tbuckley/cabot-search huggingface dataset:
PHYLOGENY OF IMMUNOGLOBULIN STRUCTURE AND FUNCTION
Authors: L. W. Clem, P. A. Small
Journal: The Journal of Experimental Medicine (1970)

The giant grouper, Epinephelus itaira, was shown to synthesize 16 and 6.4S antibodies specific for the dinitrophenyl determinant (DNP). Sera obtained at various intervals between 1 month and 2 yr after initial immunization contained both species of antibody; no temporal synthesis was evident. Equilibrium dialysis studies employing epsilon-dinitrophenyl-amino caproic acid were conducted with purified grouper antibodies specific for DNP. The 16S antibody preparations obtained at 1 and 2 months of immunization showed heterogeneity of hapten binding indicative of two populations of combining sites. One-half of these sites (an average of four sites per 16S molecule) exhibited an average intrinsic association constant (K(o)) of approximately 10(6)M(-1); the K(o) of the remaining four-sites was approximately 10(4)M(-1). Thus, the valence of the grouper 16S antibody molecule appears to be eight although the distribution of the high and low K(o) sites is unknown, i.e., are they each on the same or on different molecules? The 16S antibody preparations obtained after more prolonged immunization exhibited increasingly lower K(o) values; the so-called low K(o) sites were no longer detectable. These findings are in contrast to reports of rabbit IgG antibodies showing an increase in K(o) with increased time. The 6.4S antibody preparations obtained from the 1 and 2 month antisera had K(o) values of approximately 10(6)M(-1) and a valence of one. These antibodies would not precipitate with antigen. The 6.4S antibody preparations obtained at later times showed decreasing K(o) values comparable to those of the 16S antibodies from the same bleedings. Studies on the thermodynamic parameters of the hapten-antibody interaction showed the grouper 16 and 6.4S antibodies to be similar to each other. These data also showed that the enthalpy and entropy changes of grouper antibody-hapten reactions resemble those reported for rabbit IgG antibodies to this hapten. It is thus suggested that, although considerable evolution of immunoglobulin classes has occurred between fish and rabbits, the antibody combining site may have remained relatively unchanged during a large part of evolutionary time.
Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib
Authors: Tona M. Gilmer, Louann Cable, Krystal Alligood, David Rusnak, Glenn Spehar, Kathleen T. Gallagher, Ermias Woldu, H. Luke Carter, Anne T. Truesdale, Lisa Shewchuk, Edgar R. Wood
Journal: Cancer Research (2008)

Abstract The goal of this study was to characterize the effects of non–small cell lung carcinoma (NSCLC)-associated mutations in epidermal growth factor receptor (EGFR/ErbB1) and HER2 (ErbB2) on interactions with the dual tyrosine kinase inhibitor lapatinib. Biochemical studies show that commonly observed variants of EGFR [G719C, G719S, L858R, L861Q, and Δ746–750 (del15)] are enzyme activating, increasing the tyrosine kinase Vmax and increasing the Km(app) for ATP. The point mutations G719C and L861Q had minor effects on lapatinib Kis, whereas EGFR mutations L858R and del15 had a higher Ki for lapatinib than wild-type EGFR. Structural analysis of wild-type EGFR-lapatinib complexes and modeling of the EGFR mutants were consistent with these data, suggesting that loss of structural flexibility and possible stabilization of the active-like conformation could interfere with lapatinib binding, particularly to the EGFR deletion mutants. Furthermore, EGFR deletion mutants were relatively resistant to lapatinib-mediated inhibition of receptor autophosphorylation in recombinant cells expressing the variants, whereas EGFR point mutations had a modest or no effect. Of note, EGFR T790M, a receptor variant found in patients with gefitinib-resistant NSCLC, was also resistant to lapatinib-mediated inhibition of receptor autophosphorylation. Two HER2 insertional variants found in NSCLC were less sensitive to lapatinib inhibition than two HER2 point mutants. The effects of lapatinib on the proliferation of human NSCLC tumor cell lines expressing wild-type or variant EGFR and HER2 cannot be explained solely on the basis of the biochemical activity or receptor autophosphorylation in recombinant cells. These data suggest that cell line genetic heterogeneity and/or multiple determinants modulate the role played by EGFR/HER2 in regulating cell proliferation. [Cancer Res 2008;68(2):571–9]
Bronchopleural fistula complicating massive pulmonary infarction
Authors: E. R. McFadden, F. Luparello
Journal: Thorax (1969)

The clinical course of a patient who developed a lung abscess with a bronchopleural fistula following a massive infarction is described. Comparison of the events in this patient9s illness with others reported in the literature reveals a recognizable syndrome which is characterized by three phases. The initial illness consists of massive infarction with its well-recognized sequelae. Following a short period of improvement, the second phase begins with the production of copious amounts of blood-tinged or purulent sputum, accompanied by fever, leucocytosis, and cardiac decompensation. This phase lasts several days to weeks and signifies excavation of the infarcted area. After another period of relative quiescence, the third phase, characterized by the abrupt onset of fever, pleuritic pain, cough, and acute dyspnoea, begins. These symptoms herald bronchopleural fistula. In view of the high mortality, prompt recognition of this syndrome and vigorous treatment appear to be mandatory.
High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma
Authors: Ajay K. Gopal, Joseph G. Rajendran, Stephen H. Petersdorf, David G. Maloney, Janet F. Eary, Brent L. Wood, Theodore A. Gooley, Sharon A. Bush, Lawrence D. Durack, Paul J. Martin, Dana C. Matthews, Frederick R. Appelbaum, Irwin D. Bernstein, Oliver W. Press
Journal: Blood (2002)
Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans
Authors: Erik Schoenmakers, Maura Agostini, Catherine Mitchell, Nadia Schoenmakers, Laura Papp, Odelia Rajanayagam, Raja Padidela, Lourdes Ceron-Gutierrez, Rainer Doffinger, Claudia Prevosto, Jian’an Luan, Sergio Montano, Jun Lu, Mireille Castanet, Nick Clemons, Matthijs Groeneveld, Perrine Castets, Mahsa Karbaschi, Sri Aitken, Adrian Dixon, Jane Williams, Irene Campi, Margaret Blount, Hannah Burton, Francesco Muntoni, Dominic O’Donovan, Andrew Dean, Anne Warren, Charlotte Brierley, David Baguley, Pascale Guicheney, Rebecca Fitzgerald, Alasdair Coles, Hill Gaston, Pamela Todd, Arne Holmgren, Kum Kum Khanna, Marcus Cooke, Robert Semple, David Halsall, Nicholas Wareham, John Schwabe, Lucia Grasso, Paolo Beck-Peccoz, Arthur Ogunko, Mehul Dattani, Mark Gurnell, Krishna Chatterjee
Journal: Journal of Clinical Investigation (2010)

Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.
The Left Ventricular Ejection Time in Elderly Subjects
Authors: JOS L. WILLEMS, JOS ROELANDT, HILAIRE DE GEEST, HUGO KESTELOOT, JOZEF V. JOOSSENS
Journal: Circulation (1970)

The left ventricular ejection time (LVET) was studied by means of the carotid artery tracing in 512 elderly subjects (205 male and 307 female) who were between 60 and 90 years old (mean age, 70.5 years). A highly significant correlation was found between heart rate (HR) and LVET. The data on these aged subjects were compared and analyzed with the results previously reported concerning young and middle-aged adults. A small but significant increase of LVET with aging, independent of changes in HR and blood pressure, could be demonstrated by multiple regression analysis. A statistically significant difference existed between the sexes. The influence on LVET of parameters other than HR was small.
Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma.
Authors: D. J. Evans, P. J. Barnes, S. M. Spaethe, E. L. van Alstyne, M. I. Mitchell, B. J. O'Connor
Journal: Thorax (1996)

BACKGROUND: Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown. METHODS: The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge. RESULTS: There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between placebo and LY293111. By contrast, treatment with LY293111 significantly reduced the number of neutrophils in BAL fluid expressed as both absolute cell numbers and percentage cell differential counts: absolute cell counts, median (range) 0.04 (0.02-0.15) x 10(6) after LY293111, 0.09 (0.02-0.43) x 10(6) after placebo; percentage differential cell counts 0.35 (0.1-2.0) after LY293111, 0.80 (0.1-3.6) after placebo (p &lt; 0.05). Eosinophils, macrophages, and lymphocytes in BAL fluid did not differ between treatments. There was a significant reduction in the concentration of myeloperoxidase (MPO) with both placebo (16 (6.6) ng/ml) and LY293111 (3.5 (1.8) ng/ml) and of LTB4 (placebo 4.6 (1.2) pg/ml, LY293111 2.2 (0.2) pg/ml). Concentrations of LTC4 and interleukin 8 were reduced, although not significantly, whereas concentrations of interleukin 6, GM-CSF, and TNF-alpha were unchanged by LY293111. CONCLUSIONS: These results demonstrate an influence of LTB4 on neutrophil influx and activation in the airway following allergen challenge. Despite this anti-inflammatory effect, there was no measured physiological benefit and this questions the functional role of the neutrophil in the pathophysiology of allergen induced asthma.
ALCOHOL, CORONARY DISEASE, AND HYPERTENSION
Authors: A. L. Klatsky, M.D
Journal: Annual Review of Medicine (1996)

▪ Abstract Disparities in the relationships between alcohol consumption and various cardiovascular conditions are now evident, with complex interrelationships between conditions. An inverse relationship of alcohol use to coronary heart disease is supported by many population studies. Interpretation of these data as a protective effect of alcohol against coronary disease is strengthened by plausible mechanisms. Although some experimental data suggest the hypothesis that wine, in particular, has additional protective benefit, prospective studies show no consensus on this point. Strong, consistent epidemiologic data support a relationship of heavier drinking to hypertension. Intervention studies show a pressor effect of alcohol, which appears and regresses within several days, but a mechanism has not yet been established. As with most aspects of alcohol and health effects, the data do not suggest monotonic relationships of alcohol with these conditions. Thus, amount of alcohol taken is a crucial consideration. Advice to concerned persons needs to take into account individual factors in drinkers or potential drinkers.
Comparison of serial changes in coronary arteries after Palmaz-Schatz stent implantation and balloon angioplasty: a histopathological and immunohistochemical study
Authors: K. Inouo, N. Nakamura, T. Nagamatsu, K. Imanaka-Yoshida, R. Matsuura
Journal: Journal of the American College of Cardiology (1998)
CD137-mediated immunotherapy for allergic asthma
Authors: Tobias Polte, Juergen Foell, Christoph Werner, Heinz-Gerd Hoymann, Armin Braun, Stefan Burdach, obert S. Mittler,, Gesine Hansen
Journal: Journal of Clinical Investigation (2006)

The prevalence of asthma continues to increase. Asthma is caused by a Th2 cell-driven immune response. Its optimal treatment remains a challenge, and a sufficient immunotherapeutic approach to treating asthma has yet to be found. Using a murine asthma model, we show that a single injection of an anti-CD137 (4-1BB) mAb prevents the development of airway hyperreactivity, eosinophilic airway inflammation, excessive mucus production, and elevated IgE during the observation period of 7 weeks. Most importantly, even established disease is completely reversed by anti-CD137 mAb administration. The protection is associated with markedly reduced Th2 cytokine production and increased secretion of the Th1 cytokine IFN-gamma. While B lymphocytes are partly depleted, the number of CD8+ T cells is increased. Blockade of IFN-gamma and depletion of CD8+ T cells during treatment with anti-CD137 mAb reduces in part but does not abrogate the protective effect of CD137 mAb. In contrast, CD137 mAb-mediated CD4+ T cell anergy is critical for the observed effects, since transfer of CD4+ T cells from CD137 mAb-treated mice conveyed protection. These data demonstrate, for the first time to our knowledge, the capacity of anti-CD137 mAb to ameliorate allergic asthma, and they indicate CD137 as a possible target for therapeutic intervention in this disease.
Phenotype of recovering lymphoid cell populations after marrow transplantation.
Authors: K A Ault, J H Antin, D Ginsburg, S H Orkin, J M Rappeport, M L Keohan, P Martin, B R Smith
Journal: The Journal of Experimental Medicine (1985)

Four patients who received bone marrow transplants were studied sequentially during the posttransplant period to define the pattern of recovering lymphoid cell types. Three patients received T cell-depleted, HLA-matched marrow, and one received untreated marrow from an identical twin. Blood lymphoid cells were labeled with 25 different pairs of monoclonal antibodies. In each sample, one antibody was conjugated to fluorescein and one to phycoerythrin, thus allowing simultaneous assessment of the expression of the two markers using the fluorescence activated cell sorter. A total of 14 antibodies were used, routinely including HLE, Leu-M3, Leu-4, Leu-1, Leu-5, Leu-9, Leu-6, Leu-2, Leu-3, HLA-DR, Leu-7, Leu-11, Leu-15, and Leu-12. Other antibodies were used to further define some populations. This study has allowed us to define six distinct cell types that have appeared in all four patients by day 90 posttransplantation, and which account for 90-100% of all circulating lymphoid cells. These cell types are (a) T helper cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-3, and variable amounts of HLA-DR; (b) T suppressor cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-2, and variable amounts of HLA-DR; (c) B cells expressing Leu-12, B1, HLA-DR, IgD, and IgM, but none of the T cell antigens; (d) an unusual B cell phenotype (Leu-1 B) expressing all of the B cell markers, and also having low amounts of Leu-1, but none of the other T cell antigens; (e) natural killer (NK) cells expressing Leu-11, Leu-15, Leu-5 but none of the other T cell or B cell markers; (f) NK cells expressing Leu-11, Leu-15, Leu-5, and low levels of Leu-2. Both NK types also express Leu-7 on some, but not all cells. The relative frequencies of these cell types varied among the patients and with time, but the striking findings were the presence of relatively few mature T cells, large numbers of NK cells, and the preponderance of the unusual Leu-1 B cell over conventional B cells in all three patients who developed B cells. Sorting experiments confirmed the NK activity of the major NK cell phenotypes, and DNA analysis confirmed that all of the cells studied were of donor origin. In addition, analysis of Ig genes in one patient showed that the Leu-1 B cells were not clonally rearranged.(ABSTRACT TRUNCATED AT 400 WORDS)
Size and strength of the respiratory and quadriceps muscles in patients with chronic asthma
Authors: PF de Bruin, J Ueki, A Watson, NB Pride
Journal: European Respiratory Journal (1997)

There have been few studies of respiratory and limb muscle size and function in middle-aged patients with asthma and persistent airways obstruction. We have compared the forces generated by the respiratory and thigh muscles with their dimensions assessed by ultrasound in nine middle-aged patients with chronic asthma (mean age 56 (SD 8) yrs; functional residual capacity/total lung capacity ratio (FRC/TLC) 60 (10)%), and in nine normal subjects (aged 53 (7) yrs; FRC/TLC 55 (5)%). Diaphragm thickness was measured at the zone of apposition by B-mode ultrasound during relaxation (DiTrelax) and during a maximum-effort inspiratory manoeuvre (DiTpI,max) at FRC. Cross-sectional area of the relaxed rectus femoris muscle (ARF) was determined by ultrasound at mid-thigh level. Isometric strength of the right quadriceps muscle group was measured during maximum voluntary contraction. Asthmatic patients had preserved quadriceps strength and ARF but moderately impaired maximum inspiratory pressure (PI,max) (-52 (18) cmH2O) and thicker DiTrelax (2.2 (0.4) mm), compared to normal subjects (-73 (21) cmH2O and 1.7 (0.3) mm, respectively). Middle-aged patients with chronic asthma and a small increase in functional residual capacity/total lung capacity ratio have preserved limb muscle force and dimensions, modestly impaired inspiratory muscle strength, and slightly increased thickness of the costal diaphragm. Future studies of respiratory muscle function in asthma should be aided by measurement of diaphragm thickness and of limb muscle strength and size. Such studies are required particularly in older patients with severe hyperinflation who are most likely to have impairment of muscle function.
Death Rate from Peptic Ulcer in Great Britain, 1912-38
Authors: H. Tidy
Journal: BMJ (1944)

This communication is a study of the trends of the crude death rates during the period 1912-38 for peptic ulcer and for gastric and duodenal ulcer separately, in males and females, for England and Wales, London (Administrative County), Rural Districts of England and Wales, and for Scotland.There are indications that striking changes have taken place during the last 20 years of the period.The data are from the Annual Reviews of the Registrar-Generals for England and Wales and for Scotland and the Annual Reports of the London County Council.With regard to age, the number of deaths has been taken sepa- rately for the age groups 20-39 years and for 40 years and over, and the death rates calculated per million living in the age group and sex group and area concerned in the various years.The death rates have also been calculated for the total of the age groups over 20 years.Deaths from gastric ulcer were first recorded separately for England and Wales in 1901.For duodenal ulcer, deaths were first recorded separately for England and Wales in 1911, and for London, Rural Districts of England, and Scotland in 1921 deaths had previously been included in a mixed group of diseases of the stomach or intestines, but had not been classified with ulcer of the stomach.)The Registrar-General's Return of Deaths for England and Wales also gives statistics for Urban Districts and County Boroughs.Both may be regarded as mixed urban and rural populations scattered over the country.A test of a few death rates indicates that these do not greatly differ from each other or from the rates for England and Wales as a whole, and they will not be further referred to.London's is a purely urban population, and that of Rural Districts of England and Wales is the nearest approach available tO a rural population.The statistics for peptic ulcer for London and for the Rural Districts have been recorded on three different systems between 1912 and 1937.From 1912 to 1920 gastric ulcer alone is
Pulmonary Gas Exchange Response to Oxygen Breathing in Acute Lung Injury
Authors: CRISTINA SANTOS, MIQUEL FERRER, JOSEP ROCA, ANTONI TORRES, CARME HERNÁNDEZ, ROBERT RODRIGUEZ-ROISIN
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The mechanisms and time course of the pulmonary gas exchange response to 100% O2 breathing in acute respiratory failure needing mechanical ventilation were studied in eight patients with acute lung injury (ALI) (48 ± 18 yr [mean ± SD]) and in four patients (66 ± 2 yr) with chronic obstructive pulmonary disease (COPD). We postulated that, in patients with ALI while breathing 100% O2, the primary mechanism of hypoxemia, i.e., increased intrapulmonary shunt, would further worsen (increase) as a result of reabsorption atelectasis. Respiratory and inert gases, and systemic and pulmonary hemodynamics were measured at maintenance fraction of inspired oxygen (Fi O2 -m), at 30 and 60 min while breathing 100% O2, and then at 30 min of resuming Fi O2 -m. During 100% O2 breathing, in patients with ALI, PaO2 (by 207 and 204 mm Hg; p < 0.01 each), PaCO2 (by 4 mm Hg each) (p < 0.05 each), and intrapulmonary shunt (from 16 ± 10% to 22 ± 11% and 23 ± 11%) (p < 0.05 each) increased respectively. By contrast, in patients with COPD, PaO2 (by 387 and 393 mm Hg; p < 0.001 each), PaCO2 (by 4 and 5 mm Hg) and the dispersion of pulmonary blood flow (log SDQ) (from 1.33 ± 0.10 to 1.60 ± 0.20 and 1.80 ± 0.30 [p < 0.05]) increased, respectively. In patients with ALI, the breathing of 100% O2 deteriorates intrapulmonary shunt owing to collapse of unstable alveolar units with very low ventilation–perfusion (V˙ a/Q˙) ratios, as opposed to patients with COPD, in whom only the dispersion of the blood flow distribution is disturbed, suggesting release of hypoxic pulmonary vasoconstriction. Santos C, Ferrer M, Roca J, Torres A, Hernández C, Rodriguez-Roisin R. Pulmonary gas exchange response to oxygen breathing in acute lung injury.