bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fetal in vivo continuous cardiovascular function during chronic hypoxia
Authors: Allison B. J. , Brain K. L. , Niu Y. , Kane A. D. , Herrera E. A. , Thakor A. S. , Botting K. J. , Cross C. M. , Itani N. , Skeffington K. L. , Beck C. , Giussani D. A. 
Published: March 2016

Key points
The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing.
We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth‐restricted fetus.
This technology permits wireless recording in free‐moving animals of longitudinal maternal and fetal cardiovascular function, including beat‐to‐beat alterations in pressure and blood flow signals in regional circulations.
The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism.
AbstractAlthough the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (Δ: 4.8 ± 1.6 vs. 0.5 ± 1.4 μmol l−1, P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase‐derived reactive oxygen species.
Relationship between Adherence to Oral Antibiotics and Postdischarge Clinical Outcomes among Patients Hospitalized with Staphylococcus aureus Skin Infections
Authors: Eells Samantha J. , Nguyen Megan , Jung Jina , Macias-Gil Raul , May Larissa , Miller Loren G. 
Published: March 2016

ABSTRACT

Skin and soft tissue infections are common and frequently recur. Poor adherence to antibiotic therapy may lead to suboptimal clinical outcomes. However, adherence to oral antibiotic therapy for skin and soft tissue infections and its relationship to clinical outcomes have not been examined. We enrolled adult patients hospitalized with uncomplicated skin and soft tissue infections caused by
Staphylococcus aureus
who were being discharged with oral antibiotics to complete therapy. We fit the participants' pill bottles with an electronic bottle cap that recorded each pill bottle opening, administered an in-person standardized questionnaire at enrollment, 14 days, and 30 days, and reviewed the participants' medical records to determine outcomes. Our primary outcome was poor clinical response, defined as a change in antibiotic therapy, new incision-and-drainage procedure, or new skin infection within 30 days of hospital discharge. Of our 188 participants, 87 had complete data available for analysis. Among these participants, 40 (46%) had a poor clinical response at 30 days. The mean electronically measured adherence to antibiotic therapy was significantly different than the self-reported adherence (57% versus 96%;
P
< 0.0001). In a multivariable model, poor clinical response at 30 days was associated with patients having lower adherence, being nondiabetic, and reporting a lack of illicit drug use within the previous 12 months (
P
< 0.05). In conclusion, we found that patient adherence to oral antibiotic therapy for a skin and soft tissue infection after hospital discharge was low (57%) and associated with poor clinical outcome. Patients commonly overstate their medication adherence, which may make identification of patients at risk for nonadherence and poor outcomes challenging. Further studies are needed to improve postdischarge antibiotic adherence after skin and soft tissue infections.
In Vitro
Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014)
Authors: de Jonge Boudewijn L. M. , Karlowsky James A. , Kazmierczak Krystyna M. , Biedenbach Douglas J. , Sahm Daniel F. , Nichols Wright W. 
Published: March 2016

ABSTRACT

The activity of ceftazidime-avibactam was assessed against 961 isolates of meropenem-nonsusceptible
Enterobacteriaceae
. Most meropenem-nonsusceptible metallo-β-lactamase (MBL)-negative isolates (97.7%) were susceptible to ceftazidime-avibactam. Isolates that carried KPC or OXA-48-like β-lactamases, both alone and in combination with extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamases, were 98.7% and 98.5% susceptible to ceftazidime-avibactam, respectively. Meropenem-nonsusceptible, carbapenemase-negative isolates demonstrated 94.7% susceptibility to ceftazidime-avibactam. Ceftazidime-avibactam activity was compromised only in isolates for which carbapenem resistance was mediated through metallo-β-lactamases.
Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease
Authors: Ferro Beatriz E. , Srivastava Shashikant , Deshpande Devyani , Pasipanodya Jotam G. , van Soolingen Dick , Mouton Johan W. , van Ingen Jakko , Gumbo Tawanda 
Published: March 2016

ABSTRACT

Mycobacterium abscessus
causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary
M. abscessus
infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC
80
). The tigecycline efficacy was 5.38 ± 2.35 log
10
CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log
10
CFU/ml below the pretreatment inoculum (1-log kill) of
M. abscessus
in the hollow-fiber system. The EC
80
AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC
80
or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC
80
and 46% for 1-log kill. For both the EC
80
target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was ≤0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment.
Haemophilus ducreyi Seeks Alternative Carbon Sources and Adapts to Nutrient Stress and Anaerobiosis during Experimental Infection of Human Volunteers
Authors: Gangaiah Dharanesh , Zhang Xinjun , Baker Beth , Fortney Kate R. , Gao Hongyu , Holley Concerta L. , Munson Robert S. , Liu Yunlong , Spinola Stanley M. 
Published: March 2016

ABSTRACT

Haemophilus ducreyi
causes the sexually transmitted disease chancroid in adults and cutaneous ulcers in children. In humans,
H. ducreyi
resides in an abscess and must adapt to a variety of stresses. Previous studies (D. Gangaiah, M. Labandeira-Rey, X. Zhang, K. R. Fortney, S. Ellinger, B. Zwickl, B. Baker, Y. Liu, D. M. Janowicz, B. P. Katz, C. A. Brautigam, R. S. Munson, Jr., E. J. Hansen, and S. M. Spinola, mBio 5:e01081-13, 2014,
http://dx.doi.org/10.1128/mBio.01081-13
) suggested that
H. ducreyi
encounters growth conditions in human lesions resembling those found in stationary phase. However, how
H. ducreyi
transcriptionally responds to stress during human infection is unknown. Here, we determined the
H. ducreyi
transcriptome in biopsy specimens of human lesions and compared it to the transcriptomes of bacteria grown to mid-log, transition, and stationary phases. Multidimensional scaling showed that the
in vivo
transcriptome is distinct from those of
in vitro
growth. Compared to the inoculum (mid-log-phase bacteria),
H. ducreyi
harvested from pustules differentially expressed ∼93 genes, of which 62 were upregulated. The upregulated genes encode homologs of proteins involved in nutrient transport, alternative carbon pathways (
l
-ascorbate utilization and metabolism), growth arrest response, heat shock response, DNA recombination, and anaerobiosis.
H. ducreyi
upregulated few genes (
hgbA
,
flp-tad
, and
lspB-lspA2
) encoding virulence determinants required for human infection. Most genes regulated by CpxRA, RpoE, Hfq, (p)ppGpp, and DksA, which control the expression of virulence determinants and adaptation to a variety of stresses, were not differentially expressed
in vivo
, suggesting that these systems are cycling on and off during infection. Taken together, these data suggest that the
in vivo
transcriptome is distinct from those of
in vitro
growth and that adaptation to nutrient stress and anaerobiosis is crucial for
H. ducreyi
survival in humans.
FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6
Authors: Bhattacharyya Sanghamitra , Ghosh Santosh K. , Shokeen Bhumika , Eapan Betty , Lux Renate , Kiselar Janna , Nithianantham Stanley , Young Andrew , Pandiyan Pushpa , McCormick Thomas S. , Weinberg Aaron 
Published: March 2016

ABSTRACTWe previously identified a cell wall-associated protein fromFusobacterium nucleatum, a Gram-negative bacterium of the oral cavity, that induces human beta defensin 2 (hBD-2) in primary human oral epithelial cells (HOECs) and designated it FAD-I (Fusobacterium-associateddefensininducer). Here, we report differential induction of hBD-2 by different strains ofF. nucleatum; ATCC 25586 and ATCC 23726 induce significantly more hBD-2 mRNA than ATCC 10953. Heterologous expression of plasmid-bornefadIfrom the highly hBD-2-inducing strains in a ΔfadImutant of ATCC 10953 resulted in hBD-2 induction to levels comparable to those of the highly inducing strains, indicating that FAD-I is the principalF. nucleatumagent for hBD-2 induction in HOECs. Moreover, anti-FAD-I antibodies blockedF. nucleatuminduction of hBD-2 by more than 80%. Recombinant FAD-I (rFAD-I) expressed inEscherichia colitriggered levels of hBD-2 transcription and peptide release in HOECs similar to those of native FAD-I (nFAD-I) isolated fromF. nucleatumATCC 25586. Tandem mass spectrometry revealed a diacylglycerol modification at the cysteine residue in position 16 for both nFAD-I and rFAD-I. Cysteine-to-alanine substitution abrogated FAD-I's ability to induce hBD-2. Finally, FAD-I activation of hBD-2 expression was mediated via both Toll-like receptor-1/2 (TLR-1/2) and TLR-2/6 heterodimerization. Microbial molecules like FAD-I may be utilized in novel therapeutic ways to bolster the host innate immune response at mucosal surfaces.
Vfr Directly Activates
exsA
Transcription To Regulate Expression of the Pseudomonas aeruginosa Type III Secretion System
Authors: Marsden Anne E. , Intile Peter J. , Schulmeyer Kayley H. , Simmons-Patterson Ethan R. , Urbanowski Mark L. , Wolfgang Matthew C. , Yahr Timothy L. 
Published: March 2016

ABSTRACT

The
Pseudomonas aeruginosa
cyclic AMP (cAMP)-Vfr system (CVS) is a global regulator of virulence gene expression. Regulatory targets include type IV pili, secreted proteases, and the type III secretion system (T3SS). The mechanism by which CVS regulates T3SS gene expression remains undefined. Single-cell expression studies previously found that only a portion of the cells within a population express the T3SS under inducing conditions, a property known as bistability. We now report that bistability is altered in a
vfr
mutant, wherein a substantially smaller fraction of the cells express the T3SS relative to the parental strain. Since bistability usually involves positive-feedback loops, we tested the hypothesis that virulence factor regulator (Vfr) regulates the expression of
exsA
. ExsA is the central regulator of T3SS gene expression and autoregulates its own expression. Although
exsA
is the last gene of the
exsCEBA
polycistronic mRNA, we demonstrate that Vfr directly activates
exsA
transcription from a second promoter (P

exsA

) located immediately upstream of
exsA
. P

exsA

promoter activity is entirely Vfr dependent. Direct binding of Vfr to a P

exsA

promoter probe was demonstrated by electrophoretic mobility shift assays, and DNase I footprinting revealed an area of protection that coincides with a putative Vfr consensus-binding site. Mutagenesis of that site disrupted Vfr binding and P

exsA

promoter activity. We conclude that Vfr contributes to T3SS gene expression through activation of the P

exsA

promoter, which is internal to the previously characterized
exsCEBA
operon.

IMPORTANCE
Vfr is a cAMP-dependent DNA-binding protein that functions as a global regulator of virulence gene expression in
Pseudomonas aeruginosa
. Regulation by Vfr allows for the coordinate production of related virulence functions, such as type IV pili and type III secretion, required for adherence to and intoxication of host cells, respectively. Although the molecular mechanism of Vfr regulation has been defined for many target genes, a direct link between Vfr and T3SS gene expression had not been established. In the present study, we report that Vfr directly controls
exsA
transcription, the master regulator of T3SS gene expression, from a newly identified promoter located immediately upstream of
exsA
.
A Membrane-Embedded Amino Acid Couples the SpoIIQ Channel Protein to Anti-Sigma Factor Transcriptional Repression during Bacillus subtilis Sporulation
Authors: Flanagan Kelly A. , Comber Joseph D. , Mearls Elizabeth , Fenton Colleen , Wang Erickson Anna F. , Camp Amy H. 
Published: March 2016

ABSTRACT

SpoIIQ is an essential component of a channel connecting the developing forespore to the adjacent mother cell during
Bacillus subtilis
sporulation. This channel is generally required for late gene expression in the forespore, including that directed by the late-acting sigma factor σ
G
. Here, we present evidence that SpoIIQ also participates in a previously unknown gene regulatory circuit that specifically represses expression of the gene encoding the anti-sigma factor CsfB, a potent inhibitor of σ
G
. The
csfB
gene is ordinarily transcribed in the forespore only by the early-acting sigma factor σ
F
. However, in a mutant lacking the highly conserved SpoIIQ transmembrane amino acid Tyr-28,
csfB
was also aberrantly transcribed later by σ
G
, the very target of CsfB inhibition. This regulation of
csfB
by SpoIIQ Tyr-28 is specific, given that the expression of other σ
F
-dependent genes was unaffected. Moreover, we identified a conserved element within the
csfB
promoter region that is both necessary and sufficient for SpoIIQ Tyr-28-mediated inhibition. These results indicate that SpoIIQ is a bifunctional protein that not only generally promotes σ
G
activity in the forespore as a channel component but also specifically maximizes σ
G
activity as part of a gene regulatory circuit that represses σ
G
-dependent expression of its own inhibitor, CsfB. Finally, we demonstrate that SpoIIQ Tyr-28 is required for the proper localization and stability of the SpoIIE phosphatase, raising the possibility that these two multifunctional proteins cooperate to fine-tune developmental gene expression in the forespore at late times.

IMPORTANCE
Cellular development is orchestrated by gene regulatory networks that activate or repress developmental genes at the right time and place. Late gene expression in the developing
Bacillus subtilis
spore is directed by the alternative sigma factor σ
G
. The activity of σ
G
requires a channel apparatus through which the adjacent mother cell provides substrates that generally support gene expression. Here we report that the channel protein SpoIIQ also specifically maximizes σ
G
activity as part of a previously unknown regulatory circuit that prevents σ
G
from activating transcription of the gene encoding its own inhibitor, the anti-sigma factor CsfB. The discovery of this regulatory circuit significantly expands our understanding of the gene regulatory network controlling late gene expression in the developing
B. subtilis
spore.
Effect of obesity on cognition in adults with and without a mood disorder: study design and methods
Authors: Restivo Maria R , McKinnon Margaret C , Frey Benicio N , Hall Geoffrey B , Taylor Valerie H 
Published: March 2016

IntroductionObesity is a common medical illness that is increasingly recognised as conferring risk of decline in cognitive performance, independent of other comorbid medical conditions. Individuals with mood disorders (bipolar disorder (BD) or major depressive disorder (MDD)) display an increased prevalence of both obesity and risk factors for cardiovascular diseases. Moreover, BD and MDD are associated with impairment in cognitive functioning across multiple domains. The independent contribution of obesity to cognitive decline in this population has not been explored. This study examines the impact of obesity on cognition by comparing neuropsychological performance in obese individuals, with or without a mood disorder before and after undergoing bariatric surgery.Methods and analysisThis study compares measures of declarative memory, executive functioning and attention in obese individuals (body mass index >35 kg/m2) with BD or MDD, and 2 control populations (obese individuals without a psychiatric illness and healthy non-obese controls) prior to and following bariatric surgery. Participants (ages 18–60) receive a psychiatric diagnosis via the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; SCID). Mood ratings, physical measurements, nutritional and health questionnaires are also administered. A standardised battery of neuropsychological tests aimed at establishing performance in areas of declarative memory, executive functioning and attention are administered. Warrington'sRecognition Memory Task(RMT) and an N-Back Task are performed in a 3 T functional MRI to investigate patterns of neural activation during cognitive performance. Additionally, anatomical MRI data are obtained to investigate potential changes in neural structures. Baseline data will be analysed for between-group differences and later compared with postsurgical data to investigate cognitive change.Ethics and disseminationThis study has been approved by the Hamilton Integrated Research Ethics Board (09–3254). Results will be available in peer-reviewed scientific publications and scientific meetings presentations, and released in lay form to media.
Multidisciplinary approach to the management of children with female genital mutilation (FGM) or suspected FGM: service description and case series
Authors: Creighton Sarah M , Dear Joanna , de Campos Claudia , Williams Louise , Hodes Deborah 
Published: March 2016

ObjectiveTo describe the first dedicated clinic in the UK for children with suspected or confirmed female genital mutilation (FGM) including referral patterns, clinical findings and subsequent management.Design and settingA prospective study of all children seen in a dedicated multidisciplinary FGM clinic for children over a 1-year period.PopulationPatients aged under 18 years referred for clinical assessment or for a second opinion on Digital Versatile Disc (DVD) images.Methods and main outcome measuresData were collected on reasons for referral, demography, genital examination findings including FGM type, and clinical recommendations.Results38 children were referred of whom 18 (47%) had confirmed FGM; most frequently type 4 (61%). Social care and police referred 78% of cases. According to UK law FGM had been performed illegally in three cases. Anonymous information given to the police led to the referral of six children, none of whom had had FGM.ConclusionsMandatory reporting and increased media attention may increase the numbers of referrals of children with suspected FGM. This patient group have complex needs and management in a dedicated multidisciplinary service is essential. Paediatricians and gynaecologists should have the skills to carry out the consultation and detect all types of FGM including type 4 which was the most common type seen in this series. This is the first dedicated FGM service for children in the UK and similar clinics in high-prevalence areas should be established.
A systematic approach to the characterisation of human impact injury scenarios in sport
Authors: Payne Thomas , Mitchell Séan , Halkon Ben , Bibb Richard 
Published: March 2016

BackgroundIn contact sports (eg, American football or rugby), injuries resulting from impacts are widespread. There have been several attempts to identify and collate, within a conceptual framework, factors influencing the likelihood of an injury. To effectively define an injury event it is necessary to systematically consider all potential causal factors but none of the previous approaches are complete in this respect.AimsFirst, to develop a superior deterministic contextual sequential (DCS) model to promote a complete and logical description of interrelated injury event factors. Second, to demonstrate systematic use of the model to construct enhanced perspectives for impact-injury research.MethodPrevious models were examined and elements of best practice synthesised into a new DCS framework description categorising the types of causal factors influencing injury. The approach's internal robustness is demonstrated by consideration of its completeness, lack of redundancy and logical consistency.ResultsThe model's external validity and worth are demonstrated through its use to generate superior descriptive injury models, experimental protocols and intervention opportunities. Comprehensive research perspectives have been developed using a common rugby impact-injury scenario as an example; this includes: a detailed description of the injury event, an experimental protocol for a human-on-surrogate reconstruction, and a series of practical interventions in the sport of rugby aimed at mitigating the risk of injury.ConclusionsOur improved characterisation tool presents a structured approach to identify pertinent factors relating to an injury.