bluuebunny/crossref_metadata_2025_split huggingface dataset:
NLRP3 Is a Critical Regulator of Inflammation and Innate Immune Cell Response during Mycoplasma pneumoniae Infection
Authors: Segovia Jesus A. , Chang Te-Hung , Winter Vicki T. , Coalson Jacqueline J. , Cagle Marianna P. , Pandranki Lavanya , Bose Santanu , Baseman Joel B. , Kannan Thirumalai R. 
Published: October 2017

ABSTRACT

Mycoplasma pneumoniae
is an atypical bacterial respiratory pathogen known to cause a range of airway inflammation and lung and extrapulmonary pathologies. We recently reported that an
M. pneumoniae
-derived ADP-ribosylating and vacuolating toxin called community-acquired respiratory distress syndrome (CARDS) toxin is capable of triggering NLRP3 (NLR-family, leucine-rich repeat protein 3) inflammasome activation and interleukin-1β (IL-1β) secretion in macrophages. However, it is unclear whether the NLRP3 inflammasome is important for the immune response during
M. pneumoniae
acute infection. In the current study, we utilized
in vitro
and
in vivo
models of
M. pneumoniae
infection to characterize the role of the NLRP3 inflammasome during acute infection.
M. pneumoniae-
infected macrophages deficient for inflammasome components NLRP3, ASC (apoptosis speck-like protein containing a caspase activation and recruitment domain), or caspase-1 failed to process and secrete IL-1β. The MyD88/NF-κB signaling pathway was found to be critical for proinflammatory gene expression in macrophages infected with
M. pneumoniae
. C57BL/6 mice deficient for NLRP3 expression were unable to produce IL-1β in the airways during acute infection, and lack of this inflammatory response led to deficient immune cell activation and delayed bacterial clearance. These findings are the first to report the importance of the NLRP3 inflammasome in regulating the inflammatory response and influencing the progression of
M. pneumoniae
during acute infection.
Heparinase Is Essential for Pseudomonas aeruginosa Virulence during Thermal Injury and Infection
Authors: Dzvova Nyaradzo , Colmer-Hamood Jane A. , Griswold John A. , Hamood Abdul N. 
Published: October 2017

ABSTRACT

The opportunistic pathogen
Pseudomonas aeruginosa
is a major cause of sepsis in severely burned patients. If it is not eradicated from the wound, it translocates to the bloodstream, causing sepsis, multiorgan failure, and death. We recently described the
P. aeruginosa
heparinase-encoding gene,
hepP
, whose expression was significantly enhanced when
P. aeruginosa
strain UCBPP_PA14 (PA14) was grown in whole blood from severely burned patients. Further analysis demonstrated that
hepP
contributed to the
in vivo
virulence of PA14 in the
Caenorhabditis elegans
model. In this study, we utilized the murine model of thermal injury to examine the contribution of
hepP
to the pathogenesis of
P. aeruginosa
during burn wound infection. Mutation of
hepP
reduced the rate of mortality from 100% for mice infected with PA14 to 7% for mice infected with PA14::
hepP
. While comparable numbers of PA14 and PA14::
hepP
bacteria were recovered from infected skin, only PA14 was recovered from the livers and spleens of infected mice. Despite its inability to spread systemically, PA14::
hepP
formed perivascular cuffs around the blood vessels within the skin of the thermally injured/infected mice. Intraperitoneal inoculation of the thermally injured mice, bypassing the need for translocation, produced similar results. The rate of mortality for mice infected with PA14::
hepP
was 0%, whereas it was 66% for mice infected with PA14. As before, only PA14 was recovered from the livers and spleens of infected mice. These results suggest that
hepP
plays a crucial role in the pathogenesis of PA14 during burn wound infection, most likely by contributing to PA14 survival in the bloodstream of the thermally injured mouse during sepsis.
SwrD (YlzI) Promotes Swarming in Bacillus subtilis by Increasing Power to Flagellar Motors
Authors: Hall Ashley N. , Subramanian Sundharraman , Oshiro Reid T. , Canzoneri Alexandra K. , Kearns Daniel B. 
Published: October 2017

ABSTRACT

The bacterium
Bacillus subtilis
is capable of two kinds of flagellum-mediated motility: swimming, which occurs in liquid, and swarming, which occurs on a surface. Swarming is distinct from swimming in that it requires secretion of a surfactant, an increase in flagellar density, and perhaps additional factors. Here we report a new gene,
swrD
, located within the 32 gene
fla-che
operon dedicated to flagellar biosynthesis and chemotaxis, which when mutated abolished swarming motility. SwrD was not required for surfactant production, flagellar gene expression, or an increase in flagellar number. Instead, SwrD was required to increase flagellar power. Mutation of
swrD
reduced swimming speed and torque of tethered flagella, and all
swrD
-related phenotypes were restored when the stator subunits MotA and MotB were overexpressed either by spontaneous suppressor mutations or by artificial induction. We conclude that swarming motility requires flagellar power in excess of that which is needed to swim.

IMPORTANCE
Bacteria swim in liquid and swarm over surfaces by rotating flagella, but the difference between swimming and swarming is poorly understood. Here we report that SwrD of
Bacillus subtilis
is necessary for swarming because it increases flagellar torque and cells mutated for
swrD
swim with reduced speed. How flagellar motors generate power is primarily studied in
Escherichia coli
, and SwrD likely increases power in other organisms, like the
Firmicutes
,
Clostridia
,
Spirochaetes
, and the
Deltaproteobacteria
.
Real-time differentiation of adenomatous and hyperplastic diminutive colorectal polyps during analysis of unaltered videos of standard colonoscopy using a deep learning model
Authors: Byrne Michael F , Chapados Nicolas , Soudan Florian , Oertel Clemens , Linares Pérez Milagros , Kelly Raymond , Iqbal Nadeem , Chandelier Florent , Rex Douglas K 
Published: October 2017

BackgroundIn general, academic but not community endoscopists have demonstrated adequate endoscopic differentiation accuracy to make the ‘resect and discard’ paradigm for diminutive colorectal polyps workable. Computer analysis of video could potentially eliminate the obstacle of interobserver variability in endoscopic polyp interpretation and enable widespread acceptance of ‘resect and discard’.Study design and methodsWe developed an artificial intelligence (AI) model for real-time assessment of endoscopic video images of colorectal polyps. A deep convolutional neural network model was used. Only narrow band imaging video frames were used, split equally between relevant multiclasses. Unaltered videos from routine exams not specifically designed or adapted for AI classification were used to train and validate the model. The model was tested on a separate series of 125 videos of consecutively encountered diminutive polyps that were proven to be adenomas or hyperplastic polyps.ResultsThe AI model works with a confidence mechanism and did not generate sufficient confidence to predict the histology of 19 polyps in the test set, representing 15% of the polyps. For the remaining 106 diminutive polyps, the accuracy of the model was 94% (95% CI 86% to 97%), the sensitivity for identification of adenomas was 98% (95% CI 92% to 100%), specificity was 83% (95% CI 67% to 93%), negative predictive value 97% and positive predictive value 90%.ConclusionsAn AI model trained on endoscopic video can differentiate diminutive adenomas from hyperplastic polyps with high accuracy. Additional study of this programme in a live patient clinical trial setting to address resect and discard is planned.
Prognostic validation of a non-laboratory and a laboratory based cardiovascular disease risk score in multiple regions of the world
Authors: Joseph Philip , Yusuf Salim , Lee Shun Fu , Ibrahim Quazi , Teo Koon , Rangarajan Sumathy , Gupta Rajeev , Rosengren Annika , Lear Scott A , Avezum Alvaro , Lopez-Jaramillo Patricio , Gulec Sadi , Yusufali Afzalhussein , Chifamba Jephat , Lanas Fernando , Kumar Rajesh , Mohammadifard Noushin , Mohan Viswanathan , Mony Prem , Kruger Annamarie , Liu Xu , Guo Baoxia , Zhao Wenqi , Yang Youzhu , Pillai Rajamohanan , Diaz Rafael , Krishnapillai Ambigga , Iqbal Romaina , Yusuf Rita , Szuba Andrzej , Anand Sonia S 
Published: October 2017

ObjectiveTo evaluate the performance of the non-laboratory INTERHEART risk score (NL-IHRS) to predict incident cardiovascular disease (CVD) across seven major geographic regions of the world. The secondary objective was to evaluate the performance of the fasting cholesterol-based IHRS (FC-IHRS).MethodsUsing measures of discrimination and calibration, we tested the performance of the NL-IHRS (n=100 475) and FC-IHRS (n=107 863) for predicting incident CVD in a community-based, prospective study across seven geographic regions: South Asia, China, Southeast Asia, Middle East, Europe/North America, South America and Africa. CVD was defined as the composite of cardiovascular death, myocardial infarction, stroke, heart failure or coronary revascularisation.ResultsMean age of the study population was 50.53 (SD 9.79) years and mean follow-up was 4.89 (SD 2.24) years. The NL-IHRS had moderate to good discrimination for incident CVD across geographic regions (concordance statistic (C-statistic) ranging from 0.64 to 0.74), although recalibration was necessary in all regions, which improved its performance in the overall cohort (increase in C-statistic from 0.69 to 0.72, p<0.001). Regional recalibration was also necessary for the FC-IHRS, which also improved its overall discrimination (increase in C-statistic from 0.71 to 0.74, p<0.001). In 85 078 participants with complete data for both scores, discrimination was only modestly better with the FC-IHRS compared with the NL-IHRS (0.74 vs 0.73, p<0.001).ConclusionsExternal validations of the NL-IHRS and FC-IHRS suggest that regionally recalibrated versions of both can be useful for estimating CVD risk across a diverse range of community-based populations. CVD prediction using a non-laboratory score can provide similar accuracy to laboratory-based methods.
High-sensitivity cardiac troponin I and risk of cardiovascular disease in an Australianpopulation-based cohort
Authors: Zhu Kun , Knuiman Matthew , Divitini Mark , Murray Kevin , Lim Ee Mun , St John Andrew , Walsh John P , Hung Joseph 
Published: October 2017

ObjectiveHigh-sensitivity cardiac troponin I (hs-cTnI) is an emerging biomarker for cardiovascular risk. We examined hs-cTnI as a predictor of mortality and cardiovascular outcomes in an Australian population-based cohort and evaluated if a sex difference exists.MethodsSerum hs-cTnI was measured in the Busselton Health Study 1994/1995 Cohort (n=3939). Outcome measures were total and cardiovascular mortality, cardiovascular disease (CVD) and coronary heart disease (CHD) events, heart failure and stroke.ResultsHs-cTnI was detectable (>1.2 ng/L) in 66.1% of participants (males 81.8%, females 54.4%) at baseline. There were 886 deaths (including 361 from CVD) and 940 CVD events during 20-year follow-up. Adjusting for Framingham Risk Score variables, hs-cTnI was a significant predictor of total mortality (HR (95% CI): 1.16 (1.09 to 1.24)), CVD mortality (1.33 (1.23 to 1.44)), CVD events (1.18 (1.11 to 1.25)), CHD events (1.11 (1.03 to 1.20)), heart failure (1.44 (1.31 to 1.58)) and stroke (1.13 (1.03 to 1.24)) per doubling of hs-cTnI at baseline. HRs remained significant in CVD-free individuals at baseline (n=3215), except for CHD events. There were no significant interactions between sex and hs-cTnI as a predictor of outcomes. Compared with individuals with hs-cTnI ≤1.2 ng/L, men with hs-cTnI ≥6.0 ng/L and women with hs-cTnI ≥4.0 ng/L had an HR of 2.18 (1.42 to 3.37) and 1.84 (1.30 to 2.62), respectively, for any CVD event, which persisted in the CVD-free subgroup.ConclusionsCardiac troponin I, measured with a high-sensitive assay, is an independent predictor of fatal and non-fatal CVD events and may help identify at-risk individuals in a general population.
Alcohol control policies and alcohol consumption: an international comparison of 167 countries
Authors: Madureira-Lima Joana , Galea Sandro 
Published: October 2017

BackgroundAlcohol control policy has a fundamental role in limiting negative health, economic and social harm caused by alcohol consumption. However, there is substantial international heterogeneity in country-level policy adoption, implementation and monitoring. Comparative measures so far focused on Europe or the Organisation for Economic Co-operation and Development countries.MethodsWe created an Alcohol Control Policy Index (ACPI) for 167 countries using five different methodological approaches. National policies were sourced from WHO’s Global Information System on Alcohol and Health. We assessed ACPI’s criterion-related validity by calculating the strength of the association among the different approaches. As for content validity, we tested whether the resulting scores explained variations in alcohol per capita consumption cross-nationally, controlling for gross domestic product, population age, urbanisation and world region using OLS and random coefficients models.ResultsIndex scores and ranks from different methodological approaches are highly correlated (r=0.99). Higher scores were associated with lower consumption across the five methods. For each 1 score increase in the ACPI, the reduction in per capita alcohol consumption varies from −0.024 L (95% CI (−0.043 to −0.004) to −0.014 L (95% CI (−0.034 to 0.005). We obtain larger coefficients and p values <0.005 when estimating random coefficients.ConclusionACPI offers a measure of alcohol control policy across countries that makes use of a larger number of countries than its predecessors, as well as a wider range of methodologies for its calculation, both of which contribute to its validity. Furthermore, it shows that the statutory strictness of alcohol control policies is associated with lower levels of alcohol consumption.
Influence of affordability of alcohol on educational disparities in alcohol-related mortality in Finland and Sweden: a time series analysis
Authors: Herttua Kimmo , Östergren Olof , Lundberg Olle , Martikainen Pekka 
Published: October 2017

BackgroundPrices of alcohol and income tend to influence how much people buy and consume alcohol. Price and income may be combined into one measure, affordability of alcohol. Research on the association between affordability of alcohol and alcohol-related harm is scarce. Furthermore, no research exists on how this association varies across different subpopulations. We estimated the effects of affordability of alcohol on alcohol-related mortality according to gender and education in Finland and Sweden.MethodsVector-autoregressive time series modelling was applied to the quarter-annual aggregations of alcohol-related deaths and affordability of alcohol in Finland in 1988–2007 and in Sweden in 1991–2008. Alcohol-related mortality was defined using information on both underlying and contributory causes of death. We calculated affordability of alcohol index using information on personal taxable income and prices of various types of alcohol.ResultsAmong Finnish men with secondary education, an increase of 1% in the affordability of total alcohol was associated with an increase of 0.028% (95% CI 0.004 to 0.053) in alcohol-related mortality. Similar associations were also found for affordability for various types of alcohol and for beer only in the lowest education group. We found few other significant positive associations for other subpopulations in Finland or Sweden. However, reverse associations were found among secondary-educated Swedish women.ConclusionsOverall, the associations between affordability of alcohol and alcohol-related mortality were relatively weak. Increased affordability of total alcoholic beverages was associated with higher rates of alcohol-related mortality only among Finnish men with secondary education.
Sleep and REM sleep behaviour disorder in Parkinson’s disease with impulse control disorder
Authors: Fantini Maria Livia , Figorilli Michela , Arnulf Isabelle , Zibetti Maurizio , Pereira Bruno , Beudin Patricia , Puligheddu Monica , Cormier-Dequaire Florence , Lacomblez Lucette , Benchetrit Eve , Corvol Jean Christophe , Cicolin Alessandro , Lopiano Leonardo , Marques Ana , Durif Franck 
Published: October 2017

IntroductionBecause the association between rapid eye movement sleep behaviour disorder (RBD) and impulse control disorders (ICDs) in Parkinson’s disease (PD) has been debated, we assessed the sleep characteristics and the frequency of RBD using video-polysomnography (v-PSG) in patients with PD with versus without ICDs.MethodsEighty non-demented patients with PD consecutively identified during routine evaluation at three movement disorders centres were enrolled in a case–control study. Forty patients (22 men; mean age: 62.6±9.7 years, Hoehn & Yahr: 2.1±0.6) with one or more current ICDs were age-matched and sex-matched with 40 patients with no history of ICDs (22 men, mean age: 64.9±7.8 years, Hoehn & Yahr: 2.2±0.6). They underwent a detailed sleep interview followed by a full-night in-lab v-PSG. Sleep was scored blindly to ICDs condition and RBD diagnosis included a clinical complaint of enacted dreams and/or documented behaviour during rapid eye movement (REM) sleep, with the presence of quantified REM sleep without atonia (RSWA).ResultsPatients with ICDs had a higher arousal index and higher RSWA than those without ICDs (51.9%±28.2%vs 32.2±27.1%, p=0.004). In addition, RBD was more frequent in the ICD group (85%vs53%, p=0.0001). RBD was still associated with ICDs in a multivariate regression analysis including age of onset, PD duration and severity, treatment duration, levodopa-equivalent and dopamine agonist-equivalent daily doses and antidepressant use (OR: 4.9 (95% CI 1.3 to 18.5), p=0.02).ConclusionsThis large, controlled series of patients with PD with ICDs assessed by v-PSG confirms the association between ICDs and RBD. Increased surveillance of symptoms of ICDs should be recommended in patients with PD with RBD.
Effects of a 24-h naproxen dose on hydration and electrolyte measures during moderate-intensity cycling in the heat
Authors: Emerson Dawn M. , Torres-McGehee Toni M. , Davis J. Mark , Chen Stephen C.L. , Durstine J. Larry , Pfeifer Craig E. , Emerson Charles C. , Stone Justin V. , Bivona Joseph D. 
Published: October 2017

Few controlled laboratory studies have examined the negative effects non-steroidal anti-inflammatory drugs can have on fluid–electrolyte balance during exercise. Our objective was to determine whether a 24-h naproxen dose negatively affected hydration and electrolyte measures before, during, and 3 h after 90 min of cycling in a hot or ambient environment. Using a double blind, randomized and counterbalanced cross-over design, 11 volunteers (six male, five female) completed four trials, with conditions as follows: (1) placebo and ambient, (2) placebo and heat, (3) naproxen and ambient, and (4) naproxen and heat. We found no statistically significant differences among experimental conditions for any dependent measures. Though not statistically significant, mean fluid volume was higher and urine volume was lower during naproxen trials compared with placebos. Mean aggregate plasma sodium was <135 mmol/L at all time points and did not significantly change over time. Overall plasma potassium significantly increased pre- (3.9 ± 0.4) to post-exercise (4.2 ± 0.4 mmol/L, p = 0.02). In conclusion, an acute naproxen dose did not significantly alter hydration–electrolyte balance. The trend for naproxen to increase fluid volume and decrease urine volume suggests the start of fluid retention, which should concern individuals at risk for hyponatremia or with pre-existing cardiovascular conditions.
Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor–Redirected T Cells Against Multiple Myeloma
Authors: Wang Xiuli , Walter Miriam , Urak Ryan , Weng Lihong , Huynh Christian , Lim Laura , Wong ChingLam W. , Chang Wen-Chung , Thomas Sandra H. , Sanchez James F. , Yang Lu , Brown Christine E. , Pichiorri Flavia , Htut Myo , Krishnan Amrita Y. , Forman Stephen J. 
Published: October 2017

AbstractPurpose: Multiple myeloma remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel chimeric antigen receptors (CAR) for the treatment of multiple myeloma and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy.Experimental Design: We redirected central memory T cells to express second-generation CAR-specific for CS1 and adoptively transferred them into multiple myeloma tumor-bearing mice to test their anti-multiple myeloma activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide in vitro. The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat multiple myeloma–bearing mice as combinatorial therapy.Results: CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T-cell expansion in vitro enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the antitumor activity and persistence of adoptively transferred CS1 CAR T cells in vivo.Conclusions: The study demonstrates that lenalidomide improves the anti-multiple myeloma properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma. Clin Cancer Res; 24(1); 106–19. ©2017 AACR.
Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain
Authors: Priceman Saul J. , Tilakawardane Dileshni , Jeang Brook , Aguilar Brenda , Murad John P. , Park Anthony K. , Chang Wen-Chung , Ostberg Julie R. , Neman Josh , Jandial Rahul , Portnow Jana , Forman Stephen J. , Brown Christine E. 
Published: October 2017

Abstract
Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease.
Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain.
Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease.
Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95–105. ©2017 AACR.