tbuckley/cabot-search huggingface dataset:
Selective Protection against Conidia by Mononuclear and against Mycelia by Polymorphonuclear Phagocytes in Resistance to Aspergillus
Authors: Andreas Schaffner, Herndon Douglas, Abraham Braude
Journal: Journal of Clinical Investigation (1982)

By comparing natural immunity to Aspergillus fumigatus (AF) in vivo with the action of human or mouse phagocytes against AF in vitro, we delineated two sequential lines of defense against AF. The first line of defense was formed by macrophages and directed against spores. Macrophages prevented germination and killed spores in vitro and rapidly eradicated conidia in vivo, even in neutropenic and athymic mice. The second was the neutrophilic granulocyte (PMN), which protected against the hyphal form of AF. Human and mouse PMN killed mycelia in vitro. Normal, but not neutropenic mice, stopped hyphal growth, and eradicated mycelia. Either line of defense acting alone protected mice from high challenge doses. Natural immunity collapsed only when both the reticuloendothelial system and PMN were impaired. These findings are in keeping with the clinical observation that high doses of cortisone and neutropenia are the main risk factors for invasive aspergillosis. Cortisone inhibited the conidiacidal activity of mouse macrophages in vivo and of human or mouse mononuclear phagocytes in vitro. Cortisone damaged this first line of defense directly and not through the influence of T lymphocytes or other systems modifying macrophage function as shown in athymic mice and in vitro. In addition, daily high doses of cortisone in mice reduced the mobilization of PMN so that the second line of defense was also impaired. Thus, cortisone can break down natural resistance on its own. Myelosuppression rendered mice susceptible only when the first line of defense was overpowered by high challenge doses, by activated spores that cannot be killed by macrophages, or by cortisone suppression of the conidiacidal activity of macrophages. The host, thus, can call upon two independent phagocytic cell lines that form graded defense systems against aspergillus. These lines of defense function in the absence of a specific immune response, which seems superfluous in the control and elimination of this fungus.
A Critical Role for Phosphatidylinositol (3,4,5)-Trisphosphate–Dependent Rac Exchanger 1 in Endothelial Junction Disruption and Vascular Hyperpermeability
Authors: Ram P. Naikawadi, Ni Cheng, Stephen M. Vogel, Feng Qian, Dianqing Wu, Asrar B. Malik, Richard D. Ye
Journal: Circulation Research (2012)

The small GTPase Rac is critical to vascular endothelial functions, yet its regulation in endothelial cells remains unclear. Understanding the upstream pathway may delineate Rac activation mechanisms and its role in maintaining vascular endothelial barrier integrity.By investigating phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 (P-Rex1), one of the Rac-specific guanine nucleotide exchange factors previously known for G protein-coupled receptor signaling, we sought to determine whether Rac-guanine nucleotide exchange factor is nodal for signal integration and potential target for drug intervention.Using gene deletion and small interference RNA silencing approach, we investigated the role of P-Rex1 in human lung microvascular endothelial cells. Tumor necrosis factor α (TNF-α) exposure led to disruption of endothelial junctions, and silencing P-Rex1 protected junction integrity. TNF-α stimulated Rac activation and reactive oxygen species production in a P-Rex1-dependent manner. Removal of P-Rex1 significantly reduced intercellular adhesion molecule-1 expression, polymorphonuclear leukocyte transendothelial migration, and leukocyte sequestration in TNF-α-challenged mouse lungs. The P-Rex1 knockout mice were also refractory to lung vascular hyperpermeability and edema in a lipopolysaccharide-induced sepsis model.These results demonstrate for the first time that P-Rex1 expressed in endothelial cells is activated downstream of TNF-α, which is not a G protein-coupled receptor agonist. Our data identify P-Rex1 as a critical mediator of vascular barrier disruption. Targeting P-Rex1 may effectively protect against TNF-α- and lipopolysaccharide-induced endothelial junction disruption and vascular hyperpermeability.
Study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients
Authors: R. Mounier, C. Adrie, A. Français, M. Garrouste-Orgeas, C. Cheval, B. Allaouchiche, S. Jamali, A. T. Dinh-Xuan, D. Goldgran-Toledano, Y. Cohen, E. Azoulay, J-F. Timsit, J-D. Ricard
Journal: European Respiratory Journal (2009)

The aim of the present study was to examine whether prone positioning (PP) affects ventilator associated-pneumonia (VAP) and mortality in patients with acute lung injury/adult respiratory distress syndrome. 2,409 prospectively included patients were admitted over 9 yrs (2000–2008) to 12 French intensive care units (ICUs) (OUTCOMEREA). The patients required invasive mechanical ventilation (MV) and had arterial oxygen tension/inspiratory oxygen fraction ratios &lt;300 during the first 48 h. Controls were matched to PP patients on the PP propensity score (±10%), MV duration longer than that in PP patients before the first turn prone, and centre. VAP incidence was similar in the PP and control groups (24 versus 13 episodes·1,000 patient-days MV −1 respectively, p = 0.14). After adjustment, PP did not decrease VAP occurrence (HR 1.64 (95% CI 0.70–3.84); p = 0.25) but significantly delayed hospital mortality (HR 0.56 (95% CI 0.39–0.79); p = 0.001), without decreasing 28-day mortality (37% in both groups). Post hoc analyses indicated that PP did not protect against VAP but, when used for &gt;1 day, might decrease mortality and benefit the sickest patients (Simplified Acute Physiology Score &gt;50). In ICU patients with hypoxaemic acute respiratory failure, PP had no effect on the risk of VAP. PP delayed mortality without decreasing 28-day mortality. PP &gt;1 day might decrease mortality, particularly in the sickest patients.
Injury surveillance in multi-sport events: the International Olympic Committee approach
Authors: A Junge, L Engebretsen, J M Alonso, P Renström, M Mountjoy, M Aubry, J Dvorak
Journal: British Journal of Sports Medicine (2008)

Background: The protection of athletes’ health by preventing injuries is an important task for international sports federations. Standardised injury surveillance provides not only important epidemiological information, but also directions for injury prevention, and the opportunity for monitoring long-term changes in the frequency and circumstances of injury. Numerous studies have evaluated sports injuries during the season, but few have focused on injuries during major sport events such as World Championships, World Cups or the Olympic Games. Objectives: To provide an injury surveillance system for multi-sports tournaments, using the 2008 Olympic Games in Beijing as an example. Methods: A group of experienced researchers reviewed existing injury report systems and developed a scientific sound and concise injury surveillance system for large multi-sport events. Results: The injury report system for multi-sport events is based on an established system for team sports tournaments and has proved feasible for individual sports during the International Association of Athletics Federations World Championships in Athletics 2007. The most important principles and advantages of the system are comprehensive definition of injury, injury report by the physician responsible for the athlete, a single-page report of all injuries, and daily report irrespective of whether or not an injury occurred. Implementation of the injury surveillance system, all definitions, the report form, and the analysis of data are described in detail to enable other researchers to implement the injury surveillance system in any sports tournament. Conclusion: The injury surveillance system has been accepted by experienced team physicians and shown to be feasible for single-sport and multi-sport events. It can be modified depending on the specific objectives of a certain sport or research question; however, a standardised use of injury definition, report forms and methodology will ensure the comparability of results.
Asthma exacerbations during long term beta agonist use: influence of beta 2 adrenoceptor polymorphism
Authors: D R. Taylor
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Polymorphisms of the β<sub>2</sub> adrenoceptor influence receptor function in vitro and asthma phenotypes in vivo. However, their importance in determining responses to inhaled β agonist treatment has not been clearly defined. <h3>METHODS</h3> In a retrospective analysis of previously published data we have examined relationships between polymorphisms at codons 16 and 27 of the β<sub>2</sub> adrenoceptor and clinical outcomes in a randomised, placebo controlled, crossover trial of regularly scheduled salbutamol and salmeterol in 115 patients with mild to moderate asthma. Genotyping was obtained for positions 16 and 27 in 108 and 107 patients, respectively. For position 16, 17 patients (16%) were homozygous Arg-Arg, 40 (37%) were heterozygous Arg-Gly, and 51 (47%) were homozygous Gly-Gly. <h3>RESULTS</h3> Within the homozygous Arg-16 group major exacerbations were more frequent during salbutamol treatment than with placebo (1.91 (95% CI 1.07 to 3.12) per year versus 0.81 (95% CI 0.28 to 1.66) per year; p = 0.005). No significant treatment related differences occurred for heterozygous Arg-Gly patients (salbutamol 0.11 (95% CI 0.01 to 0.40), placebo 0.54 (95% CI 0.26 to 1.00) exacerbations per year) or homozygous Gly-16 patients (salbutamol 0.38 (95% CI 0.17 to 0.73), placebo 0.30 (95% CI 0.12 to 0.61) exacerbations per year). No adverse changes occurred for any position 16 subgroup with salmeterol. There was no significant relationship between position 27 genotypes and treatment related outcomes. <h3>CONCLUSION</h3> Homozygous Arg-16 patients are susceptible to clinically important increases in asthma exacerbations during chronic dosing with the short acting β<sub>2</sub> agonist salbutamol.
Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice.
Authors: J Wang, T Koizumi, T Watanabe
Journal: The Journal of Experimental Medicine (1996)

Mice deficient in the src related protein tyrosine kinase, Lyn, exhibit splenomegaly and accumulate lymphoblast-like and plasma cells in spleen as they age, resulting in elevated levels of serum IgM (10-20-fold of control) and glomerulonephritis due to the presence of immune complexes containing auto-reactive antibodies. It remains unclear, however, how antibody-producing cells are accumulated in the lymphoid tissues of Lyn-/- mice. To elucidate the role of Lyn in B cell function, we have studied the proliferative responses to various stimuli and Fas-mediated apoptosis in B cells from young Lyn-/- mice which do not yet show apparent abnormality such as splenomegaly. Compared with control B cells, Lyn-/- B cells were hyper responsive to anti-IgM-induced proliferation and defective in Fc gamma RIIB-mediated suppression of B cell antigen receptor (BCR) signaling, indicating that Lyn is involved in the negative regulation of BCR signaling. In addition, the BCR-mediated signal in Lyn-/- B cells, unlike that in control B cells, failed to act in synergy with either CD40- or IL-4 receptor-triggered signal in inducing a strong proliferative response, suggesting that the BCR signaling pathway in Lyn-/- B cells is altered from that in control B cells. Furthermore, Lyn-/- B cells were found to be impaired in the induction of Fas expression after CD40 ligation and exhibited a reduced susceptibility to Fas-mediated apoptosis. Moreover, BCR cross-linking in Lyn-/- B cells suppressed Fas expression induced by costimulation with CD40 ligand and IL-4. Collectively, these results suggest that the accumulation of lymphoblast-like and plasma cells in Lyn-/- mice may be caused in part, by the accelerated activation of B cells in the absence of Lyn, as well as the impaired Fas-mediated apoptosis after the activation.
Divergent Roles of Angiotensin II AT <sub>1</sub> and AT <sub>2</sub> Receptors in Modulating Coronary Microvascular Function
Authors: Cuihua Zhang, Travis W. Hein, Wei Wang, Lih Kuo
Journal: Circulation Research (2003)

Angiotensin II (Ang II) is a potent vasoconstrictor in the peripheral circulation and has been implicated in many cardiovascular diseases associated with elevated oxidative stress. However, its direct vasomotor action and its linkage to oxidative stress–induced vascular dysfunction in the coronary microcirculation remain elusive. In this study, we directly assessed the vasomotor action of Ang II in isolated porcine coronary arterioles and also examined whether Ang II can modulate endothelium-dependent nitric oxide (NO)-mediated dilation via superoxide production. Ang II evoked vasoconstriction at a low concentration (1 nmol/L) and dilations at higher concentrations (&gt;10 nmol/L). Ang II type 1 (AT 1 ) receptor antagonist losartan abolished vasoconstriction, whereas Ang II type 2 (AT 2 ) receptor antagonist PD 123319 eliminated vasodilation. Adenosine stimulated a significant arteriolar NO production and dilation. NO synthase inhibitor N G -monomethyl- l -arginine (L-NMMA) abolished stimulated NO production and attenuated vasodilation. Pretreating vessels with a subvasomotor concentration of Ang II (0.1 nmol/L, 60 minutes) mimicked inhibitory effects of L-NMMA. Ang II–mediated inhibition was not observed in the presence of L-NMMA or after endothelial removal but was prevented by losartan, superoxide scavenger TEMPOL, or NADPH oxidase inhibitor apocynin. Dihydroethidium staining showed that Ang II elicited losartan- and TEMPOL-sensitive superoxide production in arterioles. These results demonstrate that Ang II evokes AT 1 receptor–mediated vasoconstriction and AT 2 receptor–mediated vasodilation of coronary arterioles. Ang II at a subvasomotor level impairs endothelium-dependent NO-mediated dilation attributable to elevated superoxide production via AT 1 receptor activation of NADPH oxidase. These data may partly explain the impaired coronary flow regulation in heart diseases associated with an upregulated renin-angiotensin system.
Relation between viral fitness and immune escape within the hepatitis C virus protease
Authors: J Soderholm
Journal: Gut (2005)

<b>Background:</b> The hepatitis C virus (HCV) mutates within human leucocyte antigen (HLA) class I restricted immunodominant epitopes of the non-structural (NS) 3/4A protease to escape cytotoxic T lymphocyte (CTL) recognition and promote viral persistence. However, variability is not unlimited, and sometimes almost absent, and factors that restrict viral variability have not been defined experimentally. <b>Aims:</b> We wished to explore whether the variability of the immunodominant CTL epitope at residues 1073–1081 of the NS3 protease was limited by viral fitness. <b>Patients:</b> Venous blood was obtained from six patients (four HLA-A2+) with chronic HCV infection and from one HLA-A2+ patient with acute HCV infection. <b>Methods:</b> NS3/4A genes were amplified from serum, cloned in a eukaryotic expression plasmid, sequenced, and expressed. CTL recognition of naturally occurring and artificially introduced escape mutations in HLA-A2-restricted NS3 epitopes were determined using CTLs from human blood and genetically immunised HLA-A2-transgenic mice. HCV replicons were used to test the effect of escape mutations on HCV protease activity and RNA replication. <b>Results:</b> Sequence analysis of NS3/4A confirmed low genetic variability. The major viral species had functional proteases with 1073–1081 epitopes that were generally recognised by cross reactive human and murine HLA-A2 restricted CTLs. Introduction of mutations at five positions of the 1073–1081 epitope prevented CTL recognition but three of these reduced protease activity and RNA replication. <b>Conclusions:</b> Viral fitness can indeed limit the variability of HCV within immunological epitopes. This helps to explain why certain immunological escape variants never appear as a major viral species in infected humans.
Inhaled corticosteroids and the risk of a first exacerbation in COPD patients
Authors: M.N. de Melo, P. Ernst, S. Suissa
Journal: European Respiratory Journal (2004)

The role of inhaled corticosteroids (ICS) in asthma is well established, but their benefit in the management of chronic obstructive pulmonary disease (COPD) is still controversial. The current study assessed whether ICS are effective in preventing a first exacerbation of COPD. A cohort of newly treated COPD patients was formed from the Administrative Databases of Saskatchewan Health. The outcome was the occurrence of a first moderate or severe exacerbation from 1990-1999. Moderate exacerbations involved prescriptions for an antibiotic and an oral corticosteroid on the same day. Severe exacerbations were hospitalisations with a primary discharge diagnosis of COPD. A nested case-control design was used and matched on year of birth and cohort entry. Rate ratios (RR) were further adjusted for use of other medication and other confounders. There were 995 exacerbations among 4,455 subjects. The rate of a first exacerbation was increased with any use of ICS in the year prior to the index date (RR: 1.27; 95% CI: 1.08-1.48) and with current use (RR: 1.51; 95% CI: 1.22-1.87), and it increased with increasing daily doses of ICS. Inhaled corticosteroids do not seem to be beneficial in reducing the risk of a first exacerbation of chronic obstructive pulmonary disease.
Selling Translational Research: Is Science a Value-Neutral Autonomous Enterprise?
Authors: Zubin Master, Vural Özdemir
Journal: The American Journal of Bioethics (2008)

Click to increase image sizeClick to decrease image size ACKNOWLEDGMENTS Disclaimer: The views expressed here are strictly those of the authors and do not reflect the positions of the Government of Canada or of academic institutions. Dr. Özdemir is supported by an ethics operating seed research grant from the Canadian Institutes of Health Research (CIHR) and a career scientist award in ethics, science and society research from the Fonds de la recherche en Santé du Québec (FRSQ).
Lipoxin (LXA4) as a novel therapy for idiopathic pulmonary fibrosis
Authors: K.M. Roach, L. Woodman, C. Feghali-Bostwick, P. Bradding
Journal: European Respiratory Journal (2014)

Background   Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapyThe key cell driving the development of fibrosis is the myofibroblast. Lipoxin (LXA 4 ) is an anti-inflammatory lipid, important in the resolution of inflammation and has potential anti-fibrotic activity. However, the effects of LXA 4  on primary human lung myofibroblasts (HLMF) have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA 4  on TGFβ1-dependent responses in IPF and non-fibrotic control (NFC) HLMFs.   Methods   HLMFs were isolated from IPF and NFC patients and grown  in vitro . The effects of LXA 4  were examined on myofibroblast wound healing, collagen secretion, and αSMA expression were examined in association with the Smad 2/3 pathway.   Results   LXA 4  significantly inhibited FBS-dependent HLMF wound healing (P=0.0365) and TGFβ1-stimulted collagen secretion 10 pM (P=0.0201) and 10 nM (P=0.0190). Furthermore, LXA 4  reduced constitutive αSMA expression indicating regression from a myofibroblast to fibroblast phenotype (P=0.0212). LXA 4  also significantly attenuated TGFβ-induced Smad 2/3 nuclear translocation.   Conclusions   We show for the first time that LXA 4  significantly attenuates pro-fibrotic myofibroblast function. LXA 4  may therefore offer a novel approach to the treatment of IPF, with the potential for delivery as an aerosol.  This work was funded by the MRC.
Exhaled nitric oxide in asthmatic children exposed to relevant allergens: effect of flunisolide
Authors: G.L. Piacentini, A. Bodini, S. Costella, L. Vicentini, P. Mazzi, Y. Suzuki, D. Peroni, A.L. Boner
Journal: European Respiratory Journal (2000)

Inhaled corticosteroids are capable of reducing the level of exhaled nitric oxide (expiratory nitric oxide fraction (FE,NO)) in asthmatic patients in a dose-dependent fashion. The aim of this study was to evaluate whether or not treatment with an inhaled steroid can prevent changes in FE,NO after the exposure to relevant allergens, following avoidance, in asthmatic children allergic to house dust mite. Thirty-two house dust mite-allergy asthmatic children were randomly allocated to treatment with inhaled flunisolide (500 microg b.i.d) or placebo and evaluated before and 2 weeks after a period of natural exposure to mite antigens. Lung function and FE,NO were evaluated. FE,NO was increased in the placebo-treated group after antigen exposure. Treatment with inhaled flunisolide prevented such increase in FE,NO (p&lt;0.001). No change was observed in lung function parameters. Inhaled flunisolide is effective in preventing the increase in airway inflammation observed in allergic asthmatic children re-exposed to allergens.
Determination of total gastric volume, gastric secretion and residual meal using the double sampling technique of George.
Authors: E J Beckers, N J Rehrer, F Brouns, F Ten Hoor, W H Saris
Journal: Gut (1988)

In literature several techniques are described for the measurement of gastric emptying. One of these is the double sampling technique of George which has the advantage that it enables multiple measurements of total gastric volume in one experiment. In order to estimate net gastric emptying, however, it is important to differentiate between the test meal volume present in the stomach and gastric secretion. In the present study George9s technique was extended with a calculation procedure to estimate gastric secretion and net test meal outflow. An in vitro experiment was carried out which showed an accuracy of 5-10% for this method. An in vivo comparison was made with Hunt9s chloride technique, which is used for estimating gastric secretion. Sixteen subjects participated in a 60 minute test with water as a test meal. Regression analysis showed a high degree of correlation (R2 = 0.99) between Hunt9s method and the proposed method. The data obtained indicate that the proposed method gives a reliable estimation of net gastric emptying and is simple to do as no further measurements have to be carried out other than those needed for George9s method.
Direct Estimation of Kinetic Parametric Images for Dynamic PET
Authors: Guobao Wang, Jinyi Qi
Journal: Theranostics (2013)

Dynamic positron emission tomography (PET) can monitor spatiotemporal distribution of radiotracer in vivo.The spatiotemporal information can be used to estimate parametric images of radiotracer kinetics that are of physiological and biochemical interests.Direct estimation of parametric images from raw projection data allows accurate noise modeling and has been shown to offer better image quality than conventional indirect methods, which reconstruct a sequence of PET images first and then perform tracer kinetic modeling pixel-by-pixel.Direct reconstruction of parametric images has gained increasing interests with the advances in computing hardware.Many direct reconstruction algorithms have been developed for different kinetic models.In this paper we review the recent progress in the development of direct reconstruction algorithms for parametric image estimation.Algorithms for linear and nonlinear kinetic models are described and their properties are discussed.