Leukocytes Are Recruited through the Bronchial Circulation to the Lung in a Spontaneously Hypertensive Rat Model of COPD

Chronic obstructive pulmonary disease (COPD) kills approximately 2.8 million people each year, and more than 80% of COPD cases can be attributed to smoking. Leukocytes recruited to the lung contribute to COPD pathology by releasing reactive oxygen metabolites and proteolytic enzymes. In this work, we investigated where leukocytes enter the lung in the early stages of COPD in order to better understand their effect as a contributor to the development of COPD. We simultaneously evaluated the parenchyma and airways for neutrophil accumulation, as well as increases in the adhesion molecules and chemokines that cause leukocyte recruitment in the early stages of tobacco smoke induced lung disease. We found neutrophil accumulation and increased expression of adhesion molecules and chemokines in the bronchial blood vessels that correlated with the accumulation of leukocytes recovered from the lung. The expression of adhesion molecules and chemokines in other vascular beds did not correlate with leukocytes recovered in bronchoalveolar lavage fluid (BALF). These data strongly suggest leukocytes are recruited in large measure through the bronchial circulation in response to tobacco smoke. Our findings have important implications for understanding the etiology of COPD and suggest that pharmaceuticals designed to reduce leukocyte recruitment through the bronchial circulation may be a potential therapy to treat COPD

Comparing comorbidity measures for predicting mortality and hospitalization in three population-based cohorts

<p>Abstract</p> <p>Background</p> <p>Multiple comorbidity measures have been developed for risk-adjustment in studies using administrative data, but it is unclear which measure is optimal for specific outcomes and if the measures are equally valid in different populations. This research examined the predictive performance of five comorbidity measures in three population-based cohorts.</p> <p>Methods</p> <p>Administrative data from the province of Saskatchewan, Canada, were used to create the cohorts. The general population cohort included all Saskatchewan residents 20+ years, the diabetes cohort included individuals 20+ years with a diabetes diagnosis in hospital and/or physician data, and the osteoporosis cohort included individuals 50+ years with diagnosed or treated osteoporosis. Five comorbidity measures based on health services utilization, number of different diagnoses, and prescription drugs over one year were defined. Predictive performance was assessed for death and hospitalization outcomes using measures of discrimination (<it>c</it>-statistic) and calibration (Brier score) for multiple logistic regression models.</p> <p>Results</p> <p>The comorbidity measures with optimal performance were the same in the general population (<it>n </it>= 662,423), diabetes (<it>n </it>= 41,925), and osteoporosis (<it>n </it>= 28,068) cohorts. For mortality, the Elixhauser index resulted in the highest <it>c</it>-statistic and lowest Brier score, followed by the Charlson index. For hospitalization, the number of diagnoses had the best predictive performance. Consistent results were obtained when we restricted attention to the population 65+ years in each cohort.</p> <p>Conclusions</p> <p>The optimal comorbidity measure depends on the health outcome and not on the disease characteristics of the study population.</p

MicroRNA and mRNA expression profiling in rat acute respiratory distress syndrome

Background: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary epithelial injury and extensive inflammation of the pulmonary parenchyma. Systematic analyses of microRNA (miRNA) and mRNA expression profiling in ARDS provide insights into understanding of molecular mechanisms of the pathogenesis of ARDS. The objective of this study was to identify miRNA and mRNA interactions in a rat model of ARDS by combining miRNA and mRNA microarray analyses.Methods: Rat model of ARDS was induced by saline lavage and mechanical ventilation. The expression profiles of both mRNAs and miRNAs in rat ARDS model were performed by microarray analyses. Microarray data were further verified by quantitative RT-PCR. Functional annotation on dys-regulated mRNAs and miRNAs was carried out by bioinformatics analysis.Results: The expression of 27 miRNAs and 37 mRNAs were found to be significantly changed. The selected miRNAs and genes were further verified by quantitative real-time PCR. The down-regulated miRNAs included miR-24, miR-26a, miR-126, and Let-7a, b, c, f. The up-regulated miRNAs were composed of miR-344, miR-346, miR-99a, miR-127, miR-128b, miR-135b, and miR-30a/b. Gene ontology and functional annotation analyses indicated that up-regulated mRNAs, such as Apc, Timp1, and Sod2, were involved in the regulation of apoptosis. Bioinformatics analysis showed the inverse correlation of altered miRNAs with the expression of their predicted target mRNAs. While Sod2 was inversely correlated with Let-7a, b, c, f., Ebf1 and Apc were inversely correlated with miR-24 and miR-26a, respectively. miR-26a, miR-346, miR-135b, miR-30a/b, miR-344, and miR-18a targeted multiple altered mRNAs. Gabrb1, Sod2, Eif2ak1, Fbln5, and Tspan8 were targeted by multiple altered miRNAs.Conclusion: The expressions of miRNAs and mRNAs were altered in a rat model of ARDS. The identified miRNA-mRNA pairs may play critical roles in the pathogenesis of ARDS.Peer reviewedPathobiologyOklahoma Center for Respiratory and Infectious DiseasesPhysiological Science

From Computer Metaphor to Computational Modeling: The Evolution of Computationalism

In this paper, I argue that computationalism is a progressive research tradition. Its metaphysical assumptions are that nervous systems are computational, and that information processing is necessary for cognition to occur. First, the primary reasons why information processing should explain cognition are reviewed. Then I argue that early formulations of these reasons are outdated. However, by relying on the mechanistic account of physical computation, they can be recast in a compelling way. Next, I contrast two computational models of working memory to show how modeling has progressed over the years. The methodological assumptions of new modeling work are best understood in the mechanistic framework, which is evidenced by the way in which models are empirically validated. Moreover, the methodological and theoretical progress in computational neuroscience vindicates the new mechanistic approach to explanation, which, at the same time, justifies the best practices of computational modeling. Overall, computational modeling is deservedly successful in cognitive (neuro)science. Its successes are related to deep conceptual connections between cognition and computation. Computationalism is not only here to stay, it becomes stronger every year

Perioperative events influence cancer recurrence risk after surgery.

Surgery is a mainstay treatment for patients with solid tumours. However, despite surgical resection with a curative intent and numerous advances in the effectiveness of (neo)adjuvant therapies, metastatic disease remains common and carries a high risk of mortality. The biological perturbations that accompany the surgical stress response and the pharmacological effects of anaesthetic drugs, paradoxically, might also promote disease recurrence or the progression of metastatic disease. When cancer cells persist after surgery, either locally or at undiagnosed distant sites, neuroendocrine, immune, and metabolic pathways activated in response to surgery and/or anaesthesia might promote their survival and proliferation. A consequence of this effect is that minimal residual disease might then escape equilibrium and progress to metastatic disease. Herein, we discuss the most promising proposals for the refinement of perioperative care that might address these challenges. We outline the rationale and early evidence for the adaptation of anaesthetic techniques and the strategic use of anti-adrenergic, anti-inflammatory, and/or antithrombotic therapies. Many of these strategies are currently under evaluation in large-cohort trials and hold promise as affordable, readily available interventions that will improve the postoperative recurrence-free survival of patients with cancer

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified