August 2015

Several important classes of antifungal agents, including the azoles, act by blocking ergosterol biosynthesis. It was recently reported that the azoles cause massive disruption of the fungal vacuole in the prevalent human pathogen
Candida albicans
. This is significant because normal vacuolar function is required to support
C. albicans
pathogenicity. This study examined the impact of the morpholine antifungals, which inhibit later steps of ergosterol biosynthesis, on
C. albicans
vacuolar integrity. It was found that overexpression of either the
ERG2
or
ERG24
gene, encoding C-8 sterol isomerase or C-14 sterol reductase, respectively, suppressed
C. albicans
sensitivity to the morpholines. In addition, both
erg2Δ/Δ
and
erg24Δ/Δ
mutants were hypersensitive to the morpholines. These data are consistent with the antifungal activity of the morpholines depending upon the simultaneous inhibition of both Erg2p and Erg24p. The vacuoles within both
erg2Δ/Δ
and
erg24Δ/Δ
C. albicans
strains exhibited an aberrant morphology and accumulated large quantities of the weak base quinacrine, indicating enhanced vacuolar acidification compared with that of control strains. Both
erg
mutants exhibited significant defects in polarized hyphal growth and were avirulent in a mouse model of disseminated candidiasis. Surprisingly, in a mouse model of vaginal candidiasis, both mutants colonized mice at high levels and induced a pathogenic response similar to that with the controls. Thus, while targeting Erg2p or Erg24p alone could provide a potentially efficacious therapy for disseminated candidiasis, it may not be an effective strategy to treat vaginal infections. The potential value of drugs targeting these enzymes as adjunctive therapies is discussed.
Evaluating the effectiveness of care integration strategies in different healthcare systems in Latin America: the EQUITY-LA II quasi-experimental study protocol
Authors: Vázquez María-Luisa , Vargas Ingrid , Unger Jean-Pierre , De Paepe Pierre , Mogollón-Pérez Amparo Susana , Samico Isabella , Albuquerque Paulette , Eguiguren Pamela , Cisneros Angelica Ivonne , Rovere Mario , Bertolotto Fernando
Published: August 2015

Introduction

Although fragmentation in the provision of healthcare is considered an important obstacle to effective care, there is scant evidence on best practices in care coordination in Latin America. The aim is to evaluate the effectiveness of a participatory shared care strategy in improving coordination across care levels and related care quality, in health services networks in six different healthcare systems of Latin America.

Methods and analysis

A controlled before and after quasi-experimental study taking a participatory action research approach. In each country, two comparable healthcare networks were selected—intervention and control. The study contains four phases: (1) A baseline study to establish network performance in care coordination and continuity across care levels, using (A) qualitative methods: semi-structured interviews and focus groups with a criterion sample of health managers, professionals and users; and (B) quantitative methods: two questionnaire surveys with samples of 174 primary and secondary care physicians and 392 users with chronic conditions per network. Sample size was calculated to detect a proportion difference of 15% and 10%, before and after intervention (α=0.05; β=0.2 in a two-sided test); (2) a bottom-up participatory design and implementation of shared care strategies involving micro-level care coordination interventions to improve the adequacy of patient referral and information transfer. Strategies are selected through a participatory process by the local steering committee (local policymakers, health care network professionals, managers, users and researchers), supported by appropriate training; (3) Evaluation of the effectiveness of interventions by measuring changes in levels of care coordination and continuity 18 months after implementation, applying the same design as in the baseline study; (4) Cross-country comparative analysis.

Ethics and dissemination

This study complies with international and national legal stipulations on ethics. Conditions of the study procedure were approved by each country's ethical committee. A variety of dissemination activities are implemented addressing the main stakeholders. Registration No.257 Clinical Research Register of the Santa Fe Health Department, Argentina.
Factors associated with induced abortion among female entertainment workers: a cross-sectional study in Cambodia
Authors: Yi Siyan , Tuot Sovannary , Chhoun Pheak , Pal Khuondyla , Tith Khimuy , Brody Carinne
Published: August 2015

Objective

To explore risk factors associated with induced abortion among sexually active female entertainment workers (FEWs) in Cambodia.

Design

Cross-sectional study.

Setting

Phnom Penh and Siem Reap, Cambodia.

Participants

This study included 556 FEWs aged 18–47 years randomly selected from entertainment establishments in the two cities in 2014 using a two-stage cluster sampling method. Data were collected through face-to-face interviews using a structured questionnaire.

Primary outcome measure

History of induced abortion during the time working as a FEW.

Results

Of the total sample, 45.6% reported currently using a contraceptive method with condom (42.4%) being the most common method, followed by pills (25.6%). One-fourth (25%) of the respondents reported having been pregnant at least once, and 21.4% reported having at least one induced abortion during the time working as a FEW. After controlling for other covariates in a multivariate logistic regression model, FEWs with a history of induced abortion remained significantly more likely to be currently working in a karaoke bar (AOR=1.75, 95% CI 1.10 to 2.78), to have worked longer as a FEW (AOR=1.42, 95% CI 1.06 to 1.43), to have had a greater number of sexual partners in the past 12 months (AOR=1.86, 95% CI 1.02 to 1.54), to be currently using a contraceptive method (AOR=1.52, 95% CI 1.01 to 2.29), to be able to find condoms when they needed them (AOR=2.03, 95% CI 1.09 to 3.82), and to report inconsistent condom use with non-commercial partners in the past 3 months (AOR=1.62, 95% CI 1.06 to 3.44).

Conclusions

This study highlights the high rates of unwanted pregnancies that ended in induced abortions among FEWs in Cambodia. Access of FEWs to quality sexual and reproductive healthcare services is deemed a high priority. Integrated interventions to improve sexual and reproductive health among these vulnerable women should be tailored to reach the most-at-risk groups.
The effectiveness of providing peer benchmarked feedback to hip replacement surgeons based on patient-reported outcome measures—results from the PROFILE (Patient-Reported Outcomes: Feedback Interpretation and Learning Experiment) trial: a cluster randomised controlled study
Authors: Boyce Maria B , Browne John P
Published: August 2015

Objective

To test whether providing surgeons with peer benchmarked feedback about patient-reported outcomes is effective in improving patient outcomes.

Design

Cluster randomised controlled trial.

Setting

Secondary care—Ireland.

Participants

Surgeons were recruited through the Irish Institute of Trauma and Orthopaedic Surgery, and patients were recruited in hospitals prior to surgery. We randomly allocated 21 surgeons and 550 patients.

Intervention

Surgeons in the intervention group received peer benchmarked patient-reported outcome measures (PROMs) feedback and education.

Main outcome variable

Postoperative Oxford Hip Score (OHS).

Results

Primary outcome data were available for 11 intervention surgeons with responsibility for 230 patients and 10 control surgeons with responsibility for 228 patients. The mean postoperative OHS for the intervention group was 40.8 (95% CI 39.8 to 41.7) and for the control group was 41.9 (95% CI 41.1 to 42.7). The adjusted effect estimate was −1.1 (95% CI −2.4 to 0.2, p=0.09). Secondary outcomes were the Hip Osteoarthritis Outcome Score (HOOS), EQ-5D and the proportion of patients reporting a problem after surgery. The mean postoperative HOOS for the intervention group was 36.2 and for the control group was 37.1. The adjusted effect estimate was −1.1 (95% CI −2.4 to 0.3, p=0.1). The mean postoperative EQ-5D for the intervention group was 0.85 and for the control group was 0.87. The adjusted effect estimate was −0.02 (95% CI −0.05 to 0.008, p=0.2). 27% of intervention patients and 24% of control patients reported at least one complication after surgery (adjusted OR=1.2, 95% CI 0.6 to 2.3, p=0.6).

Conclusions

Outcomes for patients operated on by surgeons who had received peer benchmarked PROMs data were not statistically different from the outcomes of patients operated on by surgeons who did not receive feedback. PROMs information alone seems to be insufficient to identify opportunities for quality improvement.

Trial registration number

ISRCTN 69032522.
Environmental factors and their association with emergency department hand hygiene compliance: an observational study
Authors: Carter Eileen J , Wyer Peter , Giglio James , Jia Haomiao , Nelson Germaine , Kauari Vepuka E , Larson Elaine L
Published: August 2015

Objectives

Hand hygiene is effective in preventing healthcare-associated infections. Environmental conditions in the emergency department (ED), including crowding and the use of non-traditional patient care areas (ie, hallways), may pose barriers to hand hygiene compliance. We examined the relationship between these environmental conditions and proper hand hygiene.

Methods

This was a single-site, observational study. From October 2013 to January 2014, trained observers recorded hand hygiene compliance among staff in the ED according to the World Health Organization ‘My 5 Moments for Hand Hygiene’. Multivariable logistic regression was used to analyse the relationship between environmental conditions and hand hygiene compliance, while controlling for important covariates (eg, hand hygiene indication, glove use, shift, etc).

Results

A total of 1673 hand hygiene opportunities were observed. In multivariable analyses, hand hygiene compliance was significantly lower when the ED was at its highest level of crowding than when the ED was not crowded and lower among hallway care areas than semiprivate care areas (OR=0.39, 95% CI 0.28 to 0.55; OR=0.73, 95% CI 0.55 to 0.97).

Conclusions

Unique environmental conditions pose barriers to hand hygiene compliance in the ED setting and should be considered by ED hand hygiene improvement efforts. Further study is needed to evaluate the impact of these environmental conditions on actual rates of infection transmission.
Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea
Authors: Drager Luciano F. , Polotsky Vsevolod Y. , O'Donnell Christopher P. , Cravo Sergio L. , Lorenzi-Filho Geraldo , Machado Benedito H.
Published: August 2015

Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant pathophysiological disturbance in OSA–intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field.
Differential effects of octanoate and heptanoate on myocardial metabolism during extracorporeal membrane oxygenation in an infant swine model
Authors: Kajimoto Masaki , Ledee Dolena R. , Olson Aaron K. , Isern Nancy G. , Des Rosiers Christine , Portman Michael A.
Published: August 2015

Nutritional energy support during extracorporeal membrane oxygenation (ECMO) should promote successful myocardial adaptation and eventual weaning from the ECMO circuit. Fatty acids (FAs) are a major myocardial energy source, and medium-chain FAs (MCFAs) are easily taken up by cell and mitochondria without membrane transporters. Odd-numbered MCFAs supply carbons to the citric acid cycle (CAC) via anaplerotic propionyl-CoA as well as acetyl-CoA, the predominant β-oxidation product for even-numbered MCFA. Theoretically, this anaplerotic pathway enhances carbon entry into the CAC, and provides superior energy state and preservation of protein synthesis. We tested this hypothesis in an immature swine model undergoing ECMO. Fifteen male Yorkshire pigs (26–45 days old) with 8-h ECMO received either normal saline, heptanoate (odd-numbered MCFA), or octanoate (even-numbered MCFA) at 2.3 μmol·kg body wt−1·min−1as MCFAs systemically during ECMO ( n = 5/group). The 13-carbon (13C)-labeled substrates ([2-13C]lactate, [5,6,7-13C3]heptanoate, and [U-13C6]leucine) were systemically infused as metabolic markers for the final 60 min before left ventricular tissue extraction. Extracted tissues were analyzed for the13C-labeled and absolute concentrations of metabolites by nuclear magnetic resonance and gas chromatography-mass spectrometry. Octanoate produced markedly higher myocardial citrate concentration, and led to a higher [ATP]-to-[ADP] ratio compared with other groups. Unexpectedly, octanoate and heptanoate increased the flux of propionyl-CoA relative to acetyl-CoA into the CAC compared with control. MCFAs promoted increases in leucine oxidation, but were not associated with a difference in protein synthesis rate. In conclusion, octanoate provides energetic advantages to the heart over heptanoate.
Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21
Authors: Domouzoglou Eleni M. , Naka Katerina K. , Vlahos Antonios P. , Papafaklis Michail I. , Michalis Lampros K. , Tsatsoulis Agathoklis , Maratos-Flier Eleftheria
Published: August 2015

Early detection of risk factors for enhanced primary prevention and novel therapies for treating the chronic consequences of cardiovascular disease are of the utmost importance for reducing morbidity. Recently, fibroblast growth factors (FGFs) have been intensively studied as potential new molecules in the prevention and treatment of cardiovascular disease mainly attributable to metabolic effects and angiogenic actions. Members of the endocrine FGF family have been shown to increase metabolic rate, decrease adiposity, and restore glucose homeostasis, suggesting a multiple metabolic role. Serum levels of FGFs have been associated with established cardiovascular risk factors as well as with the severity and extent of coronary artery disease and could be useful for prediction of cardiovascular death. Furthermore, preclinical investigations and clinical trials have tested FGF administration for therapeutic angiogenesis in ischemic vascular disease, demonstrating a potential role in improving angina and limb function. FGF21 has lately emerged as a potent metabolic regulator with multiple effects that ultimately improve the lipoprotein profile. Early studies show that FGF21 is associated with the presence of atherosclerosis and may play a protective role against plaque formation by improving endothelial function. The present review highlights recent investigations suggesting that FGFs, in particular FGF21, may be useful as markers of cardiovascular risk and may also serve as protective/therapeutic agents in cardiovascular disease.
Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans
Authors: Limjunyawong Nathachit , Craig John M. , Lagassé H. A. Daniel , Scott Alan L. , Mitzner Wayne
Published: August 2015

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes.
Smart imaging of acute lung injury: exploration of myeloperoxidase activity using in vivo endoscopic confocal fluorescence microscopy
Authors: Chagnon Frédéric , Bourgouin Alexandra , Lebel Réjean , Bonin Marc-André , Marsault Eric , Lepage Martin , Lesur Olivier
Published: August 2015

The pathophysiology of acute lung injury (ALI) is well characterized, but its real-time assessment at bedside remains a challenge. When patients do not improve after 1 wk despite supportive therapies, physicians have to consider open lung biopsy (OLB) to identify the process(es) at play. Sustained inflammation and inadequate repair are often observed in this context. OLB is neither easy to perform in a critical setting nor exempt from complications. Herein, we explore intravital endoscopic confocal fluorescence microscopy (ECFM) of the lung in vivo combined with the use of fluorescent smart probe(s) activated by myeloperoxidase (MPO). MPO is a granular enzyme expressed by polymorphonuclear neutrophils (PMNs) and alveolar macrophages (AMs), catalyzing the synthesis of hypoclorous acid, a by-product of hydrogen peroxide. Activation of these probes was first validated in vitro in relevant cells (i.e., AMs and PMNs) and on MPO-non-expressing cells (as negative controls) and then tested in vivo using three rat models of ALI and real-time intravital imaging with ECFM. Semiquantitative image analyses revealed that in vivo probe-related cellular/background fluorescence was associated with corresponding enhanced lung enzymatic activity and was partly prevented by specific MPO inhibition. Additional ex vivo phenotyping was performed, confirming that fluorescent cells were neutrophil elastase+(PMNs) or CD68+(AMs). This work is a first step toward “virtual biopsy” of ALI without OLB.
Adolescent Exercise in Association with Mortality from All Causes, Cardiovascular Disease, and Cancer among Middle-Aged and Older Chinese Women
Authors: Nechuta Sarah J. , Shu Xiao Ou , Yang Gong , Cai Hui , Gao Yu-Tang , Li Hong-Lan , Xiang Yong-Bing , Zheng Wei
Published: August 2015

Background: Little is known regarding the role of early-life exercise, a potentially modifiable factor, in long-term adult morbidity and mortality. We utilized the Shanghai Women's Health Study (SWHS) to investigate adolescent exercise in association with cancer, cardiovascular disease (CVD), and all-cause mortality among middle-aged and older women.

Methods: The SWHS is a prospective cohort of 74,941 Chinese women ages 40 to 70 years recruited from 1996 to 2000. In-person interviews at enrollment assessed adolescent and adult exercise history, medical and reproductive history, and other lifestyle and socioeconomic (SES) factors. Mortality follow-up occurs via annual linkage to the Shanghai Vital Statistics Registry. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were derived from Cox regression models.

Results: Adjusting for birth year and other adolescent factors, adolescent exercise was associated with reduced risk of cancer, CVD, and total mortality [HRs (95% CI), 0.83 (0.72–0.95), 0.83 (0.70–0.98), and 0.78 (0.71–0.85), respectively for ≤1.33 hours (h)/week, and 0.83 (0.74–0.93), 0.62 (0.53–0.72), and 0.71 (0.66–0.77), respectively for >1.33 h/week (reference = none)]. Results were attenuated after adjustment for adult SES and lifestyle factors. Participation in sports teams was inversely associated with cancer mortality [HR (95% CI), 0.86 (0.76–0.97)]. Joint adolescent and adult exercise was associated with reduced risk of all-cause, CVD, and cancer mortality [HRs (95% CIs), 0.80 (0.72–0.89), 0.83 (0.69–1.00), and 0.87 (0.74–1.01), respectively], adjusting for adult/adolescent factors, and adolescence exercise only was inversely associated with cancer mortality [HR (95% CI), 0.84 (0.71–0.98)].

Conclusions: Adolescent exercise participation, independent of adult exercise, was associated with reduced risk of cancer, CVD, and all-cause mortality.

Impact: Results support promotion of exercise in adolescence to reduce mortality in later life. Cancer Epidemiol Biomarkers Prev; 24(8); 1270–6. ©2015 AACR.
Can the Lung Cancer Pie Be Divided into Angiogenic Slices?
Authors: Cascone Tina , Heymach John V.
Published: August 2015

There are no validated markers for predicting benefit from angiogenesis inhibitors or classifying tumors with distinct angiogenic phenotypes. In patients with non–small cell lung cancer treated with bevacizumab and erlotinib, Franzini and colleagues find that angiogenesis- and hypoxia-associated gene expression signatures predict tumor response and/or clinical outcome, and may define distinct angiogenic patterns. Clin Cancer Res; 21(23); 5188–90. ©2015 AACR.

See related article by Franzini et al., p. 5253
Metabolic Imaging as a Biomarker of Early Radiation Response in Tumors
Authors: Lai Stephen Y. , Fuller C. David , Bhattacharya Pratip K. , Frank Steven J.
Published: August 2015

13C-pyruvate hyperpolarized magnetic resonance imaging (HP-MRI) is emerging as a viable quantitative biomarker for solid tumor response and normal tissue toxicity after radiotherapy. This technology effectively predicts response related to metabolic agents or alterations in the tumor microenvironment, but challenges remain to be addressed to ensure successful translational implementation. Clin Cancer Res; 21(22); 4996–8. ©2015 AACR.

See related article by Saito et al., p. 5073
USP44+ Cancer Stem Cell Subclones Contribute to Breast Cancer Aggressiveness by Promoting Vasculogenic Mimicry
Authors: Liu Tieju , Sun Baocun , Zhao Xiulan , Li Yanlei , Zhao Xueming , Liu Ying , Yao Zhi , Gu Qiang , Dong Xueyi , Shao Bing , Lin Xian , Liu Fang , An Jindan
Published: August 2015

Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, describes the functional plasticity of aggressive cancer cells that form vascular networks. In our previous study, breast cancer stem cells (CSC) were shown to potentially participate in VM formation. In this study, breast CSCs presented centrosome amplification (CA) phenotype and ubiquitin-specific protease 44 (USP44) upregulation. USP44 expression contributed to the establishment of bipolar spindles in breast CSCs with supernumerary centrosomes by localizing at pole-associated centrosomes. The bipolar spindle patterns of breast CSCs with CA, including planar-like and apico-basal–like, functioned differently during the VM process of CSCs. Moreover, the ability of transendothelial migration in VM-forming cells was increased. In vivo experiment results showed that CSC xenografts presented linearly patterned programmed cell necrosis, which provided a spatial foundation for VM formation as well as angiogenesis. Breast CSCs further showed increased levels of IL6 and IL8. However, USP44 silencing induced spindle multipolarity, abated VM, reduced transendothelial migration, and consequently decreased IL6 and IL8 levels in breast CSCs. Finally, USP44+ CSC subclones (ALDH1+/USP44+/IL6+/IL8+) were identified in breast cancer specimens through consecutive sections scanning. The subclones were related not only to CA, but also to VM. Statistical analysis suggested that USP44+ CSC subclones could be used as an independent prognostic biomarker of poor clinical outcomes in patients with breast cancer. Collectively, the identification of USP44+ CSC subclones may contribute to the prediction of VM formation and aggressive behavior. This study provides novel insights into the therapy for advanced breast cancer. Mol Cancer Ther; 14(9); 2121–31. ©2015 AACR.
Superoxide Dismutase 1 In Vivo Ameliorates Maternal Diabetes Mellitus–Induced Apoptosis and Heart Defects Through Restoration of Impaired Wnt Signaling
Authors: Wang Fang , Fisher Steven A. , Zhong Jianxiang , Wu Yanqing , Yang Peixin
Published: August 2015

Background—

Oxidative stress is manifested in embryos exposed to maternal diabetes mellitus, yet specific mechanisms for diabetes mellitus–induced heart defects are not defined. Gene deletion of intermediates of Wingless-related integration (Wnt) signaling causes heart defects similar to those observed in embryos from diabetic pregnancies. We tested the hypothesis that diabetes mellitus–induced oxidative stress impairs Wnt signaling, thereby causing heart defects, and that these defects can be rescued by transgenic overexpression of the reactive oxygen species scavenger superoxide dismutase 1 (SOD1).

Methods and Results—

Wild-type (WT) and SOD1-overexpressing embryos from nondiabetic WT control dams and nondiabetic/diabetic WT female mice mated with SOD1 transgenic male mice were analyzed. No heart defects were observed in WT and SOD1 embryos under nondiabetic conditions. WT embryos of diabetic dams had a 26% incidence of cardiac outlet defects that were suppressed by SOD1 overexpression. Insulin treatment reduced blood glucose levels and heart defects. Diabetes mellitus increased superoxide production, canonical Wnt antagonist expression, caspase activation, and apoptosis and suppressed cell proliferation. Diabetes mellitus suppressed Wnt signaling intermediates and Wnt target gene expression in the embryonic heart, each of which were reversed by SOD1 overexpression. Hydrogen peroxide and peroxynitrite mimicked the inhibitory effect of high glucose on Wnt signaling, which was abolished by the SOD1 mimetic, tempol.

Conclusions—

The oxidative stress of diabetes mellitus impairs Wnt signaling and causes cardiac outlet defects that are rescued by SOD1 overexpression. This suggests that targeting of components of the Wnt5a signaling pathway may be a viable strategy for suppression of congenital heart defects in fetuses of diabetic pregnancies.
Lp-PLA
2
Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages
Authors: He Shun , Chousterman Benjamin G. , Fenn Ashley , Anzai Atsushi , Nairz Manfred , Brandt Martin , Hilgendorf Ingo , Sun Yuan , Ye Yu-Xiang , Iwamoto Yoshiko , Tricot Benoit , Weissleder Ralph , Macphee Colin , Libby Peter , Nahrendorf Matthias , Swirski Filip K.
Published: August 2015

Background—

Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6C
high
and reparative Ly-6C
low
monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A
2
(Lp-PLA
2
), a member of the phospholipase A
2
family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA
2
levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA
2
in healing after MI.

Methods and Results—

In response to MI, Lp-PLA
2
levels markedly increased in the circulation. To test the functional importance of Lp-PLA
2
, we generated chimeric mice whose bone marrow–derived leukocytes were Lp-PLA
2
–deficient (
bmLp-PLA

2

−/−

). Compared with wild-type controls,
bmLp-PLA

2

−/−

mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly,
bmLp-PLA

2

−/−

mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6C
high
monocytes. During the later, reparative phase, infarcts of
bmLp-PLA

2

−/−

mice contained Ly-6C
low
macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of
bmLp-PLA

2

−/−

mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction.

Conclusions—

Lp-PLA
2
augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI.
Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function
Authors: Aleong Ryan G. , Mulvahill Matthew J. , Halder Indrani , Carlson Nichole E. , Singh Madhurmeet , Bloom Heather L. , Dudley Samuel C. , Ellinor Patrick T. , Shalaby Alaa , Weiss Raul , Gutmann Rebecca , Sauer William H. , Narayanan Kumar , Chugh Sumeet S. , Saba Samir , London Barry
Published: August 2015

Background

Reduced left ventricular (LV) ejection fraction increases the risk of ventricular arrhythmias; however,
LV
ejection fraction has a low sensitivity to predict ventricular arrhythmias. LV dilatation and mass may be useful to further risk‐stratify for ventricular arrhythmias.

Methods and Results

Patients from the Genetic Risk of Assessment of Defibrillator Events (
GRADE
) study (N=930), a study of heart failure subjects with defibrillators, were assessed for appropriate implantable cardioverter‐defibrillator shock and death, heart transplant, or ventricular assist device placement by
LV
diameter and mass.
LV
mass was divided into normal, mild, moderate, and severe classifications. Severe
LV
end‐diastolic diameter had worse shock‐free survival than normal and mild
LV
end‐diastolic diameter (
P
=0.0002 and 0.0063, respectively; 2‐year shock free, severe 74%, moderate 80%, mild 91%, normal 88%; 4‐year shock free, severe 62%, moderate 69%, mild 72%, normal 81%) and freedom from death, transplant, or ventricular assist device compared with normal and moderate LV end‐diastolic diameter (
P
<0.0001 and 0.0441, respectively; 2‐year survival: severe 78%, moderate 85%, mild 82%, normal 89%; 4‐year survival: severe 55%, moderate 64%, mild 63%, normal 74%). Severe
LV
mass had worse shock‐free survival than normal and mild LV mass (
P
=0.0370 and 0.0280, respectively; 2‐year shock free: severe 80%, moderate 81%, mild 91%, normal 87%; 4‐year shock free: severe 68%, moderate 73%, mild 76%, normal 76%) but no association with death, transplant, or ventricular assist device (
P
=0.1319). In a multivariable Cox proportional hazards analysis adjusted for
LV
ejection fraction,
LV
end‐diastolic diameter was associated with appropriate implantable cardioverter‐defibrillator shocks (hazard ratio 1.22,
P
=0.020).
LV
end‐diastolic diameter was associated with time to death, transplant, or ventricular assist device (hazard ratio 1.29,
P
=0.0009).

Conclusions

LV dilatation may complement ejection fraction to predict ventricular arrhythmias.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02045043.
Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury
Authors: Sawicki Konrad Teodor , Shang Meng , Wu Rongxue , Chang Hsiang‐Chun , Khechaduri Arineh , Sato Tatsuya , Kamide Christine , Liu Ting , Naga Prasad Sathyamangla V. , Ardehali Hossein
Published: August 2015

Background

Heme is an essential iron‐containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate‐limiting enzyme in heme synthesis, δ‐aminolevulinic acid synthase 2 (
ALAS
2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of
ALAS
2) leads to increased oxidative stress and cell death in the heart.

Methods and Results

We first showed that
ALAS
2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac‐specific overexpression of
ALAS
2. While
ALAS
2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with
ALAS
2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of
ALAS
2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to
ALAS
2‐overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased
ALAS
2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased
ALAS
2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to nonischemic cardiomyopathy.

Conclusions

Heme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.
Visual activism and social justice: Using visual methods to make young people’s complex lives visible across ‘public’ and ‘private’ spaces
Authors: Wilson Sarah , Milne EJ
Published: August 2015

Much critical social justice research, including work employing visual methods, focuses on young people’s use of public spaces leaving domestic spaces relatively unexplored. Such research tacitly maintains modernist notions of the public/private distinction in which the private sphere is considered less relevant to concerns of social justice. However, UK crime and social justice policy has increasingly intervened in the home lives of the poorest British families. Further, such policies have been legitimated by drawing on (or not contesting) media imagery that constructs these family lives almost entirely negatively, obscuring their complexity. Drawing on childhood studies research, and a project that employed visual methods to explore belonging among young people in foster, kinship or residential care, this article examines participants’ often fragile efforts to find or forge places in which they could feel ‘at home’ and imagine a future. In so doing, it invites visual activists to reconsider their understanding of public and private spaces in order to contest prevalent unsympathetic policy representations of poorer young people’s lives, to focus greater attention on their need for support, and to extend imaginations of their futures.
Who Democratizes? Western-educated Leaders and Regime Transitions
Authors: Gift Thomas , Krcmaric Daniel
Published: August 2015

Many theories attempt to explain why some countries democratize and others do not. Existing accounts, however, focus almost exclusively on structural factors and ignore individual leaders. In this article, we argue that leaders educated at Western universities are more likely to democratize than other leaders because Western education socializes leaders to prefer democracy and creates transnational linkages that alter the strategic calculus of democratization. Utilizing an original data set on the specific colleges and universities world leaders attended, we show that Western-educated leaders significantly and substantively improve a country’s democratization prospects.