tbuckley/cabot-search huggingface dataset:
Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma
Authors: S.T. Holgate, D. E. Davies, S. Puddicombe, A. Richter, P. Lackie, J. Lordan, P. Howarth
Journal: European Respiratory Journal (2003)

The aims of this article are to understand the shortfalls in thinking of asthma purely as an atopic disorder, to gain insight into the epithelial abnormalities of asthma and how these interface with the environment, and to view asthma as a disease of airway wall restructuring that engages activation of the epithelial mesenchymal trophic unit (EMTU).Furthermore, based on these developments, possible novel therapeutic targets for chronic asthma are identified. Mechanisms of airway epithelial damageIt has long been recognised that T-helper cell (Th) type-2 airway inflammation underpins airway dysfunction in asthma.Atopy is also a key feature of this disease but accounts for v40% of the population attributable risk.Based on a careful pathological and functional assessment of chronic asthma, the authors propose that altered epithelialmesenchymal communication is also fundamental to disease pathogenesis.A number of factors contribute to a thickened hyperresponsive airway that provides an ideal microenvironment for the persistence of Th2-mediated inflammation, including a more susceptible epithelium to injury, delayed epithelial repair, an altered trajectory of epithelial repair to a mucus-secreting phenotype, generation of growth factors that drive mesenchymal cell proliferation and differentiation towards increased matrix deposition and smooth muscle, and the production of neural and vascular growth factors.Cytokines and mediators derived from infiltrating inflammatory cells interact with this EMTU to augment and prolong responses.The "remodelling" changes of asthma have been observed in childhood asthma and may, indeed, precede the development of the disease.The recent recognition that atopy per se is not a key factor in the initiation of asthma (although it is important in aggravating the disease) suggests that geneenvironmental interactions involving similar processes to those occurring in branching morphogenesis are critical for the full asthma phenotype to develop.
The morality of martyrdom and the stigma of suicide
Authors: Joshua Rottman, Deborah Kelemen
Journal: Behavioral and Brain Sciences (2014)

Abstract While primarily identifying similarities between suicide terrorists and other suicidal individuals, Lankford also notes differences in how their actions are morally evaluated. Specifically, “conventional” suicide is stigmatized in a way that suicide terrorism is not. We identify the root of this condemnation, showing that suicide is intuitively considered impure and disgusting, and discuss implications of this purity-based stigma.
B Cell Adaptor Containing Src Homology 2 Domain (Bash) Links B Cell Receptor Signaling to the Activation of Hematopoietic Progenitor Kinase 1
Authors: Sachiyo Tsuji, Mariko Okamoto, Koichi Yamada, Noriaki Okamoto, Ryo Goitsuka, Rudiger Arnold, Friedemann Kiefer, Daisuke Kitamura
Journal: The Journal of Experimental Medicine (2001)

The B cell adaptor containing src homology 2 domain (BASH; also termed BLNK or SLP-65), is crucial for B cell antigen receptor (BCR)-mediated activation, proliferation, and differentiation of B cells. BCR-mediated tyrosine-phosphorylation of BASH creates binding sites for signaling effectors such as phospholipase Cγ (PLCγ)2 and Vav, while the function of its COOH-terminal src homology 2 domain is unknown. We have now identified hematopoietic progenitor kinase (HPK)1, a STE20-related serine/threonine kinase, as a protein that inducibly interacts with the BASH SH2 domain. BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. Furthermore, HPK1 augmented, whereas its kinase-dead mutant inhibited IκB kinase β (IKKβ) activation by BCR engagement. These results reveal a novel BCR signaling pathway leading to the activation of HPK1 and subsequently IKKβ, in which BASH recruits tyrosine-phosphorylated HPK1 into the BCR signaling complex.
Regulation of interleukin-1 dihydroxyvitamin D3 in human macrophages
Authors: J. D. Ji, Y. Kim, B. Lee, T.-H. Kim, J.-B. Jun, D.-H. Yoo, J. H. Woo, S. J. Choi, Y. H. Lee, J. Sohn, G. G. Song
Journal: Annals of the Rheumatic Diseases (2010)

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a key molecule for maintaining calcium homeostasis and bone metabolism. In addition to these classic actions, 1,25(OH)2D3 has important functions in the immune system. It inhibits proinflammatory T cells such as Th1 and Th17 cells, directly inhibits interferon γ and interleukin 2 (IL2) …
Maternal mortality in the UK and the need for obstetric physicians
Authors: C. Nelson-Piercy, L. Mackillop, D. J. Williams, C. Williamson, M. d. Swiet, C. Redman
Journal: BMJ (2011)

Most deaths are now caused by preventable or treatable medical conditions

Since the first report of the Confidential Enquiry into Maternal Deaths in 1952, the maternal death rate in the United Kingdom has decreased dramatically.1 This has been due to an impressive fall in deaths with direct obstetric causes, including obstetric haemorrhage, ectopic pregnancy, and venous thromboembolism. This has partly been achieved through better understanding of obstetric complications, advances in medical treatments, and the use of evidence based guidelines that implement recommendations made in previous reports.2 However, almost 60 years since the first Confidential Enquiry into Maternal Deaths report, the most recent report, published in March 2011, highlights a worrying trend in the causes of maternal mortality in the UK.1

The report states that most maternal deaths in the UK now occur in women with pre-existing or new onset medical and psychiatric conditions (“indirect causes”). The leading cause of maternal death remains cardiac disease; the second is neurological disease. Most worryingly, the number of maternal deaths due to indirect causes has significantly increased over the past 20 years (table⇓). Furthermore, most of these deaths are associated with substandard care, and in one third of cases this is classified as major substandard care, where different care might have prevented death of …
Airway effects of local challenge with hypertonic saline in exercise-induced asthma.
Authors: H K Makker, A F Walls, D Goulding, S Montefort, J J Varley, M Carroll, P H Howarth, S T Holgate
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Hypertonicity of airway lining fluid has been suggested as the stimulus for bronchoconstriction in exercise-induced asthma. We explored the airway effects of delivering a direct hypertonic stimulus to asthmatic airways via a fiberoptic bronchoscope, comparing hypertonic saline challenge by direct instillation with local aerosol delivery. A group of 18 asthmatic subjects responsive to inhaled hypertonic saline with a history of EIA were studied; the first 9 subjects received local challenge with hypertonic saline by direct instillation, and the next 9 subjects were challenged by local aerosol delivery. A control challenge with isotonic saline by either instillation or aerosol was performed at a same bronchoscopy. Local challenge with hypertonic saline by aerosol delivery was found to be more effective in inducing local bronchoconstriction (8 of 9 subjects) than instillation (2 of 6 subjects). Paired BAL fluid samples and bronchial biopsies were obtained in total of 11 and 9 subjects, respectively. Local challenge with hypertonic saline either by instillation or aerosol produced no significant change in histamine, tryptase, or PGD2 levels in BAL fluid or mast cell numbers and degranulation in bronchial biopsies. A significant correlation was observed between histamine levels in BAL fluid and airway responsiveness to inhaled hypertonic saline (rs = -0.59, p < 0.05). Bronchial biopsies showed evidence of extensive epithelial damage; however, this was not related to airway responsiveness to inhaled hypertonic saline.
A dose-ranging study of fluticasone propionate aqueous nasal spray for seasonal allergic rhinitis assessed by symptoms, rhinomanometry, and nasal cytology
Authors: E MELTZER, H ORGEL, E BRONSKY, C FURUKAWA, J GROSSMAN, C LAFORCE, R LEMANSKEJR, B PAULL, D PEARLMAN, P RATNER
Journal: Journal of Allergy and Clinical Immunology (1990)
Pain Predicts Overall Survival in Men With Metastatic Castration-Refractory Prostate Cancer
Authors: Susan Halabi, Nicholas J. Vogelzang, Alice B. Kornblith, San-San Ou, Philip W. Kantoff, Nancy A. Dawson, Eric J. Small
Journal: Journal of Clinical Oncology (2008)

Purpose Pain from castration-refractory prostate cancer (CRPC) bone metastases is a common event. Although it is assumed that pain represents an adverse prognostic factor, this variable has not been extensively evaluated. The objective of this study was to determine whether men with CRPC who had higher pain interference scores at baseline had worse clinical outcomes compared with men who had lower pain scores. Patients and Methods Data from three randomized phase III multicenter trials conducted by the Cancer and Leukemia Group B from 1992 to 1998 were combined. Eligible patients had progressive CRPC adenocarcinoma of the prostate, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic functions. Seven items from the Brief Pain Inventory were used to assess the impact of pain on a range of daily activities and quality of life, each rated on a scale from 0 to 10. Results In 599 men, the median pain interference scores was 17 (interquartile range, 4 to 34), and 38% of the men had opioid analgesic use at baseline. There was a statistically significant association between pain interference scores and risk of death. The median survival times were 17.6 months (95% CI, 16.1 to 19.1 months) and 10.2 months (95% CI, 8.6 to 11.3 months; P &lt; .001) in men with low (&lt; 17) and high (≥ 17) pain scores, respectively. Pain was inversely associated with likelihood of prostate-specific antigen decline, objective response, and time to bone progression. Conclusion This analysis demonstrates that pain is a statistically significant predictor of overall survival in men with metastatic CRPC. These results need to be validated prospectively in future phase III trials.
Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling
Authors: Carl Nathan
Journal: Journal of Clinical Investigation (2003)

Nonstandard abbreviations used: reactive oxygen intermediate(s) (ROI); reactive nitrogen intermediate(s) (RNI); phagocyte oxidase (phox); hydrogen peroxide (H2O2); mammalian target of rapamycin (mTOR); carbon monoxide (CO); hypoxia-inducible transcription factor-1α (HIF-1α); alkylhydroperoxide reductase subunit C (AhpC).
Defective inhibition of sodium on basophil histamine release in patients with allergic rhinitis and bronchial asthma
Authors: A Tedeschi, M Cottini, C Salmaso, N Milazzo, A Miadonna
Journal: European Respiratory Journal (1996)

The aim of this study was to evaluate whether Na+ exerts its inhibitory effect on basophil histamine release induced by immunoglobulin E (IgE)-dependent (anti-IgE) and IgE-independent (N-formyl-methionyl-leucyl-phenylalanine (FMLP), interleukin-3 (IL-3)) stimuli in patients with allergic rhinitis (n = 24) and allergic bronchial asthma (n = 10). Peripheral blood leucocytes were stimulated with anti-IgE, FMLP and IL-3 in the presence of high and low Na+ concentrations, and histamine release was measured using a fluorometric method. In standard Na(+)-containing medium, spontaneous and stimulated histamine release was higher in allergic patients (n = 34) (both rhinitic and asthmatic) than in healthy subjects (n = 41). Na+ removal from extracellular medium and its isosmotic substitution with choline chloride or with N-methyl-D-glucamine led to a significant increase of anti-IgE-, FMLP- and IL-3-induced histamine release in normal subjects, but not in allergic patients. The increase in Na+ concentration in the extra-cellular medium was accompanied by a dose-dependent decrease of anti-IgE- and FMLP-induced histamine release in normal subjects, but not in allergic patients. The behaviour of atopics and healthy subjects was different and not related to the basophil responsiveness to activating signals. The incubation of basophils from healthy subjects with sera from allergic patients did not have a significant influence on the inhibitory effect of Na+. Basophils from healthy subjects and atopic patients respond differently when stimulated in a low Na+ medium. The reduced sensitivity to the inhibitory effect of Na+ may contribute to basophil dysfunction in patients with respiratory allergy.
Igβ tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization
Authors: Anna Gazumyan, Amy Reichlin, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2006)

Immunoglobulin (Ig)α and Igβ initiate B cell receptor (BCR) signaling through immune receptor tyrosine activation motifs (ITAMs) that are targets of SH2 domain–containing kinases. To examine the function of Igβ ITAM tyrosine resides in mature B cells in vivo, we exchanged these residues for alanine by gene targeting (IgβAA). Mutant mice showed normal development of all B cell subtypes with the exception of B1 cells that were reduced by fivefold. However, primary B cells purified from IgβAA mice showed significantly decreased steady-state and ligand-mediated BCR internalization and higher levels of cell surface IgM and IgD. BCR cross-linking resulted in decreased Src and Syk activation but paradoxically enhanced and prolonged BCR signaling, as measured by cellular tyrosine phosphorylation, Ca++ flux, AKT, and ERK activation. In addition, B cells with the ITAM mutant receptor showed an enhanced response to a T-independent antigen. Thus, Igβ ITAM tyrosines help set BCR signaling threshold by regulating receptor internalization.
Acute effects of intermittent and continuous normocapnic hyperpnea on lung function and airway resistance in asthmatics
Authors: Philipp A. Eichenberger, Andrea Kurzen, Stephanie N. Diener, Thomas A. Scherer, Christina M. Spengler
Journal: European Respiratory Journal (2012)

Introduction : Bronchoconstriction following high-intensity ventilation in dry and/or cold air is often reported in asthmatics. We aimed to investigate the acute effect of intermittent and continuous high-intensity ventilation of humid and warm air on lung function and airway resistance.  Methods : 6 mild-moderate male asthmatics (age: 25 ± 6 (SD) yrs, FEV 1 : 98 ± 11% pred.) performed, on separate days, 6x5min (5min pauses) of intermittent normocapnic hyperpnea (INH) and 1x30min of continuous normocapnic hyperpnea (CNH) by means of partial rebreathing. Tidal volume was set at 60% VC. Breathing frequency was adjusted to reach 60% MVV. Before, every 5min during (INH only) and 5, 15, 30, 45 and 60min after termination, lung function, airway resistance (R5Hz) and reactance (X5Hz) were measured. Individual maximal changes during INH and after INH and CNH were compared to baseline.  Results : FEV 1  did not change significantly from baseline during and after INH (-5 ± 2%, p=0.05; -2 ± 4%, p=1.0) and CNH (-2 ± 3%, p=1.0). R5Hz significantly increased during INH (30 ± 11%, p=0.02) and returned to baseline at 60min after INH (5 ± 4%, p=0.41). No significant change was observed at any time after CNH (13 ± 10%, p=0.38). X5Hz did not change significantly during and after INH (28 ± 20%, p=0.26; 27 ± 13%, p=0.06) nor after CNH (19 ± 17%, p=0.71).  Conclusion : In mild-moderate asthmatics, 30min of high-intensity intermittent and continuous NH with humid and warm air resulted in no clinically relevant changes in lung function, airway resistance and reactance. Thus NH by partial rebreathing might be a promising strategy to specifically train the respiratory system of asthmatics.
Death from malignant disease after surgery for duodenal ulcer.
Authors: I M Macintyre, F O'Brien
Journal: Gut (1994)

A total of 2241 patients who had an operation for duodenal ulcer between 1947 and 1968 were followed up to determine the cause of death and to compare the observed number of deaths with the expected. Death certificates were traced for 1251 of 1387 known to have died. Observed deaths from all causes were significantly greater than expected (O/E 1.13) (95% CI 1.08 to 1.20). This was because of significant increases in deaths from neoplasms (O/E 1.25) (95% CI 1.13 to 1.39) and digestive diseases (O/E 1.71) (95% CI 1.11 to 2.59). Analysis of deaths from malignant disease showed an excess of deaths from carcinoma of lung (O/E 1.37) (95% CI 1.14 to 1.62) and from smoking related cancers (O/E 1.32) (95% CI 1.13 to 1.52) but there was no significant excess mortality from any other neoplasm. An excess of deaths within one year of the operation was seen from circulatory disease (O/E 1.85) (95% CI 1.17 to 2.78), respiratory disease (O/E 3.56) (95% CI 1.78 to 6.37), and digestive disease (O/E 21.46) (95% CI 13.75 to 31.93). These deaths are concentrated in the first postoperative month and as there is no excess mortality from circulatory, respiratory or digestive disease between 1 and 20 years postoperatively, show the direct effects of the operation as a cause of death. This together with the excess mortality from all respiratory disease confirms that excess mortality after duodenal ulcer surgery is, in the short term, the result of the operation itself and in the long term largely attributable to cigarette smoking. Operations for gastric ulcer largely account for the subsequent excess mortality from gastric cancer reported after peptic ulcer surgery. The findings do not support the theory that the operation has carcinogenic effects and do not support the case for routine endoscopic screening after operations for duodenal ulcer.
Aspirin Use and Pancreatic Cancer Mortality in a Large United States Cohort
Authors: E. J. Jacobs, C. J. Connell, C. Rodriguez, A. V. Patel, E. E. Calle, M. J. Thun
Journal: JNCI Journal of the National Cancer Institute (2004)

Results from some epidemiologic studies have suggested that aspirin use may reduce risk of pancreatic cancer, but the evidence remains limited.We examined the association between aspirin use and pancreatic cancer mortality among 987 590 U.S. adults in the Cancer Prevention Study II (CPS-II) cohort. CPS-II participants completed a self-administered questionnaire in 1982 and were followed for mortality through 2000. During follow-up, there were 4577 deaths from pancreatic cancer (2434 in men and 2143 in women). We calculated rate ratios (RR) adjusted for age, sex, race, body mass index, diabetes, and cigarette smoking status.Aspirin use was not associated with pancreatic cancer mortality. The rate ratio associated with aspirin use 30 or more times per month, compared with no use, was 0.97 (95% confidence interval [CI] = 0.86 to 1.09). Even participants who reported both frequent aspirin use (> or =30 times per month) and use for 20 or more years were not at decreased risk compared with nonusers (RR = 0.96, 95% CI = 0.69 to 1.33). We found no association between aspirin use and pancreatic cancer mortality in subgroup analyses by follow-up time, cigarette smoking status, or sex.Results from this large prospective study do not support an important effect of aspirin use on pancreatic cancer mortality.
Renovascular effects of sympathetic cotransmitters ATP and NPY are age-dependent in spontaneoulsy hypertensive rats
Authors: O VONEND, A OKONEK, J STEGBAUER, S HABBEL, I QUACK, L RUMP
Journal: Cardiovascular Research (2005)

Hypertension is characterized by sympathetic overactivity. Neuropeptide Y (NPY) and ATP are cotransmitters of norepinephrine (NE) and regulate renovascular resistance. The present study analyzes sympathetic nonadrenergic neurotransmission in hypertensive (SH-SP) and normotensive (WKY) rats. In addition, adult and young hypertensive rats were compared to investigate the role of aging on sympathetic nonadrenergic cotransmission in hypertensive disease.Pressor responses to renal nerve stimulations (RNS) and drugs were measured on isolated perfused kidneys of young (8-10 weeks) and adult (18-24 weeks) WKY, and SH-SP rats.RNS evoked contractions at 1 Hz were resistant to blockade by the alpha-adrenoceptor antagonist phentolamine (1 microM) but abolished by the P2 receptor blocker suramin (100 microM). Compared to adult WKY, RNS-induced pressor responses were unchanged in adult SH-SP and young WKY, but significantly greater in young SH-SP rats. The NPY-Y1 receptor antagonist BIBP3226 (1 microM) reduced phentolamine-resistant pressor responses in adult and young WKY, young SH-SP, but not in adult SH-SP rats. In contrast to WKY and young SH-SP rats, exogenously perfused NPY (0.1 microM) was unable to potentiate RNS-induced, phentolamine-resistant pressor responses in adult SH-SP rats. NE and the stable ATP analogue alpha,beta-mATP increased the perfusion pressor response more potently in adult SH-SP than in WKY rats.Neuronally released NPY plays a major role in potentiating RNS-induced nonadrenergic pressor responses in kidneys of WKY and young SH-SP rats. In adult SH-SP rats NPY fails to enhance these responses. In this hypertensive model ageing seems to be associated with a loss of a modulatory role of renal NPY Y1 receptors. Since pressor responses to NE and ATP are higher in SH-SP animals, functional NPY-Y1 receptor downregulation might be an adaptive mechanism.