Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa

Numerous species of bacteria use an elegant regulatory mechanism known as quorum sensing to control the expression of specific genes in a cell-density dependent manner. In Gram-negative bacteria, quorum sensing systems function through a cell-to-cell signal molecule (autoinducer) that consists of a homoserine lactone with a fatty acid side chain. Such is the case in the opportunistic human pathogen Pseudomonas aeruginosa, which contains two quorum sensing systems (las and rhl) that operate via the autoinducers, N-(3-oxododecanoyl)-L-homoserine lactone and N-butyryl-Lhomoserine lactone. The study of these signal molecules has shown that they bind to and activate transcriptional activator proteins that specifically induce numerous P. aeruginosa virulence genes. We report here that P. aeruginosa produces another signal molecule, 2-heptyl-3-hydroxy-4-quinolone, which has been designated as the Pseudomonas quinolone signal. It was found that this unique cell-to-cell signal controlled the expression of lasB, which encodes for the major virulence factor, LasB elastase. We also show that the synthesis and bioactivity of Pseudomonas quinolone signal were mediated by the P. aeruginosa las and rhl quorum sensing systems, respectively. The demonstration that 2-heptyl-3- hydroxy-4-quinolone can function as an intercellular signal sheds light on the role of secondary metabolites and shows that P. aeruginosa cell-to-cell signaling is not restricted to acyl-homoserine lactones. Originally published Proc. Natl. Acad. Sci, Vol. 96, No. 20, Sep. 199

True durability: HIV virologic suppression in an urban clinic and implications for timing of intensive adherence efforts and viral load monitoring.

Although the majority of HIV-infected patients who begin potent antiretroviral therapy should expect long-term virologic suppression, the realities in practice are less certain. Durability of viral suppression was examined to define the best timing of targeted adherence strategies and intensive viral load monitoring in an urban clinic population with multiple challenges to ART adherence. We examined the risk of viral rebound for patients who achieved two consecutive viral loads lower than the lower limit of quantification (LLOQ) within 390 days. For 791 patients with two viral loads below the LLOQ, viral rebound \u3eLLOQ from the first viral load was 36.9 % (95 % CI 32.2-41.6) in the first year, 26.9 % (95 % CI 21.7-32.1) in the year following one year of viral suppression, and 24.6 % (95 % CI 18.4-30.9) in the year following 2 years of viral suppression. However, for patients with CD4 ≥300 cells/µl who had 3-6 years of virologic suppression, the risk of viral rebound was very low. At the population level, the risk of viral rebound in a complex urban clinic population is surprisingly high even out to 3 years. Intensified monitoring and adherence efforts should target this high risk period. Thereafter, confidence in truly durable virologic suppression is improved

True durability: HIV virologic suppression in an urban clinic and implications for timing of intensive adherence efforts and viral load monitoring

Although the majority of HIV-infected patients who begin potent antiretroviral therapy should expect long-term virologic suppression, the realities in practice are less certain. Durability of viral suppression was examined to define the best timing of targeted adherence strategies and intensive viral load monitoring in an urban clinic population with multiple challenges to ART adherence. We examined the risk of viral rebound for patients who achieved two consecutive viral loads lower than the lower limit of quantification (LLOQ) within 390 days. For 791 patients with two viral loads below the LLOQ, viral rebound \u3eLLOQ from the first viral load was 36.9 % (95 % CI 32.2–41.6) in the first year, 26.9 % (95 % CI 21.7–32.1) in the year following one year of viral suppression, and 24.6 % (95 % CI 18.4–30.9) in the year following 2 years of viral suppression. However, for patients with CD4 ≥300 cells/µl who had 3–6 years of virologic suppression, the risk of viral rebound was very low. At the population level, the risk of viral rebound in a complex urban clinic population is surprisingly high even out to 3 years. Intensified monitoring and adherence efforts should target this high risk period. Thereafter, confidence in truly durable virologic suppression is improved

Myocardial infarction and stroke associated with diuretic based two drug antihypertensive regimens: population based case-control study

Objective To examine the association of myocardial infarction and stroke incidence with several commonly used two drug antihypertensive treatment regimens

Intervening to improve health indicators among Australian farm families

The Sustainable Farm Families project (http://www.sustainablefarmfamilies.org.au/) was a 3-year demonstration and education project designed to influence farmer behavior with respect to family health and well-being among cropping and grazing farmers in Victoria, New South Wales, and South Australia, Australia. The project was conducted by the Western District Health Service, Hamilton, Australia, in partnership with farmers; Farm Management 500 (peer discussion group); the Victorian Farmers Federation; Royal Melbourne Institute of Technology; and Land Connect. During the 3 years of the project, 128 farmers&mdash;men (70) and women (58)&mdash;were enrolled. The project utilized a combination of small group workshops, individualized health action plans, and health education opportunities to encourage farm safety and health behavior changes and to elicit sustained improvements in the following health indicators: body mass index (BMI), total cholesterol, fasting blood glucose, and blood pressure. Mean changes in these health indicators were analyzed using repeated measures analysis of variance (ANOVA) and McNemar\u27s test compared the proportion of individuals with elevated indicators. Among participants with elevated values at baseline, the following average reductions were observed: BMI 0.44 kg/m2 (p = .0034), total cholesterol 48.7 mg/dl (p &lt; .0001), blood glucose 10.1 mg/dl (p = .0016), systolic blood pressure 12.5 mm Hg (p &lt; .0001), and diastolic blood pressure 5.0 mm Hg (p = .0007). The proportion of participants with elevated total cholesterol at baseline decreased after 24 months (p &lt; .001). Such findings suggest that proactive intervention by farmer associations, rural health services, and government agencies may be an effective vehicle for promoting voluntary farm safety and health behavior change while empowering farm families to achieve measurable reductions in important health risk factors. <br /

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations

BACKGROUND: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored. METHODS: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis. RESULTS: We identified six loci associated with QRS (P CONCLUSIONS: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations

Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain

Object: To determine the single spin-echo T 2 relaxation times of uncoupled and J-coupled metabolites in rat brain in vivo at 14.1 T and to compare these results with those previously obtained at 9.4 T. Materials and methods: Measurements were performed on five rats at 14.1 T using the SPECIAL sequence and TE-specific basis-sets for LCModel analysis. Results and conclusion: The T 2 of singlets ranged from 98 to 148ms and T 2 of J-coupled metabolites ranged from 72ms (glutamate) to 97ms (myo-inositol). When comparing the T 2s of the metabolites measured at 14.1 T with those previously measured at 9.4 T, a decreasing trend was found (p<0.0001). We conclude that the modest shortening of T 2 at 14.1 T has a negligible impact on the sensitivity of the 1H MRS when performed at TE shorter than 10m

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables

Genome-Wide Meta-Analyses of Smoking Behaviors in African Americans

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n=32 389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance ($\beta$=0.040, s.e.=0.007, P=1.84 × 10$^{−8}$). This variant is present in the 5′-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans