Gonadotrophin-mediated miRNA expression in testis at onset of puberty in rhesus monkey: Predictions on regulation of thyroid hormone activity and DLK1-DIO3 locus

Molecular mechanisms responsible for the initiation of primate spermatogenesis remain poorly characterized. Previously, 48 h stimulation of the testes of three juvenile rhesus monkeys with pulsatile LH and FSH resulted in down-regulation of a cohort of genes recognized to favor spermatogonia stem cell renewal. This change in genetic landscape occurred in concert with amplification of Sertoli cell proliferation and the commitment of undifferentiated spermatogonia to differentiate. In this report, the non-protein coding small RNA transcriptomes of the same testes were characterized using RNA sequencing: 537 mature micro-RNAs (miRNAs), 322 small nucleolar RNAs (snoRNAs) and 49 small nuclear RNAs (snRNAs) were identified. Pathway analysis of the 20 most highly expressed miRNAs suggested that these transcripts contribute to limiting the proliferation of the primate Sertoli cell during juvenile development. Gonadotrophin treatment resulted in differential expression of 35 miRNAs, 12 snoRNAs and four snRNA transcripts. Ten differentially expressed miRNAs were derived from the imprinted delta-like homolog 1-iodothyronine deiodinase 3 (DLK1-DIO3) locus that is linked to stem cell fate decisions. Four gonadotrophin-regulated expressed miRNAs were predicted to trigger a local increase in thyroid hormone activity within the juvenile testis. The latter finding leads us to predict that, in primates, a gonadotrophin-induced selective increase in testicular thyroid hormone activity, together with the established increase in androgen levels, at the onset of puberty is necessary for the normal timing of Sertoli cell maturation, and therefore initiation of spermatogenesis. Further examination of this hypothesis requires that peripubertal changes in thyroid hormone activity of the testis of a representative higher primate be determined empirically.Fil: Aliberti, Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Servicio de Endocrinología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sethi, Rahil. University of Pittsburgh; Estados UnidosFil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Servicio de Endocrinología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chandran, Uma R.. University of Pittsburgh; Estados UnidosFil: Plant, Tony M.. University of Pittsburgh; Estados UnidosFil: Walker, William H.. University of Pittsburgh; Estados Unido

Early administration of the first antimicrobials should be considered a marker of optimal care of patients with community-acquired pneumonia rather than a predictor of outcomes

Summary Background The effect of time of the first antimicrobial dose (TFAD) on the outcomes of community-acquired pneumonia (CAP) remains a controversy. Methods This was an observational, retrospective study of consecutive adult patients hospitalized with CAP. TFAD was defined as the time in hours from arrival at the emergency department to the intravenous infusion of antimicrobial. All patients received appropriate antibiotic therapy according to available Infectious Diseases Society of America/American Thoracic Society guidelines during the time of our study. Multivariable analysis and a propensity score adjusted methodology were used to measure the association of TFAD with mortality, time to clinical stability (TCS), and length of stay in the hospital (LOS). Results Data of 372 patients with CAP were studied. A total 29 (8.4%) patients died within 30 days of hospitalization. Our propensity-adjusted logistic regression model did not show a significant association between TFAD and mortality ( p =0.148). Patients who died received antimicrobials significantly earlier than survivors: 5.7h vs. 7.5h, respectively ( p =0.04). The LOS and TCS were not significantly affected by the TFAD; the LOS hazard ratio was 0.996 (95% confidence interval 0.97–1.02; p =0.774) and the TCS hazard ratio was 1.01 (95% confidence interval 0.98–1.03; p =0.604). Conclusions TFAD does not seem to be associated with the clinical outcome of patients with CAP. Early TFAD should be considered as an important marker of optimal care of patients with CAP rather than as a factor predicting outcomes

Do Antiplatelet Medications Prevent Poor Clinical Outcomes in Patients With Community-Acquired Pneumonia? Results From the Community-Acquired Pneumonia Organization International Cohort Study

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Short Duration of Antibiotic Therapy in Hospitalized Patients with Community-Acquired Pneumonia: Results from the CAPO International Cohort Study

Introduction: Experts suggest a short duration of antibiotic therapy (DOT) in responding patients with community-acquired pneumonia (CAP). The aim of this study was to evaluate clinical outcomes after hospital discharge among patients treated with short-course antibiotic therapy (SCT) vs. long-course antibiotic therapy (LCT) for CAP. Methods: A secondary analysis of the Community-Acquired Pneumonia Organization (CAPO) database from January 2007 to June 2013 was performed, including hospitalized CAP patients who reached clinical stability within 5 days. Two groups were identified: patients who were treated with antibiotic therapy for a total duration of 5 days or less (SCT Group) vs. longer than 5 days (LCT Group). Rehospitalization and mortality were evaluated at 30 days after discharge. Results: 1,849 patients were enrolled (58% males; median age: 65 years), 179 (10%) were included in the SCT and 1,670 (90%) in the LTC group. Median DOT was 5 days in the SCT and 10 days in the LTC group, p Conclusions: A duration of antibiotic therapy of ≤ 5 days does not adversely impact clinical outcomes at 30-days after discharge compared to \u3e5 days in patients who reached early clinical stability

Correlation of Obesity With Outcomes in Hospitalized Patients With Community-Acquired Pneumonia: Results From the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study

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Clinical Characteristics and Outcomes of Patients With Community-Acquired Pneumonia—Real-Life Versus Food and Drug Administration (FDA) Trials: Results From the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study

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understanding the roles of cytokines and neutrophil activity and neutrophil apoptosis in the protective versus deleterious inflammatory response in pneumonia

SummaryInflammation is a double-edged sword in the outcome of pneumonia. On the one hand, an effective and timely inflammatory response is required to eliminate the invading respiratory pathogen. On the other, a toxic and prolonged inflammatory response may result in lung injury and poor outcomes, even in those receiving advanced medical care. This review focuses on recent understanding of the dynamics of the cytokine response, neutrophil activity, and responsiveness to cytokines and neutrophil lifespan as major elements of lung inflammation resulting in favorable or poor outcomes in lung infection primarily due to pneumococcus and influenza virus. Although some progress has been made in our understanding of the molecular mechanisms of the pneumonia inflammation axis composed of cytokines modulating neutrophil activation and neutrophil apoptosis, important questions remain to be answered. The degree of neutrophil activation, generation of reactive oxygen species, and the release of granule antimicrobial peptides play a key role in microbial pathogen clearance; however, prolonged neutrophil activation may contribute to lung injury and poor outcomes in pneumonia. Molecular markers of the mechanisms regulating neutrophil survival and apoptosis may help in the identification of novel therapeutic targets to modulate inflammation by inducing timely neutrophil apoptosis. A major task is to identify the mechanisms of dysregulation in inflammation leading to toxic responses, thereby targeting a biomarker and enabling timely therapies to modulate inflammation

Using Cluster Analysis of Cytokines to Identify Patterns of Inflammation in Hospitalized Patients with Community-acquired Pneumonia:A Pilot Study

Purpose: Patients with severe community-acquired pneumonia (CAP) are believed to have an exaggerated inflammatory response to bacterial infection. Therapies aiming to modulate the inflammatory response have been largely unsuccessful, perhaps reflecting that CAP is a heterogeneous disorder that cannot be modulated by a single anti-inflammatory approach. We hypothesize that the host inflammatory response to pneumonia may be characterized by distinct cytokine patterns, which can be harnessed for personalized therapies. Methods: Here, we use hierarchical cluster analysis of cytokines to examine if patterns of inflammatory response in 13 hospitalized patients with CAP can be defined. This was a secondary data analysis of the Community-Acquired Pneumonia Inflammatory Study Group (CAPISG) database. The following cytokines were measured in plasma and sputum on the day of admission: interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), IL-6, CXCL8 (IL-8), IL-10, IL-12p40, IL-17, interferon (IFN)γ, tumor necrosis factor (TNF)α, and CXCL10 (IP-10). Hierarchical agglomerative clustering algorithms were used to evaluate clusters of patients within plasma and sputum cytokine determinations. Results: A total of thirteen patients were included in this pilot study. Cluster analysis identified distinct inflammatory response patterns of cytokines in the plasma, sputum, and the ratio of plasma to sputum. Conclusions: Inflammatory response patterns in plasma and sputum can be identified in hospitalized patients with CAP. Characterization of the local and systemic inflammatory response may help to better discriminate patients for enrollment into clinical trials of immunomodulatory therapies

Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC)

Background A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. Methods We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. Results 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV 1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22–1.38; p&lt;0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44–1.67; p&lt;0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52–2.39; p&lt;0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29–1.56; p&lt;0.0001), 1.98 (95% CI 1.77–2.21; p&lt;0.0001) and 3.05 (95% CI 2.25–4.14; p&lt;0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01–1.24; p=0.027), for each increment in sputum purulence. Conclusion Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.</p

Bronchiectasis and asthma:Data from the European Bronchiectasis Registry (EMBARC)

Background: Asthma is commonly reported in patients with a diagnosis of bronchiectasis. Objective: The aim of this study was to evaluate whether patients with bronchiectasis and asthma (BE+A) had a different clinical phenotype and different outcomes compared with patients with bronchiectasis without concomitant asthma. Methods: A prospective observational pan-European registry (European Multicentre Bronchiectasis Audit and Research Collaboration) enrolled patients across 28 countries. Adult patients with computed tomography–confirmed bronchiectasis were reviewed at baseline and annual follow-up visits using an electronic case report form. Asthma was diagnosed by the local investigator. Follow-up data were used to explore differences in exacerbation frequency between groups using a negative binomial regression model. Survival analysis used Cox proportional hazards regression. Results: Of 16,963 patients with bronchiectasis included for analysis, 5,267 (31.0%) had investigator-reported asthma. Patients with BE+A were younger, were more likely to be female and never smokers, and had a higher body mass index than patients with bronchiectasis without asthma. BE+A was associated with a higher prevalence of rhinosinusitis and nasal polyps as well as eosinophilia and Aspergillus sensitization. BE+A had similar microbiology but significantly lower severity of disease using the bronchiectasis severity index. Patients with BE+A were at increased risk of exacerbation after adjustment for disease severity and multiple confounders. Inhaled corticosteroid (ICS) use was associated with reduced mortality in patients with BE+A (adjusted hazard ratio 0.78, 95% CI 0.63-0.95) and reduced risk of hospitalization (rate ratio 0.67, 95% CI 0.67-0.86) compared with control subjects without asthma and not receiving ICSs. Conclusions: BE+A was common and was associated with an increased risk of exacerbations and improved outcomes with ICS use. Unexpectedly we identified significantly lower mortality in patients with BE+A.</p