bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Focused Small-Molecule Screen Identifies 14 Compounds with Distinct Effects on Toxoplasma gondii
Authors: Kamau Edwin T. , Srinivasan Ananth R. , Brown Mark J. , Fair Matthew G. , Caraher Erin J. , Boyle Jon P. 
Published: August 2012

ABSTRACT

Toxoplasma gondii
is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of
Toxoplasma
-secreted kinases in the interaction of
Toxoplasma
with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-
Toxoplasma
drugs and define new pathways important for parasite survival. We selected a small (
n
= 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth of
Toxoplasma
in vitro
. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.
Early Insights into the Interactions of Different β-Lactam Antibiotics and β-Lactamase Inhibitors against Soluble Forms of Acinetobacter baumannii PBP1a and Acinetobacter sp. PBP3
Authors: Papp-Wallace Krisztina M. , Senkfor Baui , Gatta Julian , Chai Weirui , Taracila Magdalena A. , Shanmugasundaram Veerabahu , Han Seungil , Zaniewski Richard P. , Lacey Brian M. , Tomaras Andrew P. , Skalweit Marion J. , Harris Michael E. , Rice Louis B. , Buynak John D. , Bonomo Robert A. 
Published: August 2012

ABSTRACT

Acinetobacter baumannii
is an increasingly problematic pathogen in United States hospitals. Antibiotics that can treat
A. baumannii
are becoming more limited. Little is known about the contributions of penicillin binding proteins (PBPs), the target of β-lactam antibiotics, to β-lactam–sulbactam susceptibility and β-lactam resistance in
A. baumannii
. Decreased expression of PBPs as well as loss of binding of β-lactams to PBPs was previously shown to promote β-lactam resistance in
A. baumannii
. Using an
in vitro
assay with a reporter β-lactam, Bocillin, we determined that the 50% inhibitory concentrations (IC
50
s) for PBP1a from
A. baumannii
and PBP3 from
Acinetobacter
sp. ranged from 1 to 5 μM for a series of β-lactams. In contrast, PBP3 demonstrated a narrower range of IC
50
s against β-lactamase inhibitors than PBP1a (ranges, 4 to 5 versus 8 to 144 μM, respectively). A molecular model with ampicillin and sulbactam positioned in the active site of PBP3 reveals that both compounds interact similarly with residues Thr526, Thr528, and Ser390. Accepting that many interactions with cell wall targets are possible with the ampicillin-sulbactam combination, the low IC
50
s of ampicillin and sulbactam for PBP3 may contribute to understanding why this combination is effective against
A. baumannii
. Unraveling the contribution of PBPs to β-lactam susceptibility and resistance brings us one step closer to identifying which PBPs are the best targets for novel β-lactams.
Pharmacokinetics and Renal Disposition of Polymyxin B in an Animal Model
Authors: Abdelraouf Kamilia , He Jie , Ledesma Kimberly R. , Hu Ming , Tam Vincent H. 
Published: August 2012

ABSTRACTThe increasing prevalence of multidrug-resistant Gram-negative infections has led to the resurgence of systemic polymyxin B, but little is known about its pharmacokinetics. The objective of this study was to characterize the pharmacokinetics and renal disposition of polymyxin B. Eight female Sprague-Dawley rats (weight, 225 to 250 g) were administered a single intravenous polymyxin B dose (4 mg/kg of body weight). Serial serum samples were collected and assayed for major polymyxin B components using a validated ultraperformance liquid chromatography-tandem mass spectrometry method. The best-fit pharmacokinetic parameters of each component were derived and compared using one-way analysis of variance. Cumulative urine was also collected daily for 48 h and assayed for polymyxin B. Kidney drug concentrations were measured at 6 h (n= 3) and 48 h (n= 3) after the same dose. Additionally, three rats were administered 2 doses of intravenous polymyxin B (4 mg/kg) 7 days apart. Serial serum samples were collected pre- and post-renal insufficiency (induced by uranyl nitrate) and assayed for polymyxin B. The pharmacokinetic parameters of the major components did not appear to be significantly different (P> 0.05). Less than 1% of the dose was recovered unchanged in urine collected over 48 h following administration. Therapeutic drug concentrations persisted in kidney tissue at 48 h. The post-renal insufficiency to pre-renal insufficiency ratio of the area under the serum concentration-time curve from time zero to infinity was 1.33 ± 0.04. Polymyxin B components appear to have similar pharmacokinetics. Polymyxin B preferentially persists in kidneys, which suggests a selective uptake process in renal cells. A mechanism(s) other than renal excretion could be involved in polymyxin B elimination, and dosing adjustment in renal insufficiency may not be necessary.
Early Control of Mycobacterium tuberculosis Infection Requiresil12rb1Expression byrag1-Dependent Lineages
Authors: Miller Halli E. , Robinson Richard T. 
Published: August 2012

ABSTRACTIL12RB1is essential for human resistance toMycobacterium tuberculosisinfection. In the absence of a functionalIL12RB1allele, individuals exhibit susceptibility to disseminated, recurrent mycobacterial infections that are associated with defects in bothRAG1-dependent andRAG1-independent hematopoietic lineages. Despite this well-established association, a causal relationship betweenM. tuberculosissusceptibility andIL12RB1deficiency in eitherRAG1-dependent orRAG1-independent lineages has never been formally tested. Here, we use the low-dose aerosol model of experimental tuberculosis (TB) to both establish that infectedil12rb1−/−mice recapitulate important aspects of TB inIL12RB1null individuals and, more importantly, use radiation bone marrow chimeras to demonstrate that restriction ofil12rb1deficiency solely torag1-dependent lineages (i.e., T and B cells) allows for the full transfer of theil12rb1−/−phenotype. We further demonstrate that the protection afforded by adaptive lymphocyteil12rb1expression is mediated partially throughifngand that, within the same infection,il12rb1-sufficient T cells exhibit dominance overil12rb1-deficient T cells by enhancingifngexpression in the latter population. Collectively, our data establish a basic framework in which to understand howIL12RB1promotes control of this significant human disease.
Persistent Mycoplasma genitalium Infection of Human Endocervical Epithelial Cells Elicits Chronic Inflammatory Cytokine Secretion
Authors: McGowin Chris L. , Annan Rochelle S. , Quayle Alison J. , Greene Sheila J. , Ma Liang , Mancuso Miriam M. , Adegboye David , Martin David H. 
Published: August 2012

ABSTRACT

Infection with
Mycoplasma genitalium
has been associated with male and female urogenital disease syndromes, including urethritis, cervicitis, pelvic inflammatory disease (PID), and tubal factor infertility. Basic investigations of mucosal cytotoxicity, microbial persistence, and host immune responses are imperative to understanding these inflammatory urogenital syndromes, particularly in females, considering the potential severity of upper tract infections. Here, we report that
M. genitalium
can establish long-term infection of human endocervical epithelial cells that results in chronic inflammatory cytokine secretion and increased responsiveness to secondary Toll-like receptor (TLR) stimulation. Using a novel quantitative PCR assay,
M. genitalium
was shown to replicate from 0 to 80 days postinoculation (p.i.), during which at most time points the median ratio of
M. genitalium
organisms to host cells was ≤10, indicating that low organism burdens are capable of eliciting chronic inflammation in endocervical epithelial cells. This observation is consistent with clinical findings in women. Persistently secreted cytokines predominately consisted of potent chemotactic and/or activating factors for phagocytes, including interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1β (MIP-1β). Despite persistent cytokine elaboration, no host cell cytotoxicity was observed except with superphysiologic loads of
M. genitalium
, suggesting that persistent infection occurs with minimal direct damage to the epithelium. However, it is hypothesized that chronic chemokine secretion with leukocyte trafficking to the epithelium could lead to significant inflammatory sequelae. Therefore, persistent
M. genitalium
infection could have important consequences for acquisition and/or pathogenesis of other sexually transmitted infections (STIs) and perhaps explain the positive associations between this organism and human immunodeficiency virus (HIV) shedding.
Syphilis infection among homosexual men reporting contact with syphilis: a case control study
Authors: Weerakoon Ajith P , Fairley Christopher K , Read Tim RH , Bradshaw Catriona , Forrester Catherine , Bissessor Melanie , Denham Ian , Chen Marcus Y 
Published: August 2012

ObjectiveHigh rates of syphilis have been reported among men who have sex with men (MSM) internationally. Guidelines recommend presumptive treatment of sexual contacts of individuals with syphilis at the point of care. The aim of this study was to determine the proportion who were infected with syphilis and the factors predictive of infection among men reporting contact with a man with syphilis.DesignContacts who were syphilis infected (cases) were compared with those who were uninfected (controls).SettingThis study was conducted at the main public sexually transmitted diseases clinic in Victoria, Australia.ParticipantsOne hundred and seventy-two MSM presenting as sexual contacts of men with syphilis at a sexual health service in Melbourne, Australia, between July 2007 and October 2011 were assessed for syphilis.Outcome measuresProportion of MSM who are infected with syphilis and factors associated with infection.ResultsOf the 172 men who presented reporting contact with syphilis, 26 (15%, 95% CI 10 to 20%) had syphilis. One man had primary syphilis, 4 had secondary syphilis, while the remaining 21 had early latent syphilis. Infection was associated with unprotected anal sex over the prior 3 months (adjusted OR 6.1, 95% CI 1.4 to 26.8).ConclusionsOne in seven men presenting as contacts of syphilis had syphilis infection, most of whom were latently infected. Contacts reporting recent unprotected anal sex were more likely to have syphilis.
Buried-valley aquifers in the Canadian Prairies: geology, hydrogeology, and origin1Earth Science Sector (ESS) Contribution 20120131.
Authors: Cummings Don I. , Russell Hazen A.J. , Sharpe David R. 
Published: August 2012

We review over 100 years of literature on Prairie buried valleys to provide a platform for future research and policy development. Prairie buried-valley fills commonly function as aquifers that yield abundant groundwater. They have distinct geologies and a distinct stratigraphic setting, which imparts them with distinct hydrogeological properties and gives clues as to how they formed and filled. Prairie buried-valley aquifers are commonly encased in low-permeability strata: Cretaceous shale commonly underlies them, and thick (10–300 m) low-permeability Quaternary till tends to overlie them. This reduces recharge, in rare cases nearly completely, while protecting groundwater resources from contamination and drought. It also tends to lead to highly mineralized groundwater chemistries. The stratigraphic position of Prairie buried valleys also speaks to their origin: those that subtend (“hang”) from the bedrock unconformity were likely eroded by preglacial fluvial systems during late Tertiary uplift of the Rocky Mountains, whereas those that subtend from surfaces within the till package are likely glaciofluvial valleys eroded in proglacial spillway or tunnel-valley settings. Another key trait of Prairie buried valleys is that their fills tend to be heterogeneous and architecturally complex. Sand, gravel, mud, and diamicton are common; any one can dominate the fill at a given location. This heterogeneity, in conjunction with irregularity common to buried-valley bedrock floors, commonly causes aquifer compartmentalization and makes prediction of aquifer potential difficult prior to drilling. It also suggests that most Prairie buried valleys filled over time, and likely over multiple glaciations, in multiple depositional environments.
Dehydration decreases saliva antimicrobial proteins important for mucosal immunity
Authors: Fortes Matthew B. , Diment Bethany C. , Di Felice Umberto , Walsh Neil P. 
Published: August 2012

The aim of the study was to investigate the effect of exercise-induced dehydration and subsequent overnight fluid restriction on saliva antimicrobial proteins important for host defence (secretory IgA (SIgA), α-amylase, and lysozyme). On two randomized occasions, 13 participants exercised in the heat, either without fluid intake to evoke progressive body mass losses (BML) of 1%, 2%, and 3% with subsequent overnight fluid restriction until 0800 h in the following morning (DEH) or with fluids to offset losses (CON). Participants in the DEH trial rehydrated from 0800 h until 1100 h on day 2. BML, plasma osmolality (Posm), and urine specific gravity (USG) were assessed as hydration indices. Unstimulated saliva samples were assessed for flow rate (SFR), SIgA, α-amylase, and lysozyme concentrations. Posm and USG increased during dehydration and remained elevated after overnight fluid restriction (BML = 3.5% ± 0.3%, Posm = 297 ± 6 mosmol·kg–1, and USG = 1.026 ± 0.002; P < 0.001). Dehydration decreased SFR (67% at 3% BML, 70% at 0800 h; P < 0.01) and increased SIgA concentration, with no effect on SIgA secretion rate. SFR and SIgA responses remained unchanged in the CON trial. Dehydration did not affect α-amylase or lysozyme concentration but decreased secretion rates of α-amylase (44% at 3% BML, 78% at 0800 h; P < 0.01) and lysozyme (46% at 3% BML, 61% at 0800 h; P < 0.01), which were lower than in CON at these time points (P < 0.05). Rehydration returned all saliva variables to baseline. In conclusion, modest dehydration (~3% BML) decreased SFR, α-amylase, and lysozyme secretion rates. Whether the observed magnitude of decrease in saliva AMPs during dehydration compromises host defence remains to be shown.
Estimated times to exhaustion and power outputs at the gas exchange threshold, physical working capacity at the rating of perceived exertion threshold, and respiratory compensation point
Authors: Bergstrom Haley C. , Housh Terry J. , Zuniga Jorge M. , Camic Clayton L. , Traylor Daniel A. , Schmidt Richard J. , Johnson Glen O. 
Published: August 2012

The purposes of this study were to compare the power outputs and estimated times to exhaustion (Tlim) at the gas exchange threshold (GET), physical working capacity at the rating of perceived exertion threshold (PWCRPE), and respiratory compensation point (RCP). Three male and 5 female subjects (mean ± SD: age, 22.4 ± 2.8 years) performed an incremental test to exhaustion on an electronically braked cycle ergometer to determine peak oxygen consumption rate, GET, and RCP. The PWCRPEwas determined from ratings of perceived exertion data recorded during 3 continuous workbouts to exhaustion. The estimated Tlimvalues for each subject at GET, PWCRPE, and RCP were determined from power curve analyses (Tlim = axb). The results indicated that the PWCRPE(176 ± 55 W) was not significantly different from RCP (181 ± 54 W); however, GET (155 ± 42 W) was significantly less than PWCRPEand RCP. The estimated Tlimfor the GET (26.1 ± 9.8 min) was significantly greater than PWCRPE(14.6 ± 5.6 min) and RCP (11.2 ± 3.1 min). The PWCRPEoccurred at a mean power output that was 13.5% greater than the GET and, therefore, it is likely that the perception of effort is not driven by the same mechanism that underlies the GET (i.e., lactate buffering). Furthermore, the PWCRPEand RCP were not significantly different and, therefore, these thresholds may be associated with the same mechanisms of fatigue, such as increased levels of interstitial and (or) arterial [K+].
Oxygen uptake and heart rate response of 6 standardized tennis drills
Authors: Bekraoui Nabyl , Fargeas-Gluck Marie-Agnès , Léger Luc 
Published: August 2012

The purpose of this study was to compare the oxygen uptake of various on-court tennis drills. Eleven tennis players were monitored with a portable metabolic device to measure oxygen uptake of 6 different tennis drills at low and high speeds. The 6 drills were done with or without striking the ball, over half or full-width of the court, in attack or defense mode, using forehand or backhand strokes. Oxygen uptake values (mean ± SD) ranged from 33.8 ± 4.2 to 42.3 ± 5.1 mL·kg–1·min–1 when running at low speed on the full-width court in defense mode without striking the ball and when running at high speed on the full-width court in attack mode while striking the ball, respectively. Specific differences were observed. Attacking mode requires 6.5% more energy than defensive playing mode. Backhand strokes demand 7% more energy at low speed than forehand ones. Running and striking the ball costs 10% more energy than running without striking the ball. While striking the ball, shuttle running on half-width court costs 14% more energy than running on full-width courts. The specificity of the oxygen uptake responses obtained for these various tennis drills gives an improved representation of their energy cost and could be used to optimize training loads.
Population Approaches to Improve Diet, Physical Activity, and Smoking Habits
Authors: Mozaffarian Dariush , Afshin Ashkan , Benowitz Neal L. , Bittner Vera , Daniels Stephen R. , Franch Harold A. , Jacobs David R. , Kraus William E. , Kris-Etherton Penny M. , Krummel Debra A. , Popkin Barry M. , Whitsel Laurie P. , Zakai Neil A. 
Published: August 2012

Background—
Poor lifestyle behaviors, including suboptimal diet, physical inactivity, and tobacco use, are leading causes of preventable diseases globally. Although even modest population shifts in risk substantially alter health outcomes, the optimal population-level approaches to improve lifestyle are not well established.

Methods and Results—
For this American Heart Association scientific statement, the writing group systematically reviewed and graded the current scientific evidence for effective population approaches to improve dietary habits, increase physical activity, and reduce tobacco use. Strategies were considered in 6 broad domains: (1) Media and educational campaigns; (2) labeling and consumer information; (3) taxation, subsidies, and other economic incentives; (4) school and workplace approaches; (5) local environmental changes; and (6) direct restrictions and mandates. The writing group also reviewed the potential contributions of healthcare systems and surveillance systems to behavior change efforts. Several specific population interventions that achieved a Class I or IIa recommendation with grade A or B evidence were identified, providing a set of specific evidence-based strategies that deserve close attention and prioritization for wider implementation. Effective interventions included specific approaches in all 6 domains evaluated for improving diet, increasing activity, and reducing tobacco use. The writing group also identified several specific interventions in each of these domains for which current evidence was less robust, as well as other inconsistencies and evidence gaps, informing the need for further rigorous and interdisciplinary approaches to evaluate population programs and policies.

Conclusions—
This systematic review identified and graded the evidence for a range of population-based strategies to promote lifestyle change. The findings provide a framework for policy makers, advocacy groups, researchers, clinicians, communities, and other stakeholders to understand and implement the most effective approaches. New strategic initiatives and partnerships are needed to translate this evidence into action.
Long-Term Survival After Aortic Valve Replacement Among High-Risk Elderly Patients in the United States
Authors: Brennan J. Matthew , Edwards Fred H. , Zhao Yue , O'Brien Sean M. , Douglas Pamela S. , Peterson Eric D. 
Published: August 2012

Background—
Surgical aortic valve replacement (AVR) remains the standard of care for the treatment of operable, symptomatic aortic valve disease; however, to date, there are limited national data on the contemporary long-term outcomes after AVR in older individuals.

Methods and Results—
We examined long-term survival among 145 911 AVR patients ≥65 years of age undergoing AVR at 1026 centers with participation in the Society of Thoracic Surgeons Adult Cardiac Surgery Database from 1991 to 2007. In-hospital complications and long-term survival were stratified by age, Society of Thoracic Surgeons perioperative risk of mortality, and several comorbidities. The median patient age was 76 years; 16% had chronic lung disease, 6% had preoperative renal failure, 38% had heart failure, and 12% had prior cardiac surgery. The median survival in patients 65 to 69, 70 to 79, and ≥80 years of age undergoing isolated AVR was 13, 9, and 6 years, respectively. For AVR plus coronary artery bypass graft procedures, median survival was 10, 8, and 6 years, respectively. Although only 5% of isolated AVR patients had a high Society of Thoracic Surgeons perioperative risk of mortality (≥10%), their median survival was 2.5 to 2.7 years. Severe lung disease and renal failure were each associated with a ≥50% reduction in median survival among all age groups compared with those who did not have these comorbidities, whereas left ventricular dysfunction and prior cardiac operation were associated with a 25% reduction in median survival.

Conclusion—
Long-term survival after surgical AVR in the elderly is excellent, although patients with a high Society of Thoracic Surgeons perioperative risk of mortality and those with certain comorbidities carry a particularly poor long-term prognosis.