tbuckley/cabot-search huggingface dataset:
S132 Investigating the role of Pellino1, an E3 ubiquitin ligase, in modulating signalling pathways controlling the inflammatory response
Authors: J. A. Bennett, L. R. Prince, C. A. Stokes, L. C. Parker, M. K. Whyte, I. Sabroe
Journal: Thorax (2011)

Viruses, such as Rhinovirus, are a major cause of asthma exacerbations. Pellino1 was identified as an interleukin 1 receptor associated kinase binding partner and has shown to act as an E3-ubiquitin ligase that is involved in Lysine-63 polyubiquitination of interleukin 1 receptor associated kinase 1/4 and RIP1, which are key mediators of the Toll-like receptor and interleukin 1 receptor (IL-1R) signalling pathways. As such, these pathways are implicated in responses to both bacterial and viral infections. However, the functional importance of Pellino proteins in regulating immune responses and their role in airway inflammatory diseases is yet to be elucidated. We hypothesised that Pellino1 would play a critical role in regulating the inflammatory response in the lung airway epithelium. Pellino1 was knocked down in the human bronchial airway epithelial cell line BEAS2B and primary human bronchial epithelial cells (PBECs) using targeted siRNA. Knockdown of Pellino1 at the transcriptional level was measured using qPCR. Pellino1 knockdown cells were stimulated with Toll-like receptor/IL-1R agonists or the natural pathogen rhinovirus 1B (RV1B) and cytokine release was measured using ELISA. Signalling pathways were explored by western blotting.Pellino1 was expressed in BEAS2B and primary bronchial epithelial cells. Pellino1 mRNA transcript level was knocked down by 78% in BEAS2B and 94% in PBECs. Pellino1 knockdown led to reduced IL-8 generation in response to IL-1ß and a viral mimic Poly (I:C) stimulation in BEAS2B, however RANTES production was unchanged. In contrast to the BEAS2B, the primary bronchial epithelial cells exhibited preserved IL-1 signalling. However, these cells also showed a reduction in IL-8 production in response to both Poly (I:C) stimulation and RV1B infection. Pellino1 knockdown had no effect on the interferon-stimulated gene RANTES production. Pellino1 knockdown leads to reduced IL-8 production in response to a viral mimic Poly (I:C) in lung airway epithelial cells and RV1B in PBECs. These data indicate that Pellino1 regulates proinflammatory responses in airway epithelium and may be a feasible target to downregulate neutrophillic airway inflammation while retaining antiviral immunity, which would be highly beneficial in the treatment of chronic airway inflammatory disorders such as asthma and COPD. These studies were supported by an MRC/Asthma UK PhD studentship.
Changing patterns of coeliac disease frequency: an analysis of Coeliac Society membership records.
Authors: M J Langman, T H McConnell, D J Spiegelhalter, R B McConnell
Journal: Gut (1985)

Examination of Coeliac Society records from eight areas of England has shown that the number of members rose with birth dates from 1900 to 1972, apart from a decline between 1941 to 1962, and then fell steeply. The steep decline in the number of members with birth dates after 1972 is unexplained, and is unlikely to be accounted for by change in diagnostic practice or registration and may reflect a true fall in disease incidence; but the fall in numbers of members with birth dates from 1941 to 1962 is explainable by a tendency for the disease to remit in adolescence or early adult life.
Metabolism and toxicity of styrene.
Authors: K C Leibman
Journal: Environmental Health Perspectives (1975)

The absorption, blood levels, distribution, excretion, and biotransformation of styrene in man and experimental animals are briefly reviewed. The acute toxicity of styrene appears to be unrelated to its biotransformation. Reports of organ toxicity upon chronic exposure to styrene are rare; however, since the chief intermediate in styrene metabolism is an epoxide, hepatotoxicity due to covalent binding at the site of formation appears to be a possibility.
Explanatory force, antidescriptionism, and the common structure of substance concepts
Authors: Jürgen Schröder
Journal: Behavioral and Brain Sciences (1998)

Millikan's proposal of a common structure of substance concepts does not explain certain conspicuous findings in the psychological literature such as typicality effects, the context sensitivity of these effects, and slips of the tongue. Moreover, it is unclear how antidescriptionism could be relevant to psychological theorizing. Finally, it does not seem to be true that concepts of individuals, stuff, and real kinds have a common structure in older children and in adults.
Skin Telangiectases in Workers at an Aluminum Plant
Authors: Gilles Thériault, Sylvaine Cordier, Réjean Harvey
Journal: New England Journal of Medicine (1980)

OCCUPATIONAL-HEALTH physicians from a large Canadian aluminum company recently noticed the presence of numerous telangiectases on the skin of some production workers. Called to investigate, the Workmen's Compensation Commission confirmed the presence of these lesions. Some affected workers complained of the appearance of the lesions and worried about their effects on health. Researchers from the Soviet Union have reported the presence of telangiectases in workers at an aluminum electrolysis plant,1 but the lesion has received little or no attention in the Western medical literature.We attempted to determine whether these skin lesions were related to work in aluminum and to . . .
Re: Association Between Endothelin Receptor B Nonsynonymous Variants and Melanoma Risk
Authors: Ranjit K. Thirumaran, Adina Thoelke, Selma Ugurel, Kari Hemminki, Dirk Schadendorf, Rajiv Kumar
Journal: JNCI Journal of the National Cancer Institute (2006)

The endothelin signaling pathway plays a crucial role in melanocyte differentiation and migration. In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM). The coding region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 patients (11%), but only two were found in four control subjects (3%, odds ratio [OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which had previously been shown to lead to loss of function. In multivariable logistic regression analysis including skin type, eye and hair color, number of nevi, and dorsal lentigines (freckles), the association between EDNRB mutations and MM risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = .03). Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.
Outpatient Maintenance of Chronic Schizophrenic Patients with Long-acting Fluphenazine: Double-blind Placebo
Authors: S. R. Hirsch, R. Gaind, P. D. Rohde, B. C. Stevens, J. K. Wing
Journal: BMJ (1973)

A double-blind placebo trial of fluphenazine decanoate, a long-acting phenothiazine, was carried out to determine its value in maintenance therapy of chronic schizophrenic outpatients already established on the drug for a minimum period of eight weeks. In low doses it was significantly more effective than placebo in preventing relapse and admission to hospital. Relapse was accompanied by a resurgence of specifically schizophrenic symptoms and by an increase in abnormalities described by the relatives. There was no difference between the experimental and control groups in the treatment required for depression. The group on active medication required more treatment for Parkinsonism, but this difference did not reach statistical significance. In the context of a well-run special clinic for outpatient follow-up of chronic schizophrenic patients these results confirm the usefulness of long-acting fluphenazine. By inference, the benefit of this treatment highlights the need for adequate community services to deal with the residual chronic disabilities which are characteristic of these patients.
Detection of IgG rheumatoid factor by concanavalin A treatment and complement fixation with IgG rheumatoid factor.
Authors: K Tanimoto, T Moritoh, T Azuma, Y Horiuchi
Journal: Annals of the Rheumatic Diseases (1976)

Concanavalin A (Con A) froms precipitates with carbohydrate-rich protein such as IgM, IgD, IgE, and IgA. Since IgG contains little carbohydrate and does not react with Con A, the activity of IgG-rheumatoid factor (RF) can be measured in the supernate of the Con A-treated serum. When the latex fixation test (LFT) and the sensitized sheep cell agglutination test (SSCA) were perfromed in the supernate for the detection of IgG-RF, LFT was positive in 32-1% of sera, out of 137 sera originally positive for LFT, and SSCA was positive in 18-5% of sera, out of 119 sera originally positive for SSCA. IgG-RF exhibited lower complement fixing ability than IgM-RF and correlated with agglutination titres of IgG-RF, while the CH50 of the original serum did not correlate with haemolytic activities of either IgM-RF or IgG-RF.
Impact of Cytochrome P450 2C19 Loss-of-Function Polymorphism and of Major Demographic Characteristics on Residual Platelet Function After Loading and Maintenance Treatment With Clopidogrel in Patients Undergoing Elective Coronary Stent Placement
Authors: Willibald Hochholzer, Dietmar Trenk, Martin F. Fromm, Christian M. Valina, Christian Stratz, Hans-Peter Bestehorn, Heinz Joachim Büttner, Franz-Josef Neumann
Journal: Journal of the American College of Cardiology (2010)
Noninvasive Imaging for the Diagnosis of Coronary Artery Disease: Focusing the Development of New Diagnostic Technology
Authors: Maria G.M. Hunink, Karen M. Kuntz, Kirsten E. Fleischmann, Thomas J. Brady
Journal: Annals of Internal Medicine (1999)

Background: New tests, such as magnetic resonance imaging (MRI) and electron-beam computed tomography (CT), are being developed for the diagnosis of coronary artery disease. Objective: To determine the conditions that a new test must meet to be a cost-effective alternative to established imaging tests. Design: Decision model and cost-effectiveness analysis. Data Sources: Literature review and meta-analysis. Target Population: 55-year-old men and 65-year-old women presenting with chest pain. Time Horizon: Lifetime of the patient. Perspective: Health care policy. Interventions: MRI, electron-beam CT, exercise echocardiography, exercise single-photon emission CT, and coronary angiography. Outcome Measures: Target sensitivity and specificity values for a new noninvasive test. Results of Base-Case Analysis: Assuming that society is willing to pay $75 000 per quality-adjusted life-year (QALY) gained, a new test that costs $1000 would need a sensitivity of 94% and a specificity of 90% to be cost-effective. Results of Sensitivity Analysis: Assuming that society is willing to pay $50 000 per QALY gained, a new test that costs $1000 or more would never be cost-effective. For a test that costs $500, the sensitivity and specificity must each be 95%. Conclusions: New imaging techniques, such as MRI and electron-beam CT, must be relatively inexpensive and have excellent sensitivity and specificity to be cost-effective compared with other techniques for the diagnosis of coronary artery disease. Similar analyses in other areas of health care may help to focus the development of new diagnostic technology.
Ursodiol Prophylaxis against Hepatic Complications of Allogeneic Bone Marrow Transplantation
Authors: James H. Essell
Journal: Annals of Internal Medicine (1998)

Background: Hepatic complications are a major cause of illness and death after bone marrow transplantation. Objective: To confirm the results of a pilot study that indicated that ursodiol prophylaxis could reduce the incidence of veno-occlusive disease of the liver. Design: Randomized, double-blind, placebo-controlled study. Setting: Tertiary care teaching hospital. Patients: 67 consecutive patients undergoing transplantation with allogeneic bone marrow (donated by a relative) in whom busulfan plus cyclophosphamide was used as the preparative regimen and cyclosporine plus methotrexate was used to prevent graft-versus-host disease. Intervention: Before the preparative regimen was started, patients were randomly assigned to receive ursodiol, 300 mg twice daily (or 300 mg in the morning and 600 mg in the evening if body weight was > 90 kg), or placebo. Measurements: Patients were prospectively evaluated for the clinical diagnosis of veno-occlusive disease, the occurrence of acute graft-versus-host disease, and survival. Results: The incidence of veno-occlusive disease was 40% (13 of 32 patients) in placebo recipients and 15% (5 of 34 patients) in ursodiol recipients (P = 0.03). Assignment to placebo was the only pretransplantation characteristic that predicted the development of veno-occlusive disease. The most significant predictor of 100-day mortality was the diagnosis of veno-occlusive disease. The difference in actuarial risk for hematologic relapse in patients with chronic myelogenous leukemia and nonhepatic toxicities between the two groups was not statistically significant (13% in the ursodiol group and 20% in the placebo group; P > 0.2). Conclusion: Ursodiol prophylaxis seemed to decrease the incidence of hepatic complications after allogeneic bone marrow transplantation in patients who received a preparative regimen with busulfan plus cyclophosphamide.
Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure
Authors: P Harrison
Journal: Hepatology (1996)

Patients with fulminant hepatic failure (FHF) have a severe microcirculatory disturbance causing tissue hypoxia. Infusion of acetylcysteine improves survival and reduces the incidence of multiorgan failure by enhancing tissue oxygenation. Because the observed circulatory effects of acetylcysteine in FHF are similar to and synergistic with those produced by the microcirculatory vasodilator prostacyclin, we postulated that acetylcysteine might potentiate an endogenous vasodilator. Nitric oxide, a vasodilator that activates soluble guanylate cyclase, is a possible candidate as plasma cyclic 3',5'-guanosine monophosphate (cGMP) is raised in FHF, and in vitro acetylcysteine has been found to enhance soluble guanylate cyclase activity. To investigate this possible mechanism further, plasma cGMP was measured before and after acetylcysteine infusion in 24 patients with FHF and again in 6 patients after recovery from acute illness. cGMP levels were high in FHF during acute illness (median, 7.0 nmol/L [interquartile range, 2.6-10.0]) in comparison with levels taken after recovery (1.5 nmol/L [1.0-1.9]; P < .05). Levels rose further after acetylcysteine infusion in the FHF cases (mean increase, 204% [95% CI; 49 to +360]; P < .01) but not in the cases after recovery (38% [-7 to +84]). There were no significant changes in levels of plasma atrial natriuretic peptide (ANP) or cyclic adenosine monophosphate (cAMP) (mean increases, 8% [-6 to +22] and 17% [-9 to +43], respectively). The findings further support the hypothesis that the beneficial hemodynamic effects of acetylcysteine in FHF are mediated by enhancing the activity of the nitric oxide/soluble guanylate cyclase enzyme system.
Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects
Authors: Sophie Escot, Cédrine Blavet, Sonja Härtle, Jean-Loup Duband, Claire Fournier-Thibault
Journal: Circulation Research (2013)

Rationale: Cardiac neural crest cells (NCs) contribute to heart morphogenesis by giving rise to a variety of cell types from mesenchyme of the outflow tract, ventricular septum, and semilunar valves to neurons of the cardiac ganglia and smooth muscles of the great arteries. Failure in cardiac NC development results in outflow and ventricular septation defects commonly observed in congenital heart diseases. Cardiac NCs derive from the vagal neural tube, which also gives rise to enteric NCs that colonize the gut; however, so far, molecular mechanisms segregating these 2 populations and driving cardiac NC migration toward the heart have remained elusive. Objective: Stromal-derived factor-1 (SDF1) is a chemokine that mediates oriented migration of multiple embryonic cells and mice deficient for Sdf1 or its receptors, Cxcr4 and Cxcr7 , exhibit ventricular septum defects, raising the possibility that SDF1 might selectively drive cardiac NC migration toward the heart via a chemotactic mechanism. Methods and Results : We show in the chick embryo that Sdf1 expression is tightly coordinated with the progression of cardiac NCs expressing Cxcr4 . Cxcr4 loss-of-function causes delayed migration and enhanced death of cardiac NCs, whereas Sdf1 misexpression results in their diversion from their normal pathway, indicating that SDF1 acts as a chemoattractant for cardiac NCs. These alterations of SDF1 signaling result in severe cardiovascular defects. Conclusions: These data identify Sdf1 and its receptor Cxcr4 as candidate genes responsible for cardiac congenital pathologies in human.
Acanthosis Nigricans and Endocrine Disease
Authors: R. K. Winkelmann
Journal: JAMA (1960)

Among 29 patients who had the blackish-brown, verrucous lesions of benign pubertal or postpubertal acanthosis nigricans, there were 9 with endocrinopathy in the form of pituitary adenoma, Stein-Leventhal syndrome, Addison's disease, or diabetes mellitus. Of the nine, four were male and five female. The ages of these patients ranged from 14 to 39 years, congenital cases being excluded. Obesity was marked in some cases, but it was not a constant factor. Treatment of the endocrine disorder did not consistently affect the acanthosis nigricans although the patients were observed for periods up to 13 years.
WOULD BREAST COMPRESSION IMPROVE VISUALIZATION OF SMALL PRIMARY CANCERS WITH SCINTIMAMMOGRAPHY? — A FEASIBILITY STUDY.
Authors: I. N. Weinberg, A. Markowitz, S. Majewski, A. Weisenberger, L. Majewski, R. Wojcik
Journal: Clinical Nuclear Medicine (1997)

Weinberg, I. N.1; Markowitz, A.2; Majewski, S.; Weisenberger, A.; Majewski, L.; Wojcik, R.3 Author Information
Inducibility of class II major histocompatibility complex antigens by interferon gamma is associated with reduced tumorigenicity in C3H mouse fibroblasts transformed by v-Ki-ras.
Authors: W J Bateman, R Fiera, N Matthews, A G Morris
Journal: The Journal of Experimental Medicine (1991)

Paired lines of C3H mouse fibroblasts transformed with murine sarcoma virus (Kirsten strain) were prepared that express high or low levels of class II major histocompatibility complex antigen after treatment with interferon gamma (IFN-gamma). Here, we described a comparison of the tumorigenicity of these lines in euthymic syngeneic and thymus-deficient nu/nu mice and in mice depleted of IFN-gamma. The class II-inducible cells are clearly less tumorigenic than the noninducible cells in syngeneic mice, but of similar tumorigenicity in nu/nu mice and in mice treated with antibodies to deplete IFN-gamma. We propose that in this system, IFN-gamma induction of class II antigens on the tumor cell surface operates to limit tumor growth; ras expression, which inhibits induction of class II antigens, prevents this and so allows tumor growth.
Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity.
Authors: Wade V Welshons, Kristina A Thayer, Barbara M Judy, Julia A Taylor, Edward M Curran, Frederick S vom Saal
Journal: Environmental Health Perspectives (2003)

Information concerning the fundamental mechanisms of action of both natural and environmental hormones, combined with information concerning endogenous hormone concentrations, reveals how endocrine-disrupting chemicals with estrogenic activity (EEDCs) can be active at concentrations far below those currently being tested in toxicological studies. Using only very high doses in toxicological studies of EEDCs thus can dramatically underestimate bioactivity. Specifically: a) The hormonal action mechanisms and the physiology of delivery of EEDCs predict with accuracy the low-dose ranges of biological activity, which have been missed by traditional toxicological testing. b) Toxicology assumes that it is valid to extrapolate linearly from high doses over a very wide dose range to predict responses at doses within the physiological range of receptor occupancy for an EEDC; however, because receptor-mediated responses saturate, this assumption is invalid. c) Furthermore, receptor-mediated responses can first increase and then decrease as dose increases, contradicting the assumption that dose-response relationships are monotonic. d) Exogenous estrogens modulate a system that is physiologically active and thus is already above threshold, contradicting the traditional toxicological assumption of thresholds for endocrine responses to EEDCs. These four fundamental issues are problematic for risk assessment methods used by regulatory agencies, because they challenge the traditional use of extrapolation from high-dose testing to predict responses at the much lower environmentally relevant doses. These doses are within the range of current exposures to numerous chemicals in wildlife and humans. These problems are exacerbated by the fact that the type of positive and negative controls appropriate to the study of endocrine responses are not part of traditional toxicological testing and are frequently omitted, or when present, have been misinterpreted.
Second Opinion: Doctors, Diseases and Decisions in Modern Medicine
Authors: S. W G Derbyshire
Journal: BMJ (2003)

Richard Horton Granta Books, £17.99, pp 582 ISBN 1 86207 587 5 Rating: ![Graphic][1]</img> Second Opinion paints a depressing view of the world. One section begins with an invitation to imagine a virus wiping out humanity. Later author Richard Horton, editor of the Lancet , talks of “huge population pressure” producing “our own global hot zone.” Cities are “the graveyards of mankind” and society is “responsible for the accelerated evolution of infectious diseases.” In the battle with the mosquito, “the outlook for human beings is far from encouraging.” Bioterrorism “conjures up the prospect of imminent human self annihilation from technologically adept terrorists,” although ecological disaster or the tobacco or sugar industries might kill us first. In the middle of this we are facing an epidemic of HIV, yellow fever, severe acute respiratory syndrome (SARS), and West Nile disease, with the threat of Ebola looming large. This appalling situation is being met “recklessly” by governments that are sometimes apathetic and at other times zealous. Horton is clearly motivated to have health organisations pick up the slack, but … [1]: /embed/inline-graphic-1.gif