tbuckley/cabot-search huggingface dataset:
Stromal Cell–Derived Factor-1α Confers Protection Against Myocardial Ischemia/Reperfusion Injury
Authors: Xiaofeng Hu, Shujing Dai, Wen-Jian Wu, Wei Tan, Xiaoping Zhu, Jingyao Mu, Yiru Guo, Roberto Bolli, Gregg Rokosh
Journal: Circulation (2007)

Stromal cell-derived factor-1alpha (SDF-1alpha) binding to its cognate receptor, CXCR4, regulates a variety of cellular functions such as stem cell homing, trafficking, and differentiation. However, the role of the SDF-1alpha-CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown.In mice subjected to ischemic preconditioning, myocardial SDF-1alpha mRNA was found to be increased 3 hours later (P<0.05). Myocardial SDF-1alpha and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1alpha production increased significantly after 1 or 4 hours of hypoxia and 18 hours of reoxygenation in cultured myocytes (P<0.05) but did not change in fibroblast cultures. In isolated myocytes, CXCR4 activation by SDF-1alpha resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1alpha were resistant to hypoxia/reoxygenation damage, exhibiting less lactate dehydrogenase release, trypan blue uptake, and apoptotic cell death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) (P<0.05). This protective effect was blocked by the CXCR4 selective antagonist AMD3100. In vivo, administration of SDF-1alpha before 30 minutes of coronary occlusion followed by 4 hours of reperfusion decreased infarct size (P<0.05). The decrease in infarct size with SDF-1alpha administration also was blocked by AMD3100.We conclude that SDF-1alpha and its receptor, CXCR4, constitute a paracrine or autocrine axis in cardiac myocytes that is activated in response to preconditioning and hypoxic stimuli, recruiting the antiapoptotic kinases ERK and AKT and promoting an antiapoptotic program that confers protection against ischemia/reperfusion damage.
Lung function in preschool children
Authors: D Vilozni
Journal: Thorax (2003)

We read with great interest the recent paper by Nystad et al 1 on the feasibility of spirometric tests in preschool children using candle blowing incentives, in support of recent publications.2–5 As there is a dearth of spirometric reference data for this age group, we value the additional regression equations derived. However, we have several questions concerning this study.

The regression formulae presented were based …
The Peripheral Deletion of Autoreactive CD8+ T Cells Induced by Cross-presentation of Self-antigens Involves Signaling through CD95 (Fas, Apo-1)
Authors: Christian Kurts, William R. Heath, Hiroshi Kosaka, Jacques F.A.P. Miller, Francis R. Carbone
Journal: The Journal of Experimental Medicine (1998)

Recently, we demonstrated that major histocompatibility complex class I–restricted cross-presentation of exogenous self-antigens can induce peripheral T cell tolerance by deletion of autoreactive CD8+ T cells. In these studies, naive ovalbumin (OVA)-specific CD8+ T cells from the transgenic line OT-I were injected into transgenic mice expressing membrane-bound OVA (mOVA) under the control of the rat insulin promoter (RIP) in pancreatic islets, kidney proximal tubules, and the thymus. Cross-presentation of tissue-derived OVA in the renal and pancreatic lymph nodes resulted in activation, proliferation, and then the deletion of OT-I cells. In this report, we investigated the molecular mechanisms underlying this form of T cell deletion. OT-I mice were crossed to tumor necrosis factor receptor 2 (TNFR2) knockout mice and to CD95 (Fas, Apo-1) deficient mutant lpr mice. Wild-type and TNFR2-deficient OT-I cells were activated and then deleted when transferred into RIP-mOVA mice, whereas CD95-deficient OT-I cells were not susceptible to deletion by cross-presentation. Furthermore, cross-presentation led to upregulation of the CD95 molecule on the surface of wild-type OT-I cells in vivo, consistent with the idea that this is linked to rendering autoreactive T cells susceptible to CD95-mediated signaling. This study represents the first evidence that CD95 is involved in the deletion of autoreactive CD8+ T cells in the whole animal.
De novo genome sequence assembly of a filamentous fungus using Sanger, 454 and Illumina sequence data
Authors: Scott DiGuistini, Nancy Y Liao, Darren Platt, Gordon Robertson, Michael Seidel, Simon K Chan, T Roderick Docking, Inanc Birol, Robert A Holt, Martin Hirst, Elaine Mardis, Marco A Marra, Richard C Hamelin, Jörg Bohlmann, Colette Breuil, Steven JM Jones
Journal: Genome biology (2009)

Sequencing-by-synthesis technologies can reduce the cost of generating de novo genome assemblies. We report a method for assembling draft genome sequences of eukaryotic organisms that integrates sequence information from different sources, and demonstrate its effectiveness by assembling an approximately 32.5 Mb draft genome sequence for the forest pathogen Grosmannia clavigera, an ascomycete fungus. We also developed a method for assessing draft assemblies using Illumina paired end read data and demonstrate how we are using it to guide future sequence finishing. Our results demonstrate that eukaryotic genome sequences can be accurately assembled by combining Illumina, 454 and Sanger sequence data.
Should corticosteroid aerosols be used in severe chronic asthma?
Authors: H Herxheimer
Journal: Thorax (1981)

Should corticosteroid aerosols be used in severe chronic asthma?Corticosteroids play an important part in the treatment of severe chronic asthma.They are usually given in an individually determined main- tenance dose.Since 1955 attempts have also been made to influence asthma by locally administered corticosteroids such as micronised powders,' 2 and
Plasma Oxidized Low-Density Lipoprotein, a Strong Predictor for Acute Coronary Heart Disease Events in Apparently Healthy, Middle-Aged Men From the General Population
Authors: Christa Meisinger, Jens Baumert, Natalie Khuseyinova, Hannelore Loewel, Wolfgang Koenig
Journal: Circulation (2005)

Background— Oxidized LDL (oxLDL) is thought to play a key role in the inflammatory response in the arterial vessel wall. Methods and Results— In a prospective, nested, case-control study, the association between plasma oxLDL and risk of an acute coronary heart disease (CHD) event was investigated in men without prevalent CHD or diabetes mellitus at baseline. Subjects came from 2 population-based MONICA/KORA Augsburg surveys conducted in the years 1989–1990 and 1994–1995 with follow-up in 1998 (mean±SD follow-up time, 5.6±2.6 years). OxLDL was determined by ELISA in 88 men with incident CHD and in 258 age- and survey-matched controls. Hazard ratios (HRs) were estimated from conditional logistic-regression models with matching for age and survey. Baseline mean plasma oxLDL concentrations were significantly higher in subjects who subsequently experienced an event compared with controls (mean±SD, 110±32 versus 93±28 U/L; P ≤0.001). After adjustment for smoking, hypertension, obesity, physical activity, education, and alcohol consumption, the HR for a future CHD event in a comparison of the upper tertile of the oxLDL distribution with the lower tertile was 4.25 (95% confidence interval, 2.09 to 8.63; P &lt;0.001). Plasma oxLDL was the strongest predictor of CHD events compared with a conventional lipoprotein profile and other traditional risk factors for CHD. When both oxLDL and C-reactive protein were simultaneously assessed in the same model, they still predicted future CHD events even after multivariable adjustment. Conclusions— Elevated concentrations of oxLDL are predictive of future CHD events in apparently healthy men. Thus, oxLDL may represent a promising risk marker for clinical CHD complications and should be evaluated in further studies.
A Mosaic Fiber Adenovirus Serotype 5 Vector Containing Reovirus σ1 and Adenovirus Serotype 3 Knob Fibers Increases Transduction in an Ovarian Cancer <i>Ex vivo</i> System via a Coxsackie and Adenovirus Receptor–Independent Pathway
Authors: Yuko Tsuruta, Larisa Pereboeva, Joel N. Glasgow, Daniel T. Rein, Yosuke Kawakami, Ronald D. Alvarez, Rodney P. Rocconi, Gene P. Siegal, Paul Dent, Paul B. Fisher, David T. Curiel
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Adenovirus serotype 5 (Ad5) has been used for gene therapy with limited success due to insufficient infectivity in cells with low expression of the primary receptor, the coxsackie and adenovirus receptor (CAR). Evidence that adenovirus serotype receptors other than CAR may be of use was presented in previous studies that showed that the Ad3 receptor is expressed at high levels in ovarian cancer cells. We hypothesized that combined use of unique chimeric fibers in the context of novel mosaic adenovirus vectors would enhance infectivity via non-CAR pathways in ovarian cancer cells. Experimental Design: We constructed and characterized Ad5 vectors that use Ad3 knob and reovirus fibers to generate a mosaic fiber virion. Serotype 3 Dearing reovirus uses a fiber-like σ1 protein to infect cells expressing sialic acid and junction adhesion molecule 1. We therefore constructed a mosaic fiber Ad5 vector, designated Ad5/3-σ1, encoding two fibers: a σ1 chimeric fiber and the chimeric Ad5/3 fiber composed of an Ad3 knob. Results: Functionally, Ad5/3-σ1 used sialic acid, junction adhesion molecule 1, and Ad3 receptor for cell transduction and achieved maximum infectivity enhancement in ovarian cancer cells with low CAR expression. Furthermore, Ad5/3-σ1 achieved infectivity enhancement in primary tissue slices of human ovarian tumor. Conclusions: We have developed a new type of Ad5 vector with the novel tropism, possessing fibers from Ad3 and reovirus, which exhibits enhanced infectivity via CAR-independent pathway(s). In addition, the flexible genetic platform of vector allows different combination of fiber variants that can be incorporated within the same particle.
Severe Persistent Allergic Rhinitis. Inflammation but No Histologic Features of Structural Upper Airway Remodeling
Authors: Aarif O. Eifan, Nara T. Orban, Mikila R. Jacobson, Stephen R. Durham
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Increases in airway smooth muscle, extracellular matrix, and vascularity are prominent features of airway remodeling in asthma, whereas the extent of such remodeling in patients with persistent allergic rhinitis (PAR) is unknown.Objectives: To test the hypothesis that upper airway remodeling is a feature of PAR.Methods: Total nasal symptoms scores, nasal biopsies, and Th1 and Th2 cytokines from nasal lavage were assessed in subjects with severe PAR (n = 46) and healthy control subjects (n = 19). Angiolymphangiogenesis was examined using immunohistochemistry staining against CD31 (vascular endothelial cells), vascular endothelial growth factor-A, and D2-40 (lymphatic endothelial cells). Collagen and extracellular matrix proteins, such as heat shock protein-47 (markers of collagen synthesis), matrix metalloproteinase-9, and tissue inhibitor metalloproteinase-1, and α-smooth muscle actin (myofibroblasts) were evaluated as markers of activation of upper airway remodeling using image analysis, together with reticular basement membrane thickness, mucus gland area, collagen area, and submucosal effector inflammatory cells.Measurements and Main Results: Total nasal symptoms scores, visual analog scale, and total quality of life were significantly higher in PAR compared with healthy control subjects (P < 0.0001). Nasal lavage cytokine levels of IL-4 (P < 0.01), IL-5, and IL-13 (P < 0.001, respectively) were significantly higher in PAR compared with healthy control subjects. In addition there was an increase in submucosal eosinophils (P = 0.06). No statistical difference in terms of angiogenesis, lymphangiogenesis, deposition of extracellular matrix, collagen markers, reticular basement membrane thickness, or glandular percentage area was observed between PAR and healthy control subjects.Conclusions: Our data suggest that tissue remodeling is not a feature of PAR and argues that in contrast to asthma, targeting remodeling in allergic rhinitis may not be appropriate as a therapeutic approach.
Insulin Stimulates Both Endothelin and Nitric Oxide Activity in the Human Forearm
Authors: Carmine Cardillo, Sridhar S. Nambi, Crescence M. Kilcoyne, Wassim K. Choucair, Arie Katz, Michael J. Quon, Julio A. Panza
Journal: Circulation (1999)

The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties.Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (P=0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (P=0. 88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (P<0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by N(G)-monomethyl-L-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (P=0.006).These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.
Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis
Authors: V P K Nell
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> Early treatment prevents progression of joint damage in rheumatoid arthritis (RA), but diagnosis in early disease is impeded by lack of appropriate diagnostic criteria. <b>Objective:</b> To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis. <b>Methods:</b> The prospective follow up inception cohort included 200 patients with very early (&lt;3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone. <b>Results:</b> RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level for RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional diagnostic value. Remarkably, RF ⩾50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF ⩾50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease. <b>Conclusions:</b> Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF &lt;50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.
T Cell–Based Tracking of Multidrug Resistant Tuberculosis Infection after Brief Exposure
Authors: Luca Richeldi, Katie Ewer, Monica Losi, Barbara M. Bergamini, Pietro Roversi, Jonathan Deeks, Leonardo M. Fabbri, Ajit Lalvani
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Molecular epidemiology indicates significant transmission of Mycobacterium tuberculosis after casual contact with infectious tuberculosis cases. We investigated M. tuberculosis transmission after brief exposure using a T cell-based assay, the enzyme-linked-immunospot (ELISPOT) for IFN-gamma. After childbirth, a mother was diagnosed with sputum smear-positive multidrug-resistant tuberculosis. Forty-one neonates and 47 adults were present during her admission on the maternity unit; 11 weeks later, all underwent tuberculin skin testing (TST) and ELISPOT. We correlated test results with markers of exposure to the index case. The participants, who were asymptomatic and predominantly had no prior tuberculosis exposure, had 6.05 hours mean exposure (range: 0-65 hours) to the index case. Seventeen individuals, including two newborns, were ELISPOT-positive, and ELISPOT results correlated significantly with three of four predefined measures of tuberculosis exposure. For each hour sharing room air with the index case, the odds of a positive ELISPOT result increased by 1.05 (95% CI: 1.02-1.09, p = 0.003). Only four adults were TST-positive and TST results did not correlate with exposure. Thus, ELISPOT, but not TST, suggested quite extensive nosocomial transmission of multidrug-resistant M. tuberculosis after brief exposure. These results help to explain the apparent importance of casual contact for tuberculosis transmission, and may have implications for prevention.
Successful treatment of antineutrophil cytoplasmic antibody-associated bronchiectasis with immunosuppressive therapy
Authors: Raphael Lhote, Christine Theodore, Tasnime Issoufaly, Dominique Francois, Jean-Emmanuel Kahn, Loïc Guillevin, Elisabeth Rivaud, Camille Bron, Marc Vasse, Louis-Jean Couderc, Colas Tcherakian
Journal: European Respiratory Journal (2015)

The underlying mechanisms of bronchiectasis are poorly understood and the cause remains unknown in half of the patients [1]. Whether bronchiectasis is the direct consequence of pathogen aggression or of an abnormal immune response remains unresolved [2–4]. We report here the first case of a patient with bronchiectasis improved by an immunosuppressive regimen. Could ANCA testing in bronchiectasis help to identify patients who would benefit from immunosuppressive regimens? <http://ow.ly/L7Nat>
Faecal alpha-1-antitrypsin in chronic inflammatory bowel disease.
Authors: D W Thomas
Journal: Gut (1988)

Faecal alpha-l-antitrypsin in chronic inflammatory bowel disease SIR,-Fischbach et al' found that patients with chronic inflammatory bowel disease (CIBD) had significantly raised faecal alpha-1-antitrypsin (FAlAT) concentrations compared with controls and other patients with non-inflammatory bowel disorders.Patients with clinically active disease had higher FAlAT's than those with quiescent disease, but the difference was not significant.Clinical disease activity correlated better with ESR, albumin, orosomucoid, serum AlAT, and .'.In labelled granulocyte excretion.Their CIBD patients had lower FAlAT's compared with those we reported2 and by Meyers.3Fischbach et al suggested that this discrepancy could have been because of 'patient selection' rather than a 'technical problem'.They stated that most of their patients were not very ill; the range of disease activity scores was not presented in their paper.Fischbach and colleagues concluded that assess- ment of inflammatory activity can not be solely based upon FAlAT excretion because factors other than mucosal inflammation could result in excessive enteric protein loss.While this might be true, I disagree with some of the author's interpretations of their results.First, in our experience, patients with moderate to severe CIBD have higher FAIAT's.2One would expect lower values for patients, such as described by Fischbach et al, with only mild clinical disease.Second, it is possible that the authors' findings were the result of a technical problem with the assay.The FAlAT concentrations reported in our study2 were generated on now unavailable Calbiochem Behring M-Partigen radial immunodiffusion (RID) plates.Since then our laboratory has had extensive experience in performing this assay on different RID systems.4Other investigators have also reported variation in AIAT values done on different com- mercially available RID plates.5The manufacturer
The Emperor's New Clothes II—time for regulators to wake up and take responsibility for unnecessary asthma morbidity: time for the second aerosol ‘transition’
Authors: Mark L Everard
Journal: Thorax (2013)

The rate of technological improvement continues to accelerate. Regulators in every field dealing with consumer products continue to set ever higher standards to protect consumers from adverse events and use ‘recalls’ to remove products that prove to be harmful from the market. In the field of medical products in general the issues of ‘human factors’ and ‘usability’ are now, quite rightly, a major issue at least among regulators in the USA. The elephant in the inhaled therapy room is of course the continued use of obsolete, portable inhalers which few patients can use effectively for the treatment of asthma. Countless studies have demonstrated that the inability of patients to use these devices effectively is a major factor in perpetuating unnecessarily high levels of morbidity. They fail to meet basic usability standards and do not incorporate the facility to provide feedback to patient and clinician. More than 20 years ago regulators deemed that pressurised metered dose inhalers containing chlorofluorocarbons should be removed from the market on environmental grounds even though their use accounted for less than 0.5% of chlorofluorocarbon use. Surely asthmatic patients require the same level of protection. Unfortunately regulators appear determined to fossilise the field in a 1950′s time warp by ensuring that the failings of obsolete technology are perpetuated in any ‘generic’ device. The time has come for regulators to meet their obligations to <i>‘protect the public health by assuring the safety, effectiveness, and security of drugs, vaccines and other biological products, medical devices….’</i> and mandate the phasing out of these antiquated devices within the next decade in order to reduce the unacceptably high burden of preventable morbidity and death associated with their use.