bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Dysfunctional Tricarboxylic Acid Cycle Enhances Fitness of Staphylococcus epidermidis During β-Lactam Stress
Authors: Chittezham Thomas Vinai , Kinkead Lauren C. , Janssen Ashley , Schaeffer Carolyn R. , Woods Keith M. , Lindgren Jill K. , Peaster Jonathan M. , Chaudhari Sujata S. , Sadykov Marat , Jones Joselyn , Mohamadi AbdelGhani Sameh M. , Zimmerman Matthew C. , Bayles Kenneth W. , Somerville Greg A. , Fey Paul D. 
Published: August 2013

ABSTRACT

A recent controversial hypothesis suggested that the bactericidal action of antibiotics is due to the generation of endogenous reactive oxygen species (ROS), a process requiring the citric acid cycle (tricarboxylic acid [TCA] cycle). To test this hypothesis, we assessed the ability of oxacillin to induce ROS production and cell death in
Staphylococcus epidermidis
strain 1457 and an isogenic citric acid cycle mutant. Our results confirm a contributory role for TCA-dependent ROS in enhancing susceptibility of
S. epidermidis
toward β-lactam antibiotics and also revealed a propensity for clinical isolates to accumulate TCA cycle dysfunctions presumably as a way to tolerate these antibiotics. The increased protection from β-lactam antibiotics could result from pleiotropic effects of a dysfunctional TCA cycle, including increased resistance to oxidative stress, reduced susceptibility to autolysis, and a more positively charged cell surface.

IMPORTANCE
Staphylococcus epidermidis
, a normal inhabitant of the human skin microflora, is the most common cause of indwelling medical device infections. In the present study, we analyzed 126 clinical
S. epidermidis
isolates and discovered that tricarboxylic acid (TCA) cycle dysfunctions are relatively common in the clinical environment. We determined that a dysfunctional TCA cycle enables
S. epidermidis
to resist oxidative stress and alter its cell surface properties, making it less susceptible to β-lactam antibiotics.
Interspecies Interactions Stimulate Diversification of the Streptomyces coelicolor Secreted Metabolome
Authors: Traxler Matthew F. , Watrous Jeramie D. , Alexandrov Theodore , Dorrestein Pieter C. , Kolter Roberto 
Published: August 2013

ABSTRACT

Soils host diverse microbial communities that include filamentous actinobacteria (actinomycetes). These bacteria have been a rich source of useful metabolites, including antimicrobials, antifungals, anticancer agents, siderophores, and immunosuppressants. While humans have long exploited these compounds for therapeutic purposes, the role these natural products may play in mediating interactions between actinomycetes has been difficult to ascertain. As an initial step toward understanding these chemical interactions at a systems level, we employed the emerging techniques of nanospray desorption electrospray ionization (NanoDESI) and matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) imaging mass spectrometry to gain a global chemical view of the model bacterium
Streptomyces coelicolor
interacting with five other actinomycetes. In each interaction, the majority of secreted compounds associated with
S. coelicolor
colonies were unique, suggesting an idiosyncratic response from
S. coelicolor
. Spectral networking revealed a family of unknown compounds produced by
S. coelicolor
during several interactions. These compounds constitute an extended suite of at least 12 different desferrioxamines with acyl side chains of various lengths; their production was triggered by siderophores made by neighboring strains. Taken together, these results illustrate that chemical interactions between actinomycete bacteria exhibit high complexity and specificity and can drive differential secondary metabolite production.

IMPORTANCE
Actinomycetes, filamentous actinobacteria from the soil, are the deepest natural source of useful medicinal compounds, including antibiotics, antifungals, and anticancer agents. There is great interest in developing new strategies that increase the diversity of metabolites secreted by actinomycetes in the laboratory. Here we used several metabolomic approaches to examine the chemicals made by these bacteria when grown in pairwise coculture. We found that these interspecies interactions stimulated production of numerous chemical compounds that were not made when they grew alone. Among these compounds were at least 12 different versions of a molecule called desferrioxamine, a siderophore used by the bacteria to gather iron. Many other compounds of unknown identity were also observed, and the pattern of compound production varied greatly among the interaction sets. These findings suggest that chemical interactions between actinomycetes are surprisingly complex and that coculture may be a promising strategy for finding new molecules from actinomycetes.
Superantigens Are Critical for Staphylococcus aureus Infective Endocarditis, Sepsis, and Acute Kidney Injury
Authors: Salgado-Pabón Wilmara , Breshears Laura , Spaulding Adam R. , Merriman Joseph A. , Stach Christopher S. , Horswill Alexander R. , Peterson Marnie L. , Schlievert Patrick M. 
Published: August 2013

ABSTRACT

Infective endocarditis and kidney infections are serious complications of
Staphylococcus aureus
sepsis. We investigated the role of superantigens (SAgs) in the development of lethal sepsis, infective endocarditis, and kidney infections. SAgs cause toxic shock syndrome, but it is unclear if SAgs contribute to infective endocarditis and kidney infections secondary to sepsis. We show in the methicillin-resistant
S. aureus
strain MW2 that lethal sepsis, infective endocarditis, and kidney infections in rabbits are critically dependent on high-level SAgs. In contrast, the isogenic strain lacking staphylococcal enterotoxin C (SEC), the major SAg in this strain, is attenuated in virulence, while complementation restores disease production. SAgs’ role in infective endocarditis appears to be both superantigenicity and direct endothelial cell stimulation. Maintenance of elevated blood pressure by fluid therapy significantly protects from infective endocarditis, possibly through preventing bacterial accumulation on valves and increased SAg elimination. These data should facilitate better methods to manage these serious illnesses.

IMPORTANCE
The Centers for Disease Control and Prevention reported in 2007 that
Staphylococcus aureus
is the most significant cause of serious infectious diseases in the United States (R. M. Klevens, M. A. Morrison, J. Nadle, S. Petit, K. Gershman, et al., JAMA 298:1763–1771, 2007). Among these infections are sepsis, infective endocarditis, and acute kidney injury. Infective endocarditis occurs in 30 to 60% of patients with
S. aureus
bacteremia and carries a mortality rate of 40 to 50%. Over the past decades, infective endocarditis outcomes have not improved, and infection rates are steadily increasing (D. H. Bor, S. Woolhandler, R. Nardin, J. Brusch, D. U. Himmelstein, PLoS One 8:e60033, 2013). There is little understanding of the
S. aureus
virulence factors that are key for infective endocarditis development and kidney abscess formation. We demonstrate that superantigens are critical in the causation of all three infections. We show that their association results from both superantigenicity and direct toxic effects on endothelial cells, the latter likely contributing to delayed endothelium healing. Our studies contribute significantly to understanding the development of these illnesses and are expected to lead to development of important therapies to treat such illnesses.
Assessing the Breast Cancer Risk Distribution for Women Undergoing Screening in British Columbia
Authors: Weisstock Christina R. , Rajapakshe Rasika , Bitgood Christabelle , McAvoy Steven , Gordon Paula B. , Coldman Andrew J. , Parker Brent A. , Wilson Christine 
Published: August 2013

Abstract
Breast cancer risk estimations are both informative and useful at the population level, with many screening programs relying on these assessments to allocate resources such as breast MRI. This cross-sectional multicenter study attempts to quantify the breast cancer risk distribution for women between the ages of 40 to 79 years undergoing screening mammography in British Columbia (BC), Canada. The proportion of women at high breast cancer risk was estimated by surveying women enrolled in the Screening Mammography Program of British Columbia (SMPBC) for known breast cancer risk factors. Each respondent's 10-year risk was computed with both the Tyrer–Cuzick and Gail risk assessment models. The resulting risk distributions were evaluated using the guidelines from the National Institute for Health and Care Excellence (United Kingdom). Of the 4,266 women surveyed, 3.5% of women between the ages of 40 to 79 years were found to have a high 10-year risk of developing breast cancer using the Tyrer–Cuzick model (1.1% using the Gail model). When extrapolated to the screening population, it was estimated that 19,414 women in the SMPBC are considered to be at high breast cancer risk. These women may benefit from additional MRI screening; preliminary analysis suggests that 4 to 5 additional MRI machines would be required to screen these high-risk women. However, the use of different models and guidelines will modify the number of women qualifying for additional screening interventions, thus impacting the MRI resources required. The results of this project can now be used to inform decision-making groups about resource allocation for breast cancer screening in BC. Cancer Prev Res; 6(10); 1084–92. ©2013 AACR.
Temporal Trends in Patient Characteristics and Treatment With Intravenous Thrombolysis Among Acute Ischemic Stroke Patients at Get With the Guidelines–Stroke Hospitals
Authors: Schwamm Lee H. , Ali Syed F. , Reeves Mathew J. , Smith Eric E. , Saver Jeffrey L. , Messe Steven , Bhatt Deepak L. , Grau-Sepulveda Maria V. , Peterson Eric D. , Fonarow Gregg C. 
Published: August 2013

Background—
Substantial efforts over the past decade have increased rates of intravenous tissue plasminogen activator (tPA) use in the United States. We sought to determine changes in patient characteristics and rates of tPA use over time among hospitalized acute ischemic stroke (AIS) patients.

Methods and Results—

We analyzed all AIS patients (n=1 093 895) and those arriving ≤2 hours and treated with tPA ≤3 hours after onset (n=50 798) from 2003 to 2011 in the American Heart Association’s Get with the Guideline–Stroke (GWTG–Stroke). Categorical data were analyzed by Pearson χ
2
and continuous data by Wilcoxon test. Intravenous tPA use ≤3 hours after onset increased from 4.0% to 7.0% in all AIS admissions and 42.6% to 77.0% in AIS patients arriving ≤2 hours and fully eligible for tPA (
P
<0.001). In univariate analysis, tPA use increased over time, especially in those aged >85 years, nonwhite, and with milder strokes (National Institutes of Health Stroke Scale 0–4). Door-to-image time (median 24 versus 20 minutes) and door-to-tPA time (median 81 versus 72 minutes) also improved, with ≈65% of tPA-treated patients getting brain imaging ≤25 minutes after arrival. Multivariable analysis showed that with each additional calendar year, the odds that an eligible patient would receive tPA increased by 1.37-fold, adjusting for other covariates.

Conclusions—
The frequency of IV tPA use among all AIS patients, regardless of contraindications, nearly doubled from 2003 to 2011. Treatment with tPA has expanded to include more patients with mild deficits, nonwhite race/ethnicity, and oldest old age.
Yield of Molecular and Clinical Testing for Arrhythmia Syndromes
Authors: Hofman Nynke , Tan Hanno L. , Alders Mariëlle , Kolder Iris , de Haij Simone , Mannens Marcel M.A.M. , Lombardi Maria Paola , Lekanne dit Deprez Ronald H. , van Langen Irene , Wilde Arthur A.M. 
Published: August 2013

Background—
Sudden cardiac death is often caused by inherited arrhythmia syndromes, particularly if it occurs at a young age. In 1996, we started a cardiogenetics clinic aimed at diagnosing such syndromes and providing timely (often presymptomatic) treatment to families in which such syndromes or sudden cardiac death existed. We studied the yield of DNA testing for these syndromes using a candidate-gene approach over our 15 years of experience.

Methods and Results—
We analyzed the yield of DNA testing. In subanalyses, we studied differences in the yield of DNA testing over time, between probands with isolated or familial cases and between probands with or without clear disease-specific clinical characteristics. In cases of sudden unexplained death (antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiological investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (aged 41±19 years; 49% male) were analyzed. In 702 families (31%), a possible disease-causing mutation was detected. Most mutations were found in families with long-QT syndrome (47%) or hypertrophic cardiomyopathy (46%). Cascade screening revealed 1539 mutation-positive subjects. The mutation detection rate decreased over time, in part because probands with a less severe phenotype were studied, and was significantly higher in familial than in isolated cases. We counseled 372 families after sudden unexplained death; in 29% of them (n=108), an inherited arrhythmia syndrome was diagnosed.

Conclusions—
The proportion of disease-causing mutations found decreased over time, in part because probands with a less severe phenotype were studied. Systematic screening of families identified many (often presymptomatic) mutation-positive subjects.
Increased Atherosclerotic Lesions in LDL Receptor Deficient Mice With Hematopoietic Nuclear Receptor Rev‐erbα Knock‐ Down
Authors: Ma Hongling , Zhong Wenbin , Jiang Yingliang , Fontaine Coralie , Li Shiqian , Fu Jiangnan , Olkkonen Vesa M. , Staels Bart , Yan Daoguang 
Published: August 2013

Background
Nuclear receptor Rev‐erbα plays important roles in circadian clock timing, lipid metabolism, adipogenesis, and vascular inflammation. However, the role of Rev‐erbα in atherosclerotic lesion development has not been assessed in vivo.

Methods and Results

The nuclear receptor Rev‐erbα was knocked down in mouse haematopoietic cells by means of sh
RNA
‐lentiviral transduction, followed by bone marrow transplantation into
LDL
receptor knockout mice. The Rev‐erbα protein in peripheral macrophage was reduced by 70% as compared to control mice injected with nontargeting sh
RNA
lentivirus‐transduced bone marrow. A significant increase in atherosclerotic lesions was observed around the aorta valves as well as upon en face aorta analysis of Rev‐erbα knock‐down bone marrow recipients (
P
<0.01) as compared to the control mice, while plasma cholesterol, phospholipid, and triacylglycerol levels were not affected. Overexpression of Rev‐erbα in bone marrow mononuclear cells decreased inflammatory M1 while increasing M2 macrophage markers, while Rev‐erbα knock down increased the macrophage inflammatory phenotype in vitro and in vivo. Furthermore, treatment of differentiating macrophages with the Rev‐erbα ligand heme promoted expression of antiinflammatory M2 markers.

Conclusions
These observations identify hematopoietic cell Rev‐erbα as a new modulator of atherogenesis in mice.
Leukoaraiosis and Increased Cerebral Susceptibility to Ischemia: Lack of Confounding by Carotid Disease
Authors: Schulz Ursula G. , Grüter Basil E. , Briley Dennis , Rothwell Peter M. 
Published: August 2013

Background
Leukoaraiosis is associated with an increased risk of stroke, but the underlying mechanism remains uncertain, as do the associations with other risk factors, such as carotid disease. We aimed to determine the role of carotid disease and of other clinical variables in the development of leukoaraiosis and to define their contributions to the associated increased risk of stroke.

Methods and Results

We prospectively studied a large cohort of consecutive patients with transient ischemic attack (
TIA
) and minor stroke who attended a
TIA
clinic between 2002 and 2009. Detailed clinical data were obtained, and patients underwent magnetic resonance brain and vascular imaging. We assessed the severity of leukoaraiosis with use of the ARWMC (Age Related White Matter Changes) score: 671 patients (374 [56%] men; mean [
SD
] age 71 [11] years) were studied, of whom 415 (62%) had leukoaraiosis. In a multivariate analysis, leukoaraiosis was associated with increasing age (
P
<0.0001) and hypertension (
P
=0.01), as well as the presence of acute (
P
<0.0001) and chronic (
P
=0.014) infarction on magnetic resonance imaging. In the univariate analysis, a current and past diagnosis of stroke versus
TIA
also showed a strong association. Carotid disease was not associated with leukoaraiosis, even in the presence of a flow‐limiting (>70%) stenosis or occlusion, and the risk factor profiles for leukoaraiosis and carotid disease differed.

Conclusions

The association with more severe ischemic events (stroke versus
TIA
) and infarction on imaging is consistent with leukoaraiosis being a marker of increased cerebral susceptibility to ischemia. In contrast, the presence, severity of, and risk factors for atheromatous disease showed no association with leukoaraiosis, suggesting that these are two unrelated disease processes.
Long‐Term
miR‐669a
Therapy Alleviates Chronic Dilated Cardiomyopathy in Dystrophic Mice
Authors: Quattrocelli Mattia , Crippa Stefania , Montecchiani Celeste , Camps Jordi , Cornaglia Antonia Icaro , Boldrin Luisa , Morgan Jennifer , Calligaro Alberto , Casasco Andrea , Orlacchio Aldo , Gijsbers Rik , D'Hooge Jan , Toelen Jaan , Janssens Stefan , Sampaolesi Maurilio 
Published: August 2013

Background

Dilated cardiomyopathy (
DCM
) is a leading cause of chronic morbidity and mortality in muscular dystrophy (
MD
) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. Micro
RNA
s have been implicated as fine regulators of cardiomyopathic progression. Previously,
miR‐669a
downregulation has been linked to the severe
DCM
progression displayed by
Sgcb
‐null dystrophic mice. However, the impact of long‐term overexpression of
miR‐669a
on muscle structure and functionality of the dystrophic heart is yet unknown.

Methods and Results

Here, we demonstrate that intraventricular delivery of adeno‐associated viral (AAV) vectors induces long‐term (18 months)
miR‐669a
overexpression and improves survival of
Sgcb
‐null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover,
miR‐669a
treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/mi
RNA
profile of
DCM
markers. Furthermore, long‐term
miR‐669a
overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage.

Conclusions

Our findings provide the first evidence of long‐term beneficial impact of
AAV
‐mediated mi
RNA
therapy in a transgenic model of severe, chronic
MD
‐associated
DCM
.
Elevated Aerobic Fitness Sustained Throughout the Adult Lifespan Is Associated With Improved Cerebral Hemodynamics
Authors: Bailey Damian M. , Marley Christopher J. , Brugniaux Julien V. , Hodson Danielle , New Karl J. , Ogoh Shigehiko , Ainslie Philip N. 
Published: August 2013

Background and Purpose—

Age-related impairments in cerebral blood flow and cerebrovascular reactivity to carbon dioxide (CVR
CO2
) are established risk factors for stroke that respond favorably to aerobic training. The present study examined to what extent cerebral hemodynamics are improved when training is sustained throughout the adult lifespan.

Methods—

Eighty-one healthy males were prospectively assigned to 1 of 4 groups based on their age (young, ≤30 years versus old, ≥60 years) and lifetime physical activity levels (trained, ≥150 minutes recreational aerobic activity/week versus sedentary, no activity). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound), mean arterial pressure (MAP, finger photoplethysmography), and end-tidal partial pressure of carbon dioxide (P
ETCO
2
, capnography) were recorded during normocapnia and 3 mins of iso-oxic hypercapnea (5% CO
2
). Cerebrovascular resistance/conductance indices (CVRi/CVCi) were calculated as MAP/MCAv and MCAv/MAP, respectively, and CVR
CO2
as the percentage increase in MCAv from baseline per millimeter of mercury (mm Hg) increase in P
ETCO
2
. Maximal oxygen consumption (

O
2MAX
, online respiratory gas analysis) was determined during cycling ergometry.

Results—

By design, older participants were active for longer (49±5 versus 6±4 years,
P
<0.05). Physical activity attenuated the age-related declines in

O
2MAX
, MCAv, CVCi, and CVR
CO2
and increase in CVRi (
P
<0.05 versus sedentary). Linear relationships were observed between

O
2MAX
and both MCAv and CVR
CO2
(
r
=0.58–0.77,
P
<0.05).

Conclusions—
These findings highlight the importance of maintaining aerobic fitness throughout the lifespan given its capacity to improve cerebral hemodynamics in later-life.
A Novel and Low-Cost Sea Ice Mass Balance Buoy
Authors: Jackson Keith , Wilkinson Jeremy , Maksym Ted , Meldrum David , Beckers Justin , Haas Christian , Mackenzie David 
Published: August 2013

Abstract
The understanding of sea ice mass balance processes requires continuous monitoring of the seasonal evolution of the ice thickness. While autonomous ice mass balance (IMB) buoys deployed over the past two decades have contributed to scientists' understanding of ice growth and decay processes, deployment has been limited, in part, by the cost of such systems. Routine, basinwide monitoring of the ice cover is realistically achievable through a network of reliable and affordable autonomous instrumentation. This paper describes the development of a novel autonomous platform and sensor that replaces the traditional thermistor strings for monitoring temperature profiles in the ice and snow using a chain of inexpensive digital temperature chip sensors linked by a single-wire data bus. By incorporating a heating element into each sensor, the instrument is capable of resolving material interfaces (e.g., air–snow and ice–ocean boundaries) even under isothermal conditions. The instrument is small, low cost, and easy to deploy. Field and laboratory tests of the sensor chain demonstrate that the technology can reliably resolve material boundaries to within a few centimeters. The discrimination between different media based on sensor thermal response is weak in some deployments and efforts to optimize the performance continue.
Pica in pregnant women with diabetes: Does it really exist?
Authors: Okunoye Gbemisola O , Head Catherine , Issa Basil G 
Published: August 2013

Pica, the deliberate ingestion of non-food substances, has been described in different antenatal populations in some parts of the world. Although the aetiology remains unclear, pica has been associated with complications such as anaemia in pregnancy. Little is known regarding the existence of this phenomenon in a high-risk antenatal population such as women with diabetes in pregnancy. In this service review survey of 56 consecutive pregnant women attending our joint antenatal diabetes clinic, the practice of pica was found in 23% of the women. The commonest variant of pica in this group was pagophagy (ice) followed by amylophagy (uncooked starch). Other ingested items in this group were sand, paper, gloss paint and sponge. There is a need for increased awareness amongst antenatal health professionals regarding the existence of the phenomenon of pica. This would allow appropriate nutritional advice to be offered. Further work is required to determine the impact of the different variants of pica on glycaemic control and other important pregnancy outcomes in diabetic patients.