Broad-spectrum suppression of bacterial pneumonia by aminoglycoside-propagated Acinetobacter baumannii.

Antimicrobial resistance is increasing in pathogenic bacteria. Yet, the effect of antibiotic exposure on resistant bacteria has been underexplored and may affect pathogenesis. Here we describe the discovery that propagation of the human pathogen Acinetobacter baumannii in an aminoglycoside antibiotic results in alterations to the bacterium that interact with lung innate immunity resulting in enhanced bacterial clearance. Co-inoculation of mice with A. baumannii grown in the presence and absence of the aminoglycoside, kanamycin, induces enhanced clearance of a non-kanamycin-propagated strain. This finding can be replicated when kanamycin-propagated A. baumannii is killed prior to co-inoculation of mice, indicating the enhanced bacterial clearance results from interactions with innate host defenses in the lung. Infection with kanamycin-propagated A. baumannii alters the kinetics of phagocyte recruitment to the lung and reduces pro- and anti-inflammatory cytokine and chemokine production in the lung and blood. This culminates in reduced histopathologic evidence of lung injury during infection despite enhanced bacterial clearance. Further, the antibacterial response induced by killed aminoglycoside-propagated A. baumannii enhances the clearance of multiple clinically relevant Gram-negative pathogens from the lungs of infected mice. Together, these findings exemplify cooperation between antibiotics and the host immune system that affords protection against multiple antibiotic-resistant bacterial pathogens. Further, these findings highlight the potential for the development of a broad-spectrum therapeutic that exploits a similar mechanism to that described here and acts as an innate immunity modulator.

Rapid Detection of Urinary Tract Infections via Bacterial Nuclease Activity.

Rapid and accurate bacterial detection methods are needed for clinical diagnostic, water, and food testing applications. The wide diversity of bacterial nucleases provides a rich source of enzymes that could be exploited as signal amplifying biomarkers to enable rapid, selective detection of bacterial species. With the exception of the use of micrococcal nuclease activity to detect Staphylococcus aureus, rapid methods that detect bacterial pathogens via their nuclease activities have not been developed. Here, we identify endonuclease I as a robust biomarker for E. coli and develop a rapid ultrasensitive assay that detects its activity. Comparison of nuclease activities of wild-type and nuclease-knockout E. coli clones revealed that endonuclease I is the predominant DNase in E. coli lysates. Endonuclease I is detectable by immunoblot and activity assays in uropathogenic E. coli strains. A rapid assay that detects endonuclease I activity in patient urine with an oligonucleotide probe exhibited substantially higher sensitivity for urinary tract infections than that reported for rapid urinalysis methods. The 3 hr turnaround time is much shorter than that of culture-based methods, thereby providing a means for expedited administration of appropriate antimicrobial therapy. We suggest this approach could address various unmet needs for rapid detection of E. coli.

Mechanisms of Pyocyanin Toxicity and Genetic Determinants of Resistance in Staphylococcus aureus.

Pseudomonas aeruginosa and Staphylococcus aureus are commonly isolated from polymicrobial infections, such as wound infections and chronic respiratory infections of persons with cystic fibrosis. Despite their coisolation, P. aeruginosa produces substances toxic to S. aureus, including pyocyanin, a blue-pigmented molecule that functions in P. aeruginosa virulence. Pyocyanin inhibits S. aureus respiration, forcing it to derive energy from fermentation and adopt a small-colony variant (SCV) phenotype. The mechanisms by which S. aureus sustains infection in the presence of pyocyanin are not clear. We sought to clarify the mechanisms of pyocyanin toxicity in S. aureus as well as identify the staphylococcal factors involved in its resistance to pyocyanin toxicity. Nonrespiring S. aureus SCVs are inhibited by pyocyanin through pyocyanin-dependent reactive oxygen species (ROS) production, indicating that pyocyanin toxicity is mediated through respiratory inhibition and ROS generation. Selection on pyocyanin yielded a menadione auxotrophic SCV capable of growth on high concentrations of pyocyanin. Genome sequencing of this isolate identified mutations in four genes, including saeS, menD, NWMN_0006, and qsrR QsrR is a quinone-sensing repressor of quinone detoxification genes. Inactivation of qsrR resulted in significant pyocyanin resistance, and additional pyocyanin resistance was achieved through combined inactivation of qsrR and menadione biosynthesis. Pyocyanin-resistant S. aureus has an enhanced capability to inactivate pyocyanin, suggesting QsrR-regulated gene products may degrade pyocyanin to alleviate toxicity. These findings demonstrate pyocyanin-mediated ROS generation as an additional mechanism of pyocyanin toxicity and define QsrR as a key mediator of pyocyanin resistance in S. aureus IMPORTANCE Many bacterial infections occur in the presence of other microbes, where interactions between different microbes and the host impact disease. In patients with cystic fibrosis, chronic lung infection with multiple microbes results in the most severe disease manifestations. Staphylococcus aureus and Pseudomonas aeruginosa are prevalent cystic fibrosis pathogens, and infection with both is associated with worse outcomes. These organisms have evolved mechanisms of competing with one another. For example, P. aeruginosa produces pyocyanin, which inhibits S. aureus growth. Our research has identified how pyocyanin inhibits S. aureus growth and how S. aureus can adapt to survive in the presence of pyocyanin. Understanding how S. aureus sustains infection in the presence of P. aeruginosa may identify means of disrupting these microbial communities.

The Role of Behavioral Responses in the Total Economic Consequences of Terrorist Attacks on U.S. Air Travel Targets.

U.S. airports and airliners are prime terrorist targets. Not only do the facilities and equipment represent high-value assets, but the fear and dread that is spread by such attacks can have tremendous effects on the U.S. economy. This article presents the methodology, data, and estimates of the macroeconomic impacts stemming from behavioral responses to a simulated terrorist attack on a U.S. airport and on a domestic airliner. The analysis is based on risk-perception surveys of these two scenarios. The responses relate to reduced demand for airline travel, shifts to other modes, spending on nontravel items, and savings of potential travel expenditures by U.S. resident passengers considering flying domestic routes. We translate these responses to individual spending categories and feed these direct impact results into a computable general equilibrium (CGE) model of the U.S. economy to ascertain the indirect and total impacts on both the airline industry and the economy as a whole. Overall, the estimated impacts on GDP of both types of attacks exceed $10B. We find that the behavioral economic impacts are almost an order of magnitude higher than the ordinary business interruption impacts for the airliner attack and nearly two orders of magnitude higher for the airport attack. The results are robust to sensitivity tests on the travel behavior of U.S. residents in response to terrorism.

Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection.

Acinetobacter baumannii is a common nosocomial pathogen capable of causing severe diseases associated with significant morbidity and mortality in impaired hosts. Pattern recognition receptors, such as the Toll-like receptors (TLRs), play a key role in pathogen detection and function to alert the immune system to infection. Here, we examine the role for TLR9 signaling in response to A. baumannii infection. In a murine model of A. baumannii pneumonia, TLR9(-/-) mice exhibit significantly increased bacterial burdens in the lungs, increased extrapulmonary bacterial dissemination, and more severe lung pathology compared with those in wild-type mice. Following systemic A. baumannii infection, TLR9(-/-) mice have significantly increased bacterial burdens in the lungs, as well as decreased proinflammatory cytokine and chemokine production. These results demonstrate that TLR9-mediated pathogen detection is important for host defense against the opportunistic pathogen Acinetobacter baumannii.

Near-misses and future disaster preparedness.

Disasters garner attention when they occur, and organizations commonly extract valuable lessons from visible failures, adopting new behaviors in response. For example, the United States saw numerous security policy changes following the September 11 terrorist attacks and emergency management and shelter policy changes following Hurricane Katrina. But what about those events that occur that fall short of disaster? Research that examines prior hazard experience shows that this experience can be a mixed blessing. Prior experience can stimulate protective measures, but sometimes prior experience can deceive people into feeling an unwarranted sense of safety. This research focuses on how people interpret near-miss experiences. We demonstrate that when near-misses are interpreted as disasters that did not occur and thus provide the perception that the system is resilient to the hazard, people illegitimately underestimate the danger of subsequent hazardous situations and make riskier decisions. On the other hand, if near-misses can be recognized and interpreted as disasters that almost happened and thus provide the perception that the system is vulnerable to the hazard, this will counter the basic "near-miss" effect and encourage mitigation. In this article, we use these distinctions between resilient and vulnerable near-misses to examine how people come to define an event as either a resilient or vulnerable near-miss, as well as how this interpretation influences their perceptions of risk and their future preparedness behavior. Our contribution is in highlighting the critical role that people's interpretation of the prior experience has on their subsequent behavior and in measuring what shapes this interpretation.

Risk perception and the economic crisis: a longitudinal study of the trajectory of perceived risk.

We conducted a longitudinal survey of public response to the economic crisis to understand the trajectory of risk perception amidst an ongoing crisis. A nation-wide panel responded to seven surveys beginning in late September 2008 at the peak of the crisis and concluded in October 2009. At least 600 respondents participated in each survey, with 413 completing all seven surveys. Our online survey focused on perceptions of risk (savings, investments, retirement, job), negative emotions toward the financial crisis (sadness, anxiety, fear, anger, worry, stress), confidence in national leaders to manage the crisis (President Obama, Congress, Treasury Secretary, business leaders), and belief in one's ability to realize personal objectives despite the crisis. We employed latent growth curve modeling to analyze change in risk perception throughout the crisis. Our results suggest that, in general, people's perceptions of risk appear to decrease most rapidly during the initial phase of a crisis and then begin to level off. Negative emotion about the crisis was the most predictive of increased risk perception, supporting the notion of risk as feelings. Belief in one's ability to realize personal objectives was also predictive. Confidence in national leaders, however, was not predictive of perceived risk. Finally, our results demonstrate that groups may experience a crisis differently depending on a combination of personal characteristics such as gender, income, numeracy, and political attitude. Risk management and communication should work in sync with these mechanisms and differences across groups.

Zinc intoxication induces ferroptosis in A549 human lung cells.

Zinc (Zn) is an essential trace metal required for all forms of life, but is toxic at high concentrations. While the toxic effects of high levels of Zn are well documented, the mechanism of cell death appears to vary based on the study and concentration of Zn. Zn has been proposed as an anti-cancer treatment against non-small cell lung cancer (NSCLC). The goal of this analysis was to determine the effects of Zn on metabolism and cell death in A549 cells. Here, high throughput multi-omics analysis identified the molecular effects of Zn intoxication on the proteome, metabolome, and transcriptome of A549 human NSCLC cells after 5 min to 24 h of Zn exposure. Multi-omics analysis combined with additional experimental evidence suggests Zn intoxication induces ferroptosis, an iron and lipid peroxidation-dependent programmed cell death, demonstrating the utility of multi-omics analysis to identify cellular response to intoxicants.

The Arithmetic of Emotion: Integration of Incidental and Integral Affect in Judgments and Decisions.

Research has demonstrated that two types of affect have an influence on judgment and decision making: incidental affect (affect unrelated to a judgment or decision such as a mood) and integral affect (affect that is part of the perceiver's internal representation of the option or target under consideration). So far, these two lines of research have seldom crossed so that knowledge concerning their combined effects is largely missing. To fill this gap, the present review highlights differences and similarities between integral and incidental affect. Further, common and unique mechanisms that enable these two types of affect to influence judgment and choices are identified. Finally, some basic principles for affect integration when the two sources co-occur are outlined. These mechanisms are discussed in relation to existing work that has focused on incidental or integral affect but not both.

Discrepancies between premorbid and current IQ as a function of progressive mental deterioration.

The declining cognitive functioning typically found in patients with Alzheimer's disease presents an opportunity to study that decline. The changing magnitude of ever widening discrepancies between premorbid estimators of IQ and observed IQ increases as severity of the disease increases. Premorbid IQs estimated by these scores (the National Adult Reading Test-Revised, the reading tests of the Revised and Third Editions of the Wide Range Achievement Test, and a demographically based regression index for the Wechsler Adult Intelligence Scale-Revised) had relatively similar discrepancies from obtained WAIS-R Full Scale IQs in samples of normal elderly (n = 30), and elderly patients diagnosed with mild (n = 30) and moderate Alzheimer's disease (n = 30) dementia. The discrepancies became larger, regardless of premorbid estimator, as disease severity progressed from none to mild to moderate across the samples.

Maternal-neonatal incest.

Among all the forms of child abuse, sexual abuse during infancy is the least often discovered. Three cases of mother-child incest initiated during the neonatal period are described in this paper. The mothers all were estranged from their sexual partners, had demonstrated some confusion regarding sexual identity, and had sought assistance with chemical dependency during pregnancy.

Development and Testing of an Abbreviated Numeracy Scale: A Rasch Analysis Approach.

Research has demonstrated that individual differences in numeracy may have important consequences for decision making. In the present paper, we develop a shorter, psychometrically improved measure of numeracy-the ability to understand, manipulate, and use numerical information, including probabilities. Across two large independent samples that varied widely in age and educational level, participants completed 18 items from existing numeracy measures. In Study 1, we conducted a Rasch analysis on the item pool and created an eight-item numeracy scale that assesses a broader range of difficulty than previous scales. In Study 2, we replicated this eight-item scale in a separate Rasch analysis using data from an independent sample. We also found that the new Rasch-based numeracy scale, compared with previous measures, could predict decision-making preferences obtained in past studies, supporting its predictive validity. In Study, 3, we further established the predictive validity of the Rasch-based numeracy scale. Specifically, we examined the associations between numeracy and risk judgments, compared with previous scales. Overall, we found that the Rasch-based scale was a better linear predictor of risk judgments than prior measures. Moreover, this study is the first to present the psychometric properties of several popular numeracy measures across a diverse sample of ages and educational level. We discuss the usefulness and the advantages of the new scale, which we feel can be used in a wide range of subject populations, allowing for a more clear understanding of how numeracy is associated with decision processes. Copyright © 2012 John Wiley & Sons, Ltd.

Neurocognitive differential diagnosis of dementing diseases: Alzheimer's Dementia, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder.

Similarities in presentation of Dementia of Alzheimer's Type, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder, pose differential diagnosis challenges. The current study identifies specific neuropsychological patterns of scores for Dementia of Alzheimer's Type, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder. Neuropsychological domains directly assessed in the study included: immediate memory, delayed memory, confrontational naming, verbal fluency, attention, concentration, and executive functioning. The results reveal specific neuropsychological comparative profiles for Dementia of Alzheimer's Type, Vascular Dementia, Frontotemporal Dementia, and Major Depressive Disorder. The identification of these profiles will assist in the differential diagnosis of these disorders and aid in patient treatment.

Differences in young children's IQs on the Wechsler preschool and primary scale of intelligence-revised as a function of stratification variables.

The normative sample (N = 1,700) of the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), stratified on age, gender, ethnicity, geographic region, education, and occupation of children's parents, served as the database with which to examine the associations of demographic characteristics with Verbal Intelligence Quotients (VIQs), Performance Intelligence Quotients (PIQs), and Full Scale Intelligence Quotients (FSIQs) among young children. A 3-way multivariate analysis of variance (MANOVA) andfollow-up analyses of variance (ANOVAs) found significant effects of parent education and ethnicity, but not child's gender, on IQ. A separate 2-way MANOVA andfollow-up ANOVAsfound significant interaction effects between region and ethnicity on IQ. Parent education showed the largest association with all 3 IQs, whereas gender and age showed the least. The meaning of the hierarchy of the stratification variable associations with IQ is discussed.

Prediction of IQ in the Mayo Older Adult Normative sample using multiple methods.

Using the Mayo Older Adult Normative sample (Ivnik et al., 1992) as our database, we developed regression models for estimating premorbid Full Scale (FSIQs), Verbal (VIQs), and Performance (PIQs) IQs for elderly adults. Age, years of education, and sex were the only demographic variables that showed sufficient variability; therefore, they were used as predictor variables in three stepwise procedures. The Mayo Normative FSIQs, VIQs, and PIQs served as the dependent variables. Both education and sex added significantly to the accounting of variance of both FSIQ and VIQ ( p < .001), whereas education ( p < .001) and age ( p < .05) were significant predictors of PIQ. These models produced statistically significant multiple Rs of .54, .58, and .35 ( p < .0001), with standard errors of estimate of 9.02, 8.28, and 10.77 for FSIQ, VIQ, and PIQ, respectively. Estimated FSIQs generated with the present model and the model developed by Barona and colleagues (Barona, Reynolds, & Chastain, 1984) were compared. The correlation between estimated IQs was large, the mean difference between IQs was very small, the standard deviations were nearly equal, and the categorical distributions of the two were similar. Because the Barona model is likely to be familiar to most clinicians, these findings argue in favor of the continued use of the Barona model, even when assessing people older than the WAIS-R normative sample. Extensions of these models to the WAIS-III also are discussed.