tbuckley/cabot-search huggingface dataset:
REGULATION OF TH2 DIFFERENTIATION AND<i>Il4</i>LOCUS ACCESSIBILITY
Authors: K. Mark Ansel, Ivana Djuretic, Bogdan Tanasa, Anjana Rao
Journal: Annual Review of Immunology (2006)

Helper T cells coordinate immune responses through the production of cytokines. Th2 cells express the closely linked Il4, Il13, and Il5 cytokine genes, whereas these same genes are silenced in the Th1 lineage. The Th1/Th2 lineage choice has become a textbook example for the regulation of cell differentiation, and recent discoveries have further refined and expanded our understanding of how Th2 differentiation is initiated and reinforced by signals from antigen-presenting cells and cytokine-driven feedback loops. Epigenetic changes that stabilize the active or silent state of the Il4 locus in differentiating helper T cells have been a major focus of recent research. Overall, the field is progressing toward an integrated model of the signaling and transcription factor networks, cis-regulatory elements, epigenetic modifications, and RNA interference mechanisms that converge to determine the lineage fate and gene expression patterns of differentiating helper T cells.
NXY-059 for the Treatment of Acute Ischemic Stroke
Authors: Ashfaq Shuaib, Kennedy R. Lees, Patrick Lyden, James Grotta, Antonio Davalos, Stephen M. Davis, Hans-Christoph Diener, Tim Ashwood, Warren W. Wasiewski, Ugochi Emeribe
Journal: New England Journal of Medicine (2007)

The free-radical–trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke–Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. We sought confirmation of efficacy in a second, larger trial.
Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol
Authors: M. Diviné, P. Casassus, S. Koscielny, J. Bosq, C. Sebban, C. Le Maignan, A. Stamattoulas, B. Dupriez, M. Raphaël, J.-L. Pico, V. Ribrag
Journal: Annals of Oncology (2005)
Primum Non Nocere
Authors: Ray W. Gifford
Journal: JAMA (1977)

THE DICTUM<i>primum non nocere</i>—first, do no harm—is a carry-over from the distant past and probably originated with Hippocrates, when therapeutics was not based on sound scientific knowledge and rationale and the medicaments available were more likely to be harmful than helpful. If indeed this phrase originated with Hippocrates, it was undoubtedly taken out of context. In "Epidemics," Hippocrates wrote, "As to diseases, make a habit of two things—to help, or at least to do no harm." <h3>The Benefit-Risk Ratio</h3> This was obviously Hippocrates' attempt to define what we now call the "benefit-risk ratio" in modern therapeutics. The problem is that, strictly interpreted and applied in the modern era of scientific therapeutics,<i>primum non nocere</i>prohibits any risk and therefore effectively prevents any meaningful therapeutic endeavor. It becomes the shield of the therapeutic nihilist, the battle cry of consumer advocates to thwart new drug development, and the justification of
<i>Jinx</i>, an MCMV susceptibility phenotype caused by disruption of <i>Unc13d</i>: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis
Authors: Karine Crozat, Kasper Hoebe, Sophie Ugolini, Nancy A. Hong, Edith Janssen, Sophie Rutschmann, Suzanne Mudd, Sosathya Sovath, Eric Vivier, Bruce Beutler
Journal: The Journal of Experimental Medicine (2007)

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.
Effect of adenosine infusion on oxygen induced carbon dioxide retention in severe chronic obstructive pulmonary disease.
Authors: T L Griffiths, S S Fernando, K B Saunders
Journal: Thorax (1996)

BACKGROUND: In normal subjects intravenous adenosine infusion has been shown to stimulate ventilation with a consequent fall in arterial partial pressure of carbon dioxide (Paco2), probably by an action on the carotid bodies. The objective of this study was to determine whether the increase in Paco2 seen when patients with ventilatory failure secondary to chronic obstructive pulmonary disease (COPD) are given a high concentration of oxygen to breathe might be ameliorated by an intravenous infusion of adenosine. METHODS: Eight subjects with chronic stable ventilatory failure secondary to COPD were studied. Their mean (SE) forced expiratory volume in one second (FEV1) was 0.63 (0.12) 1 with forced vital capacity (FVC) of 1.63 (0.21) 1. They received continuous intravenous infusions of saline and adenosine in random order, double blind. The infusions were administered for two minutes at 20 micrograms/kg/min, increasing in increments of 20 micrograms/kg/min every two minutes to a maximum infusion rate of 80 micrograms/kg/min adenosine (or an equivalent saline infusion rate), or until side effects supervened. The infusions were continued at that rate for five minutes, after which the fractional inspired oxygen (FIO2) was raised to 0.50 during a further 20 minutes of the infusion at that rate. Haemoglobin oxygen saturation (SaO2) and transcutaneous PCO2 (PtcCO2) were monitored throughout the procedure. Spirometric tests were performed before and after each infusion. RESULTS: Adenosine infusion was accompanied by a fall in PtcCO2 from a mean (SE) of 7.29 (0.42) kPa to 6.95 (0.48) kPa: mean difference -0.34 (95% confidence interval, -0.56 to -0.11) kPa. During saline infusion oxygen administration resulted in an increase in transcutaneous PtcCO2 from 7.35 (0.34) kPa to 7.88 (0.28) kPa: mean difference 0.53 (95% CI 0.20 to 0.85) kPa. PtcCO2 did not rise above baseline levels when oxygen was administered during the adenosine infusion. A small fall in FVC was seen following adenosine infusion. CONCLUSIONS: The increase in PtcCO2 seen when patients with stable ventilatory failure secondary to severe COPD are given a high concentration of oxygen to breathe is counteracted by a continuous intravenous infusion of adenosine.
Neuroticism and Affective Instability: The Same or Different?
Authors: Joshua D. Miller, Paul A. Pilkonis
Journal: American Journal of Psychiatry (2006)

Objective: The purpose of this study was to examine the correlates and consequences of two constructs related to affective experience: neuroticism and affective instability. Method: One hundred thirty-two patients were assessed at intake for axis I and II symptoms, general personality traits, and specific impairments, including impairments in interpersonal functioning. The data included responses to structured and semistructured interviews, self-reports of interpersonal problems, and reports of interpersonal problems from significant others. Clinical ratings of axis I and II symptoms and of impairment were made by using the LEAD (i.e., longitudinal, expert, all data) consensus approach. Ninety-one of the 132 patients were reassessed at 12-month follow-up. Results: Neuroticism and affective instability manifested varied concurrent relations, with neuroticism being strongly related to an anxious, avoidant style and affective instability related to more externalizing personality styles. Prospectively, neuroticism predicted later symptoms, occupational impairment, and global dysfunction, whereas affective instability predicted romantic impairment. Conclusions: The findings suggest that neuroticism and affective instability—which are considered core aspects of personality pathology—are related but distinct constructs with unique correlates and different predictive abilities.
The physician assistant: would the US model meet the needs of the NHS?
Authors: L. Hutchinson, T. Marks, M. Pittilo
Journal: BMJ (2001)

The public and the government have both identified “more staff” as a way of improving the NHS.1 Problems with recruitment and retention in nursing and allied health professions and falling numbers of applicants to primary care are potential constraints on the meeting of targets. One option is to introduce a new group of staff (box 1). 2 3 Practitioners who perform “mid-level” duties in the United States include doctors in training, nurse practitioners (including advanced practice nurses and other titles), and physician assistants. These three groups perform similar duties and, at the level of the patient, act interchangeably. The American term “physician” encompasses all doctors, and physician assistants work in all branches of medicine and surgery. Physician assistants in the United States are fully trained professionals who take on a role equivalent to that of a junior doctor for their entire career. They pride themselves on their “dependent” status, have the ability to move to and from various clinical settings, have their own recertification processes, and do not compete for senior medical posts. Higher education institutions in the United Kingdom are starting to look into the education needs of such a profession. But is the US physician assistant model the right solution for the NHS?

#### Summary points

Physician assistants make a major contribution to provision of health care in the United States

They function as “mid-level” practitioners, along with doctors in training and nurse practitioners

They train and work in a biomedical model and do not perform “nursing” tasks or tasks of other therapists

Introduction of US-style physician assistants in the United Kingdom would reduce medical staffing difficulties but would not help to remove professional boundaries or barriers to expanding scope of practice

It is not known whether introduction of another healthcare career pathway would attract into the health service people …
Preserved Vasodilator Effect of Bradykinin in Dogs With Heart Failure
Authors: Jin Bo Su, Fabrice Barbe, Rémi Houel, Thanh Tam Guyene, Bertrand Crozatier, Luc Hittinger
Journal: Circulation (1998)

In heart failure (HF), vasoconstrictor systems are activated and endothelium-derived vasodilation is blunted. Bradykinin, a potent vasodilator, may play an important role in this setting. However, it is not known whether its vasodilator effect is modified in HF.Fourteen chronically instrumented dogs were studied in the control state and in pacing-induced HF (250 bpm for 3 weeks). The dose-dependent decrease in mean aortic pressure (MAP) induced by acetylcholine was significantly blunted in HF. In contrast, in both control and HF, bradykinin infusion caused similar dose-dependent decreases in MAP and increases in cardiac output (CO). This vasodilator effect of exogenous bradykinin was potentiated similarly in both states by enalaprilat, which blocks both angiotensin conversion and bradykinin degradation. For evaluating the role of endogenous bradykinin, the effects of enalaprilat were compared with those of ciprokiren, a pure renin inhibitor. In control, ciprokiren did not produce any effect. Enalaprilat, however, produced a significant decrease in MAP and a significant increase in CO, which were attributed to the inhibition of bradykinin degradation, because these effects were absent after pretreatment with Hoe 140 (a bradykinin B2 receptor antagonist). In contrast, in HF, vasodilator effects of ciprokiren were observed, but enalaprilat produced larger changes in MAP and CO, and after Hoe 140, the hemodynamic effects of enalaprilat were significantly decreased, showing the effects of endogenous bradykinin, which were similar to those measured in control.In this model of HF with a blunted endothelium-derived vasodilation, the vasodilator effects of exogenous and endogenous bradykinin are preserved. These results suggest that bradykinin may play an important role in HF, in which vasoconstriction is present and endothelium-dependent vasodilation is blunted.
Respiratory burst enzyme in human neutrophils. Evidence for multiple mechanisms of activation.
Authors: L C McPhail, P M Henson, R B Johnston
Journal: Journal of Clinical Investigation (1981)

Alteration of the surface of human neutrophils with the nonpenetrating, protein-inactivating agent p-diazobenzenesulfonic acid (DASA) was found to prevent activation of the respiratory burst by some stimuli, but not others. Production of superoxide anion (O2-) stimulated by concanavalin A or the chemotactic peptide formyl-methionyl-leucyl-phenylalanine FMLP was inhibited by DASA pretreatment, whereas O2- production stimulated by phorbol myristate acetate (PMA), sodium fluoride. or the ionophore A23187 was not inhibited by DASA. Pretreatment with DASA inhibited oxygen uptake stimulated by FMLP, but not oxygen uptake stimulated by PMA. DASA reproducibly inhibited activities of two known surface enzymes Mg++-ATPase and alkaline phosphatase, by 45-55% and 60-70%, respectively. The inhibition by DASA of O2- production did not appear to be caused by interference with binding of the affected stimuli, since pretreatment with DASA did not inhibit release of the lysosomal enzymes lysozyme and myeloperoxidase induced by concanavalin A or FMLP. Membrane-rich particulate fractions from neutrophils have been shown to contain NADPH-dependent oxidative activity that is presumably responsible for the phagocytosis-associated respiratory burst of intact cells. The PMA-activated enzyme was susceptible to inhibition of directly exposed to DASA in this particulate fraction. These findings suggest that more than one mechanism exists for activation of the respiratory burst oxidase in human neutrophils, and that the neutrophil possesses at least one oxidase that is not an ectoenzyme.
Hip chondropathy at arthroscopy: prevalence and relationship to labral pathology, femoroacetabular impingement and patient-reported outcomes
Authors: Joanne L Kemp, Michael Makdissi, Anthony G Schache, Michael G Pritchard, Thomas C B Pollard, Kay M Crossley
Journal: British Journal of Sports Medicine (2014)

This study aimed to describe chondropathy prevalence in adults who had undergone hip arthroscopy for hip pain. The relationships between chondropathy severity and (1) participant characteristics; and (2) patient-reported outcomes (PROs) at initial assessment (∼18 months postsurgery) and over a further 12 months (∼30 months postsurgery) were evaluated. Finally, the relationships between chondropathy and coexisting femoroacetabular impingement (FAI) and labral pathology at the time of surgery were evaluated.100 consecutive patients (36±12 years) who underwent hip arthroscopy 18 months previously participated. Hip Osteoarthritis and Disability Outcome Score (HOOS) and International Hip Outcome Tool (iHOT-33) data were collected prospectively at 18 months postsurgery and at 30 months postsurgery. Surgical data were collected retrospectively. Participants were grouped: Outerbridge grade 0, no chondropathy; Outerbridge grade I-II, mild chondropathy; Outerbridge III-IV, severe chondropathy. The presence of FAI or labral pathology was noted.The prevalence of chondropathy (≥grade I) at hip arthroscopy was 72%. Participants with severe chondropathy were significantly worse for all HOOS subscales and the iHOT-33 at 18 months postsurgery (HOOS-symptoms (p=0.017); HOOS-pain (p=0.024); HOOS-activity (p=0.009); HOOS-sport (p=0.004); HOOS-quality-of-life (p=0.006); iHOT-33 (p=0.013)) than those with no chondropathy. At 12-month follow-up, HOOS-quality-of-life in those without chondropathy was the only PRO that improved. Relative risk of coexisting chondropathy with labral pathology or FAI was 40%.Chondropathy was prevalent, and associated with increasing age, coexisting labral pathology or FAI. Severe chondropathy was associated with worse pain and function at 18 months postsurgery. Little improvements were observed in participants over a further 12 months, regardless of chondropathy status.
Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study
Authors: J. Dent, N. Vakil, R. Jones, P. Bytzer, U. Schoning, K. Halling, O. Junghard, T. Lind
Journal: Gut (2010)

<h3>Objective</h3> The aim of this study was to determine the accuracy of the diagnosis of gastro-oesophageal reflux disease (GORD) by the Reflux Disease Questionnaire (RDQ), family practitioners, gastroenterologists and a test of esomeprazole therapy. <h3>Methods</h3> This was a single-blind, single-arm study over 3–4 weeks from September 2005 to November 2006. Each symptom-based diagnostic assessment was made blinded to prior diagnoses. Patients were those presenting to their family practitioner with troublesome upper gastrointestinal symptoms (n=308). The RDQ was completed and a symptom-based diagnosis was made by the family practitioner. Placebo esomeprazole was started. Gastroenterologists made a symptom-based diagnosis and then performed endoscopy with 48 h oesophageal pH and symptom association monitoring to determine the presence/absence of GORD. Symptoms were recorded during treatment with 40 mg of esomeprazole for 2 weeks. The main outcome measure was RDQ scoring for the presence of GORD compared with symptom-based diagnosis by family physicians and gastroenterologists. <h3>Results</h3> GORD was present in 203/308 (66%) patients. Only 49% of the patients with GORD selected either heartburn or regurgitation as the most troublesome symptom. Sensitivity and specificity, respectively, of the symptom-based diagnosis of GORD, were 62% and 67% for the RDQ, 63% and 63% for family practitioners, and 67% and 70% for gastroenterologists. Symptom response to esomeprazole was neither sensitive nor specific for the diagnosis of GORD. <h3>Conclusions</h3> The RDQ, family practitioners and gastroenterologists have moderate and similar accuracy for diagnosis of GORD. Symptom response to a 2 week course of 40 mg of esomeprazole does not add diagnostic precision. <h3>Clinical trial number</h3> NCT00291746.
PHA-680632, a Novel Aurora Kinase Inhibitor with Potent Antitumoral Activity
Authors: Chiara Soncini, Patrizia Carpinelli, Laura Gianellini, Daniele Fancelli, Paola Vianello, Luisa Rusconi, Paola Storici, Paola Zugnoni, Enrico Pesenti, Valter Croci, Roberta Ceruti, Maria Laura Giorgini, Paolo Cappella, Dario Ballinari, Francesco Sola, Mario Varasi, Rodrigo Bravo, Jürgen Moll
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy. Experimental Design: The activity of PHA-680632 was assayed in a biochemical ATP competitive kinase assay. A wide panel of cell lines was evaluated for antiproliferative activity. Cell cycle analysis. Immunohistochemistry, Western blotting, and Array Scan were used to follow mechanism of action and biomarker modulation. Specific knockdown of the targets by small interfering RNA was followed to validate the observed phenotypes. Efficacy was determined in different xenograft models and in a transgenic animal model of breast cancer. Results: PHA-680632 is active on a wide range of cancer cell lines and shows significant tumor growth inhibition in different animal tumor models at well-tolerated doses. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. Histone H3 phosphorylation in Ser10 is mediated by Aurora B kinase, and our kinetic studies on its inhibition by PHA-680632 in vitro and in vivo show that phosphorylation of histone H3 is a good biomarker to follow activity of PHA-680632. Conclusions: PHA-680632 is the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic. On treatment, different cell lines respond differentially, suggesting the absence of critical cell cycle checkpoints that could be the basis for a favorable therapeutic window.
Pharmaceutical industry sponsorship and research outcome and quality: systematic review
Authors: J. Lexchin
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To investigate whether funding of drug studies by the pharmaceutical industry is associated with outcomes that are favourable to the funder and whether the methods of trials funded by pharmaceutical companies differ from the methods in trials with other sources of support. <b>Methods</b> Medline (January 1966 to December 2002) and Embase (January 1980 to December 2002) searches were supplemented with material identified in the references and in the authors9 personal files. Data were independently abstracted by three of the authors and disagreements were resolved by consensus. <b>Results</b> 30 studies were included. Research funded by drug companies was less likely to be published than research funded by other sources. Studies sponsored by pharmaceutical companies were more likely to have outcomes favouring the sponsor than were studies with other sponsors (odds ratio 4.05; 95% confidence interval 2.98 to 5.51; 18 comparisons). None of the 13 studies that analysed methods reported that studies funded by industry was of poorer quality. <b>Conclusion</b> Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.
Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression
Authors: U. Nitz, O. Gluz, J. Huober, H.H. Kreipe, R.E. Kates, A. Hartmann, R. Erber, M. Scholz, B. Lisboa, S. Mohrmann, V. Möbus, D. Augustin, G. Hoffmann, E. Weiss, S. Böhmer, R. Kreienberg, A. Du Bois, D. Sattler, C. Thomssen, M. Kiechle, F. Jänicke, D. Wallwiener, N. Harbeck, W. Kuhn
Journal: Annals of Oncology (2014)