Pneumonia is a major global health problem. Prostaglandin (PG) E(2) is an immunomodulatory lipid with anti-inflammatory, immunosuppressive, and pro-resolving actions. Data suggest that the E-prostanoid (EP) 2 receptor mediates immunomodulatory effects of PGE(2), but the extent to which this occurs in Streptococcus pneumoniae infection is unknown. Intratracheal lung infection of C57BL/6 mice possessing (EP2(+/+)) or lacking (EP2(-/-)) the EP2 receptor was performed, as were in vitro studies of alveolar macrophage (AM) host defense functions. Bacterial clearance and survival were significantly improved in vivo in EP2(-/-) mice and it correlated with greater neutrophilic inflammation and higher lung IL-12 levels. Upon ex vivo challenge with pneumococcus, EP2(-/-)cells expressed greater amounts of TNF-α and MIP-2 than did EP2(+/+) AMs, and had improved phagocytosis, intracellular killing, and reactive oxygen intermediate generation. These data suggest that PGE(2)-EP2 signaling may provide a novel pharmacological target for treating pneumococcal pneumonia in combination with antimicrobials.

BACKGROUND Although there is abundant evidence that human longevity is heritable, efforts to map loci responsible for variation in human lifespan have had limited success. METHODOLOGY/PRINCIPAL FINDINGS We identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related "affected individuals", defined as those in the top quartile for both excess longevity (EL = observed lifespan - expected lifespan) and familial excess longevity (FEL = weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak (Z = 4.2, Monte Carlo-adjusted p-value 0.09) was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS)[1]. Meta-analysis of linkage scores on 3p from the two studies produced a minimum nominal p-value of 1.005×10(-9) at 55 cM. Other potentially noteworthy peaks in our data occur on 18q23-24, 8q23, and 17q21. Meta-analysis results from combined UPDB and HMS data yielded additional support, but not formal replication, for linkage on 8q, 9q, and 17q. CONCLUSIONS/SIGNIFICANCE Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region.

BACKGROUND: Prospective assessment of pharmacogenetic strategies has been limited by an inability to undertake bedside genetic testing. The CYP2C19*2 allele is a common genetic variant associated with increased rates of major adverse events in individuals given clopidogrel after percutaneous coronary intervention (PCI). We used a novel point-of-care genetic test to identify carriers of the CYP2C19*2 allele and aimed to assess a pharmacogenetic approach to dual antiplatelet treatment after PCI. METHODS: Between Aug 26, 2010, and July 7, 2011, 200 patients were enrolled into our prospective, randomised, proof-of-concept study. Patients undergoing PCI for acute coronary syndrome or stable angina were randomly assigned to rapid point-of-care genotyping or to standard treatment. Individuals in the rapid genotyping group were screened for the CYP2C19*2 allele. Carriers were given 10 mg prasugrel daily, and non-carriers and patients in the standard treatment group were given 75 mg clopidogrel daily. The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment, which is a marker associated with increased adverse cardiovascular events. Interventional cardiologists and data analysts were masked to genetic status and treatment. Patients were not masked to treatment allocation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, NCT01184300. FINDINGS: After randomisation, 187 patients completed follow-up (91 rapid genotyping group, 96 standard treatment). 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a PRU value of more than 234 at day 7, compared with seven (30%) given standard treatment (p=0·0092). The point-of-care genetic test had a sensitivity of 100%(95% CI 92·3-100) and a specificity of 99·3%(96·3-100). INTERPRETATION: Point-of-care genetic testing after PCI can be done effectively at the bedside and treatment of identified CYP2C19*2 carriers with prasugrel can reduce high on-treatment platelet reactivity. FUNDING: Spartan Biosciences.

What people feel shapes their perceptions of others. In the studies reported here, we examined the assimilative influence of visceral states on social judgment. Replicating prior research, we found that participants who were outside during winter overestimated the extent to which other people were bothered by cold (Study 1), and participants who ate salty snacks without water thought other people were overly bothered by thirst (Study 2). However, in both studies, this effect evaporated when participants believed that the other people under consideration held political views opposing their own. Participants who judged these dissimilar others were unaffected by their own strong visceral-drive states, a finding that highlights the power of dissimilarity in social judgment. Dissimilarity may thus represent a boundary condition for embodied cognition and inhibit an empathic understanding of shared out-group pain. Our findings reveal the need for a better understanding of how people's internal experiences influence their perceptions of the feelings and experiences of those who may hold values different from their own.

ObjectivesTo review the role of outpatient parenteral antibiotic therapy (OPAT) in the management of infective endocarditis (IE) with the aim to guide further development of the service modality both locally and at other centres, in light of the evolving recommendations on patient suitability in international guidelines.MethodsA retrospective case review of all patients receiving OPAT for IE in Sheffield between January 2006 and October 2010 was conducted. Data were collected on site and microbiology of infection, antibiotic regimens, adverse events during OPAT therapy and outcomes were studied.ResultsA total of 36 episodes of IE were treated in 34 patients. All patients received initial treatment as inpatients. Treatment was successful in 34/36 episodes (94.4%) with no evidence of recurrence at a median of 30 months follow-up. One patient had a relapse 2 months after completion of OPAT for enterococcal endocarditis and was found to have concurrent chronic prostatitis. One patient died of a ruptured pulmonary root abscess while receiving OPAT. Adverse events occurred in 12 episodes (33.3%), of which seven were line associated. In four cases adverse events resulted in re-hospitalisation. A successful outcome was achieved in 22/24 episodes (91.7%) deemed to be less suitable for OPAT due to higher risk of complications by Infectious Diseases Society of America guidelines.ConclusionsOPAT is a safe and effective means of completing therapy for IE, including prosthetic valve endocarditis and other cases at a higher risk of complicated disease. However, the relatively high rate of adverse events highlights the need for well-developed protocols and policies for patient selection and follow-up within the context of a formal OPAT service.

Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) are common and important infectious disease agents of cats in Canada. Seroprevalence data for FeLV and FIV in various populations of Canadian cats are reviewed and recommendations for testing and management of infections by these viruses in cats in Canada are presented. Retrovirus testing in Canada is infrequent in comparison with the United States, and efforts should be focused on reducing physical and other barriers to testing, and on education of veterinarians, veterinary team members, and cat owners regarding the importance of testing. New test methodologies for FeLV and FIV are emerging, and should be independently evaluated in order to provide practitioners with information on test reliability. Finally, more information is needed on FIV subtypes in Canada to improve diagnostics and vaccines, and to provide information on disease outcomes.

The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (≥90 mm Hg) or by daytime ABP (≥85 mm Hg), a history of cardiovascular disease, and persons <18 years of age, the present analysis totaled 7295 persons, of whom 1593 had isolated systolic hypertension. During a median follow-up of 10.6 years, there was a total of 655 fatal and nonfatal cardiovascular events. The analyses were stratified by treatment status. In untreated subjects, those with white-coat hypertension (CBP ≥140/<90 mm Hg and ABP <135/<85 mm Hg) and subjects with normal BP (CBP <140/<90 mm Hg and ABP <135/<85 mm Hg) were at similar risk (adjusted hazard rate: 1.17 [95% CI: 0.87-1.57]; P=0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79-1.53]; P=0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00;[95% CI: 1.43-2.79]; P<0.0001) and treated subjects with normal BP (adjusted hazard rate: 1.98 [95% CI: 1.49-2.62]; P<0.0001) were at higher risk as compared with untreated normotensive subjects. In conclusion, subjects with sustained hypertension who have their ABP normalized on antihypertensive therapy but with residual white-coat effect by CBP measurement have an entity that we have termed,"treated normalized hypertension." Therefore, one should be cautious in applying the term "white-coat hypertension" to persons receiving antihypertensive treatment.

Flow coefficients v_{n} for n=2, 3, 4, characterizing the anisotropic collective flow in Au+Au collisions at sqrt[s_{NN}]=200  GeV, are measured relative to event planes Ψ_{n}, determined at large rapidity. We report v_{n} as a function of transverse momentum and collision centrality, and study the correlations among the event planes of different order n. The v_{n} are well described by hydrodynamic models which employ a Glauber Monte Carlo initial state geometry with fluctuations, providing additional constraining power on the interplay between initial conditions and the effects of viscosity as the system evolves. This new constraint can serve to improve the precision of the extracted shear viscosity to entropy density ratio η/s.