tbuckley/cabot-search huggingface dataset:
Rapid reduction in hospitalisations after an intervention to manage severe asthma
Authors: C. Souza-Machado, A. Souza-Machado, R. Franco, E. V. Ponte, M. L. Barreto, L. C. Rodrigues, J. Bousquet, A. A. Cruz
Journal: European Respiratory Journal (2009)

Asthma is the third cause of hospitalisations due to clinical illnesses in Brazil. The Programme for Control of Asthma in Bahia (ProAR) leads an initiative in Salvador City (Brazil) to manage severe asthma for free. The aim of this study was to identify trends in asthma hospitalisation in the entire city and to evaluate the impact of ProAR. Information on asthma hospitalisations from 1998 to 2006 was collected. We analysed trends in Salvador (2.8 million inhabitants) before and after ProAR, taking pneumonia and myocardial infarction into account for local comparison. As an external control we obtained information on asthma from Recife, which is the most comparable Brazilian city. In Salvador, asthma hospital admissions declined by 82.3% (1998–2006). A greater proportion of this reduction (74%) occurred after 2003, in parallel with the implementation of ProAR. The reduction in asthma admissions in Recife was smaller. The rates of hospitalisation in 2006 were 2.25 per 10,000 inhabitants in Salvador and 17.06 in Recife. In Salvador, we found an inverse correlation between the provision of medication for asthma and hospitalisation (-0.801; p&lt;0.0001). A rapid reduction in asthma admissions in the entire city of Salvador was associated with ProAR, a public health intervention targeting severe asthma.
Imaging Mass Spectrometry of a Specific Fragment of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Kinase 2 Discriminates Cancer from Uninvolved Prostate Tissue
Authors: Lisa H. Cazares, Dean Troyer, Savvas Mendrinos, Raymond A. Lance, Julius O. Nyalwidhe, Hind A. Beydoun, Mary Ann Clements, Richard R. Drake, O. John Semmes
Journal: Clinical Cancer Research (2009)

Histopathology is the standard approach for tissue diagnostics and centerpiece of pathology. Although the current system provides prognostic information, there is need for molecular markers that enhance diagnosis and better predict clinical prognosis. The ability to localize disease-specific molecular changes in biopsy tissue would help improve critical pathology decision making. Direct profiling of proteins from tissue using matrix-assisted laser desorption/ionization imaging mass spectrometry has the potential to supplement morphology with underlying molecular detail.A discovery set of 11 prostate cancer (PCa)-containing and 10 benign prostate tissue sections was evaluated for protein expression differences. A separate validation set of 54 tissue sections (23 PCa and 31 benign) was used to verify the results. Cryosectioning was done to yield tissue sections analyzed by a pathologist to determine tissue morphology and mirror sections for imaging mass spectrometry. Spectra were acquired and the intensity of signals was plotted as a function of the location within the tissue.An expression profile was found that discriminates between PCa and normal tissue. The overexpression of a single ion at m/z 4,355 was able to discriminate cancer from uninvolved tissue. Tandem mass spectrometry identified this marker as a fragment of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 2 (MEKK2). The ability of MEKK2 to discriminate tumor from normal cells was orthogonally confirmed.This study highlights the potential of this approach to uncover molecular detail that can be correlated with pathology decision making. In addition, the identification of MEKK2 shows the ability to discover proteins of relevance to PCa biology.
Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine
Authors: Barbara A. Slade
Journal: JAMA (2009)

In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years.To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV.Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting.Numbers of reported AEFIs, reporting rates (reports per 100,000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates.VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.
ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage.
Authors: W C Cole, C D McPherson, D Sontag
Journal: Circulation Research (1991)

The role of ATP-regulated K+ channels in protecting the myocardium against ischemia/reperfusion damage was explored using glibenclamide and pinacidil to block and activate the channels, respectively. Electrical and mechanical activity of arterially perfused guinea pig right ventricular walls was recorded simultaneously via an intracellular microelectrode and a force transducer. The preparations were subjected to either 1) 20 minutes of no-flow ischemia with or without glibenclamide (1 and 10 microM) followed by reperfusion, or 2) 30 minutes of no-flow ischemia with or without pinacidil (1 and 10 microM) followed by reperfusion. No-flow ischemia for 20 minutes produced changes in electrical and mechanical activity that were completely reversed on reperfusion; resting membrane potential declined by 13 +/- 1.2 mV, action potential duration at 90% repolarization (APD90) decreased by 62%, and developed tension fell by greater than 95%, but resting tension did not change significantly. Glibenclamide (10 microM) had no effect on activity during normal perfusion, but during ischemia, resting membrane potential fell slightly further (17 +/- 1.8 mV) and APD90 declined by only 24%. Developed tension declined more slowly and to a lesser extent, but resting tension rose significantly between 10 and 20 minutes of ischemia. Reperfusion of glibenclamide-treated tissues elicited arrhythmias (extrasystoles and tachycardia), and the preparations failed to recover mechanical function. Glibenclamide at 1 microM produced qualitatively similar effects, albeit less severe. After 30 minutes of no-flow ischemia in untreated tissues, resting tension increased by approximately 130% during the no-flow period. Reperfusion caused arrhythmias (extrasystoles, tachyarrhythmias, and fibrillation) and failed to restore resting or developed tension to preischemic levels. Pinacidil at 1 microM did not affect electrical or contractile function, but at 10 microM it had a negative inotropic effect, decreasing APD90 and developed tension by 5% and 18%, respectively. Both concentrations of the drug caused a faster and greater decline in APD90 during the no-flow period. Resting tension did not change during 30 minutes of no-flow ischemia in the presence of pinacidil, and reperfusion led to 85% and complete recovery of electrical and mechanical activity at 1 and 10 microM, respectively. The data indicate that glibenclamide enhances whereas pinacidil reduces myocardial damage caused by ischemia/reperfusion. The results are consistent with the hypothesis that activation of ATP-regulated K+ channels during ischemia is an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.
Management of Diabetic Nephropathy
Authors: Lukas Foggensteiner, Sharon Mulroy, John Firth
Journal: Journal of the Royal Society of Medicine (2001)

Diabetic nephropathy is the single most common cause of end-stage renal disease in the western world and is associated with greatly increased cardiovascular morbidity and mortality. With the rising prevalence of type 2 disease it has come to pose a heavy burden on healthcare systems worldwide. Investment in fundamental and clinical research has yielded strategies that can reduce the risk of diabetic renal disease and slow its progression.
FimH Can Directly Activate Human and Murine Natural Killer Cells via TLR4
Authors: M Firoz Mian, Nicole M Lauzon, David W Andrews, Brian D Lichty, Ali A Ashkar
Journal: Molecular Therapy (2010)

Although the importance of natural killer (NK) cells in innate immune responses against tumors or viral infections are well documented, their ability to directly recognize pathogens is less well defined. We have recently reported FimH, a bacterial fimbrial protein, as a novel Toll-like receptor (TLR)4 ligand that potently induces antiviral responses. Here, we investigated whether FimH either directly or indirectly can activate human and murine NK cells. We demonstrate that FimH potently activates both human and murine NK cells in vitro to induce cytokines [interferon (IFN)-γ and tumor necrosis factor (TNF)-α] and cytotoxicity. Importantly, NK cells directly recognize FimH-expressing pathogens as FimH+, but not FimH−, bacteria were able to activate human NK cells. FimH activation of NK cells required TLR4 and MyD88 signaling, as NK cells from both TLR4−/− and MyD88−/− mice as well as human NK-92 cells, which lack TLR4, were all unresponsive to FimH. In addition, TLR4 neutralization significantly abrogated the response of human NK cells to FimH. Activation of purified NK cells by FimH was independent of lipopolysaccharide (LPS) or other bacterial contaminations. These data demonstrate for the first time that highly purified NK cells directly recognize and respond to FimH via TLR4–MyD88 pathways to aid innate protection against cancer or microbial infections. Although the importance of natural killer (NK) cells in innate immune responses against tumors or viral infections are well documented, their ability to directly recognize pathogens is less well defined. We have recently reported FimH, a bacterial fimbrial protein, as a novel Toll-like receptor (TLR)4 ligand that potently induces antiviral responses. Here, we investigated whether FimH either directly or indirectly can activate human and murine NK cells. We demonstrate that FimH potently activates both human and murine NK cells in vitro to induce cytokines [interferon (IFN)-γ and tumor necrosis factor (TNF)-α] and cytotoxicity. Importantly, NK cells directly recognize FimH-expressing pathogens as FimH+, but not FimH−, bacteria were able to activate human NK cells. FimH activation of NK cells required TLR4 and MyD88 signaling, as NK cells from both TLR4−/− and MyD88−/− mice as well as human NK-92 cells, which lack TLR4, were all unresponsive to FimH. In addition, TLR4 neutralization significantly abrogated the response of human NK cells to FimH. Activation of purified NK cells by FimH was independent of lipopolysaccharide (LPS) or other bacterial contaminations. These data demonstrate for the first time that highly purified NK cells directly recognize and respond to FimH via TLR4–MyD88 pathways to aid innate protection against cancer or microbial infections.
Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H
Authors: Chie Kudo-Saito, Masahiro Yura, Ryusuke Yamamoto, Yutaka Kawakami
Journal: Cancer Research (2014)

Abstract Human endogenous retroviruses (HERV) are associated with many diseases such as autoimmune diseases and cancer. Although the frequent expression of a variety of HERVs in tumor cells has been demonstrated, their functional contributions in cancer are as yet unclear. Intriguingly, HERVs and other retroviruses include an immunosuppressive domain in their transmembrane envelope proteins, but its mechanism of action and cancer relevance are obscure. In this study, we demonstrate that the human endogenous retrovirus HERV-H has a critical role in tumor metastasis and immune escape. We found that expression of herv-h mRNA was elevated in metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and in primary tumor tissues from advanced colon cancer. The immunosuppressive peptide H17 derived from HERV-H was sufficient to induce EMT in tumor cells that expressed low levels of HERV-H, and it amplified this event within the tumor microenvironment. H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271+ cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271+ cells were increased in HERV-H+CCL19+ tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271+ cells, improved immune responses in vitro and in vivo accompanied by tumor regression. Together, our results argued that HERV-H is a critical determinant of immune escape in cancer, suggesting its candidacy as a promising therapeutic target to treat patients with advanced cancer. Cancer Res; 74(5); 1361–70. ©2014 AACR.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)
Authors: Nick Thatcher, Alex Chang, Purvish Parikh, José Rodrigues Pereira, Tudor Ciuleanu, Joachim von Pawel, Sumitra Thongprasert, Eng Huat Tan, Kristine Pemberton, Venice Archer, Kevin Carroll
Journal: The Lancet (2005)
Head injuries in sport.
Authors: R C Cantu
Journal: British Journal of Sports Medicine (1996)

Injuries to the head and neck are the most frequent catastrophic sports injury, and head injuries are the most common direct athletic cause of death. Although direct compressive forces may injure the brain, neural tissue is particularly susceptible to injury from shearing stresses, which are most likely to occur when rotational forces are applied to the head. The most common athletic head injury is concussion, which may very widely in severity. Intracranial haemorrhage is the leading cause of head injury death in sports, making rapid initial assessment and appropriate follow up mandatory after a head injury. Diffuse cerebral swelling is another serious condition that may be found in the child or adolescent athlete, and the second impact syndrome is a major concern in adult athletes. Many head injuries in athletes are the result of improper playing techniques and can be reduced by teaching proper skills and enforcing safety promoting rules. Improved conditioning (particularly of the neck), protective headgear, and careful medical supervision of athletes will also minimise this type of injury.
Major histocompatibility complex-restricted antibody reactivity mainly, but not exclusively, directed against cells from male donors.
Authors: A van Leeuwen, E Goulmy, J J van Rood
Journal: The Journal of Experimental Medicine (1979)

An IgM antibody, present in the serum of a female patient with aplastic anemia, is described that reacted in a modified complement-dependent cytotoxicity test with a subset of the B cells from HLA-A2-positive, but not HLA-A2-negative males. With the exception of two HLA-A2 positive females, the antibody did not react with other cells from either HLA-A2-positive or HLA-2-negative females. The cells of one of these and from HLA-A2-positive males were able to absorb the antibody from the serum. Cells from other donors were unable to absorb the antibodies. The mononuclear cells of the same patient were cytolytic in cell-mediated lympholysis (CML) for phytohemagglutinin blasts from all HLA-A2-positive males and one of the females reacting with antibody, but not with blasts from HLA-A2-negative males and all other females. Thus, the results obtained with the antibody in the complement-dependent cytotoxicity test showed an almost perfect correlation with cytolysis in CML tests. These results suggest that the IgM antibody may be the first example with major histocompatibility complex restriction. Because the antibody reacted with the cells from two female donors, the restricting determinant is not, in all probability, the H-Y determinant.
Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine
Authors: Cornelia Lindner, Benjamin Wahl, Lisa Föhse, Sebastian Suerbaum, Andrew J. Macpherson, Immo Prinz, Oliver Pabst
Journal: The Journal of Experimental Medicine (2012)

Intestinal immunoglobulin A (IgA) ensures host defense and symbiosis with our commensal microbiota. Yet previous studies hint at a surprisingly low diversity of intestinal IgA, and it is unknown to what extent the diverse Ig arsenal generated by somatic recombination and diversification is actually used. In this study, we analyze more than one million mouse IgA sequences to describe the shaping of the intestinal IgA repertoire, its determinants, and stability over time. We show that expanded and infrequent clones combine to form highly diverse polyclonal IgA repertoires with very little overlap between individual mice. Selective homing allows expanded clones to evenly seed the small but not large intestine. Repertoire diversity increases during aging in a dual process. On the one hand, microbiota-, T cell–, and transcription factor RORγt–dependent but Peyer’s patch–independent somatic mutations drive the diversification of expanded clones, and on the other hand, new clones are introduced into the repertoire of aged mice. An individual’s IgA repertoire is stable and recalled after plasma cell depletion, which is indicative of functional memory. These data provide a conceptual framework to understand the dynamic changes in the IgA repertoires to match environmental and intrinsic stimuli.
Lower respiratory tract infections in the community: towards a more rational approach
Authors: J Dorca, A Torres
Journal: European Respiratory Journal (1996)

Lower respiratory tract infections (LRTI), such as acute bronchitis, infectious exacerbation of chronic bronchitis and pneumonia, are frequent community-acquired infections affecting both the paediatric and adult population, and are one of the commonest respiratory illnesses observed in daily medical practice [1]. In most cases, LRTI cause a mild clinical picture, usually managed by general practitioners. Only a minority of episodes with a more severe presentation, or affecting patients with chronic diseases, are attended by hospital specialists. Because bacterial organisms are often involved or could potentially complicate the course of LRTI, antibiotic prescription on an empirical basis is the commonest approach, in spite of the benign and self-limited nature of the majority of episodes. Although there is a general acceptance that LRTI is the most frequent cause for antibiotic prescription in general medical practice, precise data about antibiotic regimens are scarce [2]. In addition, the number of drugs potentially active against respiratory pathogens has increased considerably and, consequently, the prescribed regimens may differ widely. In this issue of the Journal, two excellent original studies coming from the same group provide fresh data about the current patterns of diagnostic management and antibiotic prescription in LRTI among general practitioners (GPs) of five European countries: France, Germany, Italy, Spain and the United Kingdom. In one of these studies, HUCHON et al. [3] have concluded that antibiotics are excessively prescribed by European GPs; more than 80% of all LRTI, globally considered, are treated with antibiotics. This figure showed little variation as regards the different types of LRTI: community-acquired pneumonia, acute bronchitis, exacerbated chronic bronchitis, and viral respiratory tract infection. Even in this last group, 70% of cases were initially managed with antibiotics. In contrast to the relative homogeneity in antibiotic prescription rates, the authors found substantial differences in the characteristics (nature) of antibiotic treatments. According to this, oral penicillins were first choice antibiotics in the UK and France, tetracyclines were preferred in Germany, macrolides were given in Spain, and parenteral third-generation cephalosporins were commonly prescribed in Italy. The pattern of prescription was relatively independent of the characteristics of LRTI. However, the authors could find no convincing reasons for these striking differences. In an accompanying paper, also published in this issue of the Journal, WOODHEAD et al. [4] assessed the diagnostic management of LRTI by European GPs. These
Heparan Sulfate Proteoglycan Is a Mechanosensor on Endothelial Cells
Authors: Jeffry A. Florian, Jason R. Kosky, Kristy Ainslie, Zhengyu Pang, Randal O. Dull, John M. Tarbell
Journal: Circulation Research (2003)

The objective of this study was to test whether a glycosaminoglycan component of the surface glycocalyx layer is a fluid shear stress sensor on endothelial cells (ECs). Because enhanced nitric oxide (NO) production in response to fluid shear stress is a characteristic and physiologically important response of ECs, we evaluated NOx (NO2- and NO3-) production in response to fluid shear stress after enzymatic removal of heparan sulfate, the dominant glycosaminoglycan of the EC glycocalyx, from cultured ECs. The significant NOx production induced by steady shear stress (20 dyne/cm2) was inhibited completely by pretreatment with 15 mU/mL heparinase III (E.C.4.2.2.8) for 2 hours. Oscillatory shear stress (10+/-15 dyne/cm2) induced an even greater NOx production than steady shear stress that was completely inhibited by pretreatment with heparinase III. Addition of bradykinin (BK) induced significant NOx production that was not inhibited by heparinase pretreatment, demonstrating that the cells were still able to produce abundant NO after heparinase treatment. Fluorescent imaging with a heparan sulfate antibody revealed that heparinase III treatments removed a substantial fraction of the heparan sulfate bound to the surfaces of ECs. In summary, these experiments demonstrate that a heparan sulfate component of the EC glycocalyx participates in mechanosensing that mediates NO production in response to shear stress. The full text of this article is available online at http://www.circresaha.org.