tbuckley/cabot-search huggingface dataset:
STUDIES ON ANTIBODY-PRODUCING CELLS
Authors: Fred G. Gudat, T. N. Harris, Susanna Harris, Klaus Hummeler
Journal: The Journal of Experimental Medicine (1971)

A study of the kinetics of antibody-producing cells has been carried out by the use of rosette formation for detection of individual antibody-producing cells, and labeling with tritiated thymidine, in cells obtained from mouse spleens at intervals after injection of SRBC. Following a primary injection of the antigen, the number of RFC per million cells was found to increase to a peak at 5 days, then, after a decrease, to a second peak at about the 10th day. The curve of tritium labeling of RFC was also biphasic, with peaks on the 3rd and 7th day. The second increase in rosette-forming cells could be shown to involve, especially between the 7th and 9th day, a second increase in lymphoid cell RFC and, among these, 7S antibody-producing cells. When the population examined was restricted to large lymphocytes, two peaks of RFC per million cells and two peaks of labeling were again found. In this case, however, the peaks of RFC and of labeling were reached on the same day in each instance, rather than with the 2 day difference found in the entire spleen cell suspension or the entire lymphoid cell population. Electron microscopic examination of labeled rosette-forming cells showed these to be largely lymphocytes, but to include rather well differentiated plasmablasts as well. No macrophages were found among labeled RFC in the primary response. A substantial number of labeled lymphocytes were found in close contiguity with rosette-forming macrophages. The percentage of labeling in such lymphocytes was as high, on the respective days, as the percentage of labeled cells among the RFC of the entire suspension.
What is the role of genetics in occupational asthma?
Authors: C. E. Mapp
Journal: European Respiratory Journal (2009)

Occupational asthma (OA) is a disease characterised by variable airflow limitation and/or airway hyperresponsiveness, due to causes and conditions attributable to a particular occupational environment, and not to stimuli encountered outside the workplace 1. There are two types of OA, which are caused by two distinct mechanisms: immunological and nonimmunological. The former appears after a latency period and is induced by an immunoglobulin (Ig)E-dependent mechanism (triggered by most high- and some low-molecular-weight agents) or an IgE-independent mechanism (triggered by most low-molecular-weight agents). The latter type of OA is characterised by the absence of a latency period and occurs after accidental exposure to high levels of a respiratory irritant at work or outside the workplace 2.

Although the exact cause of OA is not yet known, in general OA, similarly to nonoccupational asthma, may be caused by complex interactions between genes and the environment, including gene–environment, gene–gene, gene–gene–environment, and gene–environment–environment interactions 3.

What, then, is the role of genetics in subjects with OA? And where should research focus attention?

Addressing the second of these questions, asthma genetics has received much attention and has made much progress in recent decades. Importantly, the multifactorial pathogenesis of asthma has been recognised. That is, genetic research has shown that asthma behaves as a complex disease, and that it is not caused by single gene mutations 4. These findings have opened important challenges …
Band 3 and glycophorin are progressively aggregated in density-fractionated sickle and normal red blood cells. Evidence from rotational and lateral mobility studies.
Authors: J D Corbett, D E Golan
Journal: Journal of Clinical Investigation (1993)

Band 3 aggregation in the plane of the red blood cell (RBC) membrane is postulated to be important in the pathophysiology of hemolysis of dense sickle and normal RBCs. We used the fluorescence photobleaching recovery and polarized fluorescence depletion techniques to measure the lateral and rotational mobility of band 3, glycophorins, and phospholipid analogues in membranes of density-separated intact RBCs from seven patients with sickle cell disease and eight normal controls. The fractions of laterally mobile band 3 and glycophorin decreased progressively as sickle RBC density increased. Normal RBCs also showed a progressive decrease in band 3 fractional mobility with increasing buoyant density. Rapidly rotating, slowly rotating, and rotationally immobile forms of band 3 were observed in both sickle and normal RBC membranes. The fraction of rapidly rotating band 3 progressively decreased and the fraction of rotationally immobile band 3 progressively increased with increasing sickle RBC density. Changes in the fraction of rotationally immobile band 3 were not reversible upon hypotonic swelling of dense sickle RBCs, and normal RBCs osmotically shrunken in sucrose buffers failed to manifest band 3 immobilization at median cell hemoglobin concentration values characteristic of dense sickle RBCs. We conclude that dense sickle and normal RBCs acquire irreversible membrane abnormalities that cause transmembrane protein immobilization and band 3 aggregation. Band 3 aggregates could serve as cell surface sites of autologous antibody binding and thereby lead to removal of dense sickle and normal (senescent) RBCs from the circulation.
Regulation of Cellular and Humoral Immune Responses by the SLAM and SAP Families of Molecules
Authors: Cindy S. Ma, Kim E. Nichols, Stuart G. Tangye
Journal: Annual Review of Immunology (2007)

SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell-dependent humoral immune responses, NK cell-mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.
Antibiotic Concentrations in Ascitic Fluid of Patients with Ascites and Bacterial Peritonitis
Authors: DALE N. GERDING
Journal: Annals of Internal Medicine (1977)

Thirty-six paired specimens of serum and ascitic fluid from 21 patients with peritonitis and ascites, most with sponetaneous bacterial peritonitis and alcoholic cirrhosis, were assayed for antibiotic content. Antibiotics assayed and number of determinations were gentamicin, 14; tobramycin, 7; ampicillin, 5; clindamycin, 3; penicillin G, 2; cephalothin, 2; chloramphenico, 2; and cefazolin, 1. In 31 pared specimens the ascitic fluid antibiotic concentration was about one half or more of the simultaneous serum level and in 17 assays exceeded 90% of the serum level. All antibiotics studied penetrated ascitic fluid equally well. Clinical response to antibiotic therapy was good in 12 of 16 patients with culture-proven bacterial peritonitis. Antibiotic levels in ascitic fluid exceeded the minimal inhibitory concentration of the infecting organisms in all but one patient who responded. Direct intraperitoneal instillation of antibiotics does not appear to be necessary routinely; however, there may be an initial lag of several hours before antibiotic concentrations is ascites achieve therapeutic levels.
A Simple Prognostic Score to Predict Short and Long-Term Survival Following ICU Admission in Critically Ill Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: Improved Survival Following Reduced Intensity Conditioning
Authors: William Townsend, Ailsa Holroyd, Rachel M Pearce, Stephen Mackinnon, Anthony H. Goldstone, David C Linch, Karl S Peggs, Kirsty Thomson, Mervyn Singer, Prakesh Naik, David Howell, Emma Morris
Journal: Blood (2011)
P216 Recruiting COPD inpatients to clinical research: recent experience from interventional and observational studies
Authors: A. W. Hitchings, J. W. Dodd, P. W. Jones, E. H. Baker
Journal: Thorax (2011)

<h3>Background</h3> Despite currently available treatment, 13.9% of patients admitted to hospital for exacerbations of chronic obstructive pulmonary disease (COPD) die within 3 months, and fewer than half survive 5 years. Most of the cost of COPD to the UK health service, which approaches £1bn/year, is associated with the treatment of exacerbations. There is clearly a need to improve outcomes of patients admitted to hospital for exacerbations, and yet relatively few research studies attempt to recruit patients specifically during this phase of their illness. <h3>Methods</h3> During 2010–2011, two studies were conducted within our institution recruiting patients hospitalised for COPD exacerbations. One was an observational study with relatively broad entry criteria; the other was a randomised, controlled, interventional trial with more stringent entry criteria (ISRCTN66148745). We analysed the screening logs to identify eligibility rates and potential barriers to recruitment, and to provide a guide for researchers on the feasibility of proposed studies in similar populations elsewhere. <h3>Results</h3> In the 12-month period commencing March 2010, 172 patients were screened for entry to the observational study. In the period January to June 2011, a further 72 patients, not included in the first study, were screened for entry into the clinical trial. Significant exclusion criteria for each study protocol for were identified; for comparison, these are represented across organ systems (Abstract P216 table 1). 29% of those screened for the observational study were eligible for inclusion and 11% for the clinical trial. The clinical trial identified more renal and metabolic conditions, reflecting their particular relevance to experimental drug administration. The observational study identified more physical factors, such as frailty, which may limit patients9 ability to engage with observational research tasks. <h3>Conclusion</h3> Patients hospitalised for COPD exacerbations are heterogeneous and have significant and diverse co-morbidities which may limit their eligibility for research studies. In view of this, broad entry criteria are necessary to ensure that studies in this population are feasible. With careful design, such studies will be pivotal in driving improved treatment and outcomes among these patients who, despite their poor prognosis, presently receive disproportionately little research attention.
Breathlessness, physical activity and sustainability of healthcare
Authors: Amina Aitsi-Selmi, Nicholas S. Hopkinson
Journal: European Respiratory Journal (2014)

We welcome the important paper by Grønseth et al. [1], which used data from the Burden of Obstructive Lung Disease (BOLD) project to highlight the prevalence of breathlessness across the world. As well as being significant because it is a source of suffering that should be ameliorated, we believe that attention to breathlessness, particularly in midlife, has important implications for sustainable healthcare because it allows timely diagnosis, would drive the promotion of physical activity, forms part of a strategy to reduce the burden of comorbidities and would have beneficial environmental effects. Targeting breathlessness is important for delivering sustainable future healthcare <http://ow.ly/AgKoA>
Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort
Authors: Dominick E. Shaw, Ana R. Sousa, Stephen J. Fowler, Louise J. Fleming, Graham Roberts, Julie Corfield, Ioannis Pandis, Aruna T. Bansal, Elisabeth H. Bel, Charles Auffray, Chris H. Compton, Hans Bisgaard, Enrica Bucchioni, Massimo Caruso, Pascal Chanez, Barbro Dahlén, Sven-Erik Dahlen, Kerry Dyson, Urs Frey, Thomas Geiser, Maria Gerhardsson de Verdier, David Gibeon, Yi-ke Guo, Simone Hashimoto, Gunilla Hedlin, Elizabeth Jeyasingham, Pieter-Paul W. Hekking, Tim Higenbottam, Ildikó Horváth, Alan J. Knox, Norbert Krug, Veit J. Erpenbeck, Lars X. Larsson, Nikos Lazarinis, John G. Matthews, Roelinde Middelveld, Paolo Montuschi, Jacek Musial, David Myles, Laurie Pahus, Thomas Sandström, Wolfgang Seibold, Florian Singer, Karin Strandberg, Jorgen Vestbo, Nadja Vissing, Christophe von Garnier, Ian M. Adcock, Scott Wagers, Anthony Rowe, Peter Howarth, Ariane H. Wagener, Ratko Djukanovic, Peter J. Sterk, Kian Fan Chung
Journal: European Respiratory Journal (2015)

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach. This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements. Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p&lt;0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids. Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach.
Myosin Heavy Chain Isoform Expression in the Failing and Nonfailing Human Heart
Authors: Setsuya Miyata, Wayne Minobe, Michael R. Bristow, Leslie A. Leinwand
Journal: Circulation Research (2000)

Abstract —In the heart, the relative proportions of the 2 forms of the motor protein myosin heavy chain (MyHC) have been shown to be affected by a wide variety of pathological and physiological stimuli. Hearts that express the faster MyHC motor protein, α, produce more power than those expressing the slower MyHC motor protein, β, leading to the hypothesis that MyHC isoforms play a major role in the determination of cardiac contractility. We showed previously that a significant amount of αMyHC mRNA is expressed in nonfailing human ventricular myocardium and that αMyHC mRNA expression is decreased 15-fold in end-stage failing left ventricles. In the present study, we determined the MyHC protein isoform content of human heart samples of known MyHC mRNA composition. We demonstrate that αMyHC protein was easily detectable in 12 nonfailing hearts. αMyHC protein represented 7.2±3.2% of total MyHC protein (compared with ≈35% of the MyHC mRNA), suggesting that translational regulation may be operative; in contrast, there was effectively no detectable αMyHC protein in the left ventricles of 10 end-stage failing human hearts.
Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels
Authors: Wei-Min Chen, Michael R. Erdos, Anne U. Jackson, Richa Saxena, Serena Sanna, Kristi D. Silver, Nicholas J. Timpson, Torben Hansen, Marco Orrù, Maria Grazia Piras, Lori L. Bonnycastle, Cristen J. Willer, Valeriya Lyssenko, Haiqing Shen, Johanna Kuusisto, Shah Ebrahim, Natascia Sestu, William L. Duren, Maria Cristina Spada, Heather M. Stringham, Laura J. Scott, Nazario Olla, Amy J. Swift, Samer Najjar, Braxton D. Mitchell, Debbie A. Lawlor, George Davey Smith, Yoav Ben-Shlomo, Gitte Andersen, Knut Borch-Johnsen, Torben Jørgensen, Jouko Saramies, Timo T. Valle, Thomas A. Buchanan, Alan R. Shuldiner, Edward Lakatta, Richard N. Bergman, Manuela Uda, Jaakko Tuomilehto, Oluf Pedersen, Antonio Cao, Leif Groop, Karen L. Mohlke, Markku Laakso, David Schlessinger, Francis S. Collins, David Altshuler, Gonçalo R. Abecasis, Michael Boehnke, Angelo Scuteri, Richard M. Watanabe
Journal: Journal of Clinical Investigation (2008)

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 × 10–7). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 × 10–26, and combining results from all studies resulted in an overall P value for association of 6.4 × 10–33. Across these studies, fasting glucose concentrations increased 0.01–0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
Absence of angiotensin II type 1 receptor in bone marrow–derived cells is detrimental in the evolution of renal fibrosis
Authors: Masashi Nishida, Hidehiko Fujinaka, Taiji Matsusaka, James Price, Valentina Kon, Agnes B. Fogo, Jeffrey M. Davidson, MacRae F. Linton, Sergio Fazio, Toshio Homma, Hiroaki Yoshida, Iekuni Ichikawa
Journal: Journal of Clinical Investigation (2002)

We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on macrophages in renal fibrosis. Fourteen days after the induction of unilateral ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the Agtr1 gene (Agtr1(-/-)) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtr1(+/+) marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes - including TGF-beta1, alpha1(I) collagen, and alpha1(III) collagen - was substantially higher in the obstructed kidneys of mice with Agtr1(-/-) marrow than in those with Agtr1(+/+) marrow at day 14 but not at day 5 of UUO. Mice with Agtr1(-/-) marrow were characterized by reduced numbers of peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo assays revealed a significantly impaired phagocytic capability in Agtr1(-/-) macrophages. In vivo treatment of Agtr1(+/+) mice with losartan reduced phagocytic capability of Agtr1(+/+) macrophages to a level comparable to that of Agtr1(-/-) macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone marrow-derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.
Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance
Authors: S. Vincent Rajkumar, Robert A. Kyle, Terry M. Therneau, L. Joseph Melton, Arthur R. Bradwell, Raynell J. Clark, Dirk R. Larson, Matthew F. Plevak, Angela Dispenzieri, Jerry A. Katzmann
Journal: Blood (2005)
Positive and Negative Selection on Noncoding DNA in Drosophila simulans
Authors: P. R. Haddrill, D. Bachtrog, P. Andolfatto
Journal: Molecular Biology and Evolution (2008)

There is now a wealth of evidence that some of the most important regions of the genome are found outside those that encode proteins, and noncoding regions of the genome have been shown to be subject to substantial levels of selective constraint, particularly in Drosophila. Recent work has suggested that these regions may also have been subject to the action of positive selection, with large fractions of noncoding divergence having been driven to fixation by adaptive evolution. However, this work has focused on Drosophila melanogaster, which is thought to have experienced a reduction in effective population size (Ne), and thus a reduction in the efficacy of selection, compared with its closest relative Drosophila simulans. Here, we examine patterns of evolution at several classes of noncoding DNA in D. simulans and find that all noncoding DNA is subject to the action of negative selection, indicated by reduced levels of polymorphism and divergence and a skew in the frequency spectrum toward rare variants. We find that the signature of negative selection on noncoding DNA and nonsynonymous sites is obscured to some extent by purifying selection acting on preferred to unpreferred synonymous codon mutations. We investigate the extent to which divergence in noncoding DNA is inferred to be the product of positive selection and to what extent these inferences depend on selection on synonymous sites and demography. Based on patterns of polymorphism and divergence for different classes of synonymous substitution, we find the divergence excess inferred in noncoding DNA and nonsynonymous sites in the D. simulans lineage difficult to reconcile with demographic explanations.
Significance of HER2 Low-Level Copy Gain in Barrett's Cancer: Implications for Fluorescence <i>In situ</i> Hybridization Testing in Tissues
Authors: Sandra Rauser, Roland Weis, Herbert Braselmann, Marcus Feith, Hubert J. Stein, Rupert Langer, Peter Hutzler, Michael Hausmann, Silke Lassmann, Jörg Rüdiger Siewert, Heinz Höfler, Martin Werner, Axel Walch
Journal: Clinical Cancer Research (2007)

Abstract Purpose: HER2 may be a relevant biomarker in Barrett's cancer. We compared three HER2 laboratory methods, standard fluorescence in situ hybridization (FISH), image-based three-dimensional FISH in thick (16 μm) sections, and immunohistochemistry, to predict patient outcome. Experimental Design: Tissue microarray sections from 124 Barrett's cancer patients were analyzed by standard FISH on thin (4 μm) sections and by image-based three-dimensional FISH on thick (16 μm) sections for HER2 and chromosome-17, as well for p185HER2 by immunohistochemistry. Correlations with clinical and follow-up data were examined. Results: Only three-dimensional FISH on thick (16 μm) sections revealed HER2 gene copy gain to be associated with increased disease-specific mortality (relative risk, 2.1; 95% confidence interval, 1.06-4.26; P = 0.033). In contrast, standard FISH on thin (4 μm) sections and immunohistochemistry failed to predict clinical outcome. Low-level gain of HER2 occurred frequently in Barrett's cancer (≥2.5-4.0 HER2 copies, 59.7%; HER2-to-chromosome-17 ratio, ≥1.1-2.0; 61.2%) and defined a subpopulation for patient outcome as unfavorable as HER2 gene amplification [disease-free survival, P = 0.017 (HER2 copies)]. This low-level group was neither definable by standard FISH nor immunohistochemistry. No prognostic significance was found for chromosome-17 aneusomy. Conclusions: Low-level copy gains of HER2 define a biologically distinct subpopulation of Barrett's cancer patients. Importantly, these subtle copy number changes are not reliably detected by standard FISH in thin (4 μm) tissue sections, highlighting a thus far unrecognized weakness in HER2 FISH testing. These results should be taken into account for accurate evaluation of biomarkers by FISH and for HER2 FISH testing in tissue sections.