tbuckley/cabot-search huggingface dataset:
Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease
Authors: René R. Wenzel, Martin Fleisch, Sidney Shaw, Georg Noll, Urs Kaufmann, Rita Schmitt, C. Richard Jones, Martine Clozel, Bernhard Meier, Thomas F. Lüscher
Journal: Circulation (1998)

Background —Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease. Methods and Results —In a double-blind, placebo-controlled randomized study, we investigated the effects of the ET A /ET B endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure ( P &lt;0.05), whereas heart rate increased slightly ( P &lt;0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes ( P &lt;0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels ( P &lt;0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated. Conclusions —Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ET A /ET B endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease.
Bayesian Model Adequacy and Choice in Phylogenetics
Authors: Jonathan P. Bollback
Journal: Molecular Biology and Evolution (2002)

Bayesian inference is becoming a common statistical approach to phylogenetic estimation because, among other reasons, it allows for rapid analysis of large data sets with complex evolutionary models. Conveniently, Bayesian phylogenetic methods use currently available stochastic models of sequence evolution. However, as with other model-based approaches, the results of Bayesian inference are conditional on the assumed model of evolution: inadequate models (models that poorly fit the data) may result in erroneous inferences. In this article, I present a Bayesian phylogenetic method that evaluates the adequacy of evolutionary models using posterior predictive distributions. By evaluating a model's posterior predictive performance, an adequate model can be selected for a Bayesian phylogenetic study. Although I present a single test statistic that assesses the overall (global) performance of a phylogenetic model, a variety of test statistics can be tailored to evaluate specific features (local performance) of evolutionary models to identify sources failure. The method presented here, unlike the likelihood-ratio test and parametric bootstrap, accounts for uncertainty in the phylogeny and model parameters.
Functional Regulatory Divergence of the Innate Immune System in Interspecific Drosophila Hybrids
Authors: Erin M. Hill-Burns, Andrew G. Clark
Journal: Molecular Biology and Evolution (2010)

In order to investigate divergence of immune regulation among Drosophila species, we have engaged in a study of innate immune function in F1 hybrids of Drosophila melanogaster and D. simulans. If pathways have diverged between the species such that incompatibilities have arisen between interacting components of the immune network, we expect the hybrids to display dysregulation of immune genes. We have quantified gene induction in hybrid and parental flies in response to bacterial infection. These results show that although the hybrids do not suffer widespread immune breakdown, they show significantly different regulation of many immune genes relative to the parents. We examine this divergence in terms of additivity and expression differences among genes, observing distinct patterns of dysregulation among functional groups within the pathways of the innate immune system. The functional groups most sensitive to misexpression in the hybrids are the downstream components of the network, indicative of some propagation of dysregulation throughout the immune pathways. Interestingly, this dysregulation does not appear to associate with phenotypic differences in bacterial load after infection in hybrids, possibly highlighting some robustness of function of the innate immune response to perturbations like hybridization.
Cost effectiveness of etanercept (Enbrel) in combination with methotrexate in the treatment of active rheumatoid arthritis based on the TEMPO trial
Authors: G Kobelt
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To estimate the cost effectiveness of combination treatment with etanercept plus methotrexate in comparison with monotherapies in patients with active rheumatoid arthritis (RA) using a new model that incorporates both functional status and disease activity. <b>Methods:</b> Effectiveness data were based on a 2 year trial in 682 patients with active RA (TEMPO). Data on resource consumption and utility related to function and disease activity were obtained from a survey of 616 patients in Sweden. A Markov model was constructed with five states according to functional status (Health Assessment Questionnaire (HAQ)) subdivided into high and low disease activity. The cost for each quality adjusted life year (QALY) gained was estimated by Monte Carlo simulation. <b>Results:</b> Disease activity had a highly significant effect on utilities, independently of HAQ. For resource consumption, only HAQ was a significant predictor, with the exception of sick leave. Compared with methotrexate alone, etanercept plus methotrexate over 2 years increased total costs by €14 221 and led to a QALY gain of 0.38. When treatment was continued for 10 years, incremental costs were €42 148 for a QALY gain of 0.91. The cost per QALY gained was €37 331 and €46 494, respectively. The probability that the cost effectiveness ratio is below a threshold of €50 000/QALY is 88%. <b>Conclusion:</b> Incorporating the influence of disease activity into this new model allows better assessment of the effects of anti-tumour necrosis factor treatment on patients' general wellbeing. In this analysis, the cost per QALY gained with combination treatment with etanercept plus methotrexate compared with methotrexate alone falls within the acceptable range.
Response to Comment on: Bosi et al. Intensive Structured Self-Monitoring of Blood Glucose and Glycemic Control in Noninsulin-Treated Type 2 Diabetes: The PRISMA Randomized Trial. Diabetes Care 2013;36:2887–2894
Authors: Emanuele Bosi, Marina Scavini, Antonio Ceriello, Domenico Cucinotta, Antonio Tiengo, Raffaele Marino, Erminio Bonizzoni, Francesco Giorgino
Journal: Diabetes Care (2013)

We thank Kleefstra et al. (1) for their interest in our study (2). However, we disagree with the assertions regarding the clinical relevance of our findings on the use of self-monitoring of blood glucose (SMBG) in noninsulin-treated type 2 diabetes.

Although the traditional approach to evaluating the efficacy of pharmacological interventions in type 2 diabetes studies is to report between-group differences in HbA1c reductions, this approach may not be appropriate for assessing the impact of “behavior-based” interventions such as structured SMBG. In pharmacological studies, a medication is administered and investigators measure its efficacy in lowering glucose by comparing the reduction in HbA1c values over time in all patients in the intervention and control group (intent-to-treat [ITT] population). Several researchers, erroneously in our opinion, apply this approach …
Accelerated Partial Breast Irradiation As a Part of Breast Conservation Therapy
Authors: Douglas W. Arthur, Frank A. Vicini
Journal: Journal of Clinical Oncology (2005)

Historically, the treatment paradigm for early-stage breast cancer has included treatment of the whole breast. Breast conservation therapy (BCT), irradiation of the whole breast following lumpectomy, requires daily treatment for 6 to 6.5 weeks. Although this is a successful and welltolerated treatment, many patients choose to avoid whole breast irradiation as a result of the time and travel difficulties they are unable to overcome. In response, accelerated partial breast irradiation (APBI) has been investigated as a possible alternative to conventional postlumpectomy treatment. By limiting the volume of breast tissue targeted for treatment, the present data suggests that the radiation dose delivery can be safely accelerated and reduced to a treatment time of 5 days. As a result, APBI has the potential to provide more women with an alternative BCT option. This report reviews the background, concepts supporting APBI, treatment techniques used, available data from single institutional studies, and the details of presently active and planned phase III trials. The compilation of the currently available results supports the national phase III trial (National Surgican Adjuvant Breast and Bowel Project [NSABP] B39/Radiation Therapy Oncology Group [RTOG] 0413), which will begin soon, and practitioners are urged to contribute patients. Both inside and outside the trial, a meticulous quality assurance program is required for optimal results using APBI. The importance of future investigation to establish the limitations of this new treatment approach and to define the role of specific treatment techniques is emphasized.
Specific Relation Between Abdominal Obesity and Early-Phase Hyperglycemia Is Modulated by Hepatic Insulin Resistance in Healthy Older Women
Authors: Loretta DiPietro, James Dziura, Catherine W. Yeckel
Journal: Diabetes Care (2009)

OBJECTIVE To describe the impact of abdominal obesity and hepatic insulin resistance on phase-specific glycemic responses in older women. RESEARCH DESIGN AND METHODS We studied 23 healthy older women (60–88 years old). Abdominal obesity was defined by an abdominal circumference ≥95 cm. Plasma glucose and insulin were measured in response to a 3-h oral glucose tolerance test. Insulin suppression of hepatic glucose production was determined using in vivo clamp techniques. RESULTS Despite identical prevailing insulin concentrations, glucose excursions 30 min postchallenge (but not later) were greater in women with abdominal obesity than in those without (162 ± 19 vs. 132 ± 16 mg/dl; P &amp;lt; 0.01). There was a strong correlation between hepatic glucose production suppression under low-dose insulin infusion and early-phase glucose excursions from the oral glucose tolerance test (r = −0.83; P &amp;lt; 0.001) in women with abdominal obesity, but not in women without (r = 0.44; P &amp;lt; 0.11). CONCLUSIONS Abdominal obesity relates specifically to early-phase hyperglycemia via hepatic insulin resistance, even in healthy older women.
Phase III Randomized, Intergroup Trial Assessing Imatinib Mesylate At Two Dose Levels in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing the Kit Receptor Tyrosine Kinase: S0033
Authors: Charles D. Blanke, Cathryn Rankin, George D. Demetri, Christopher W. Ryan, Margaret von Mehren, Robert S. Benjamin, A. Kevin Raymond, Vivien H.C. Bramwell, Laurence H. Baker, Robert G. Maki, Michael Tanaka, J. Randolph Hecht, Michael C. Heinrich, Christopher D.M. Fletcher, John J. Crowley, Ernest C. Borden
Journal: Journal of Clinical Oncology (2008)

To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily).Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen.Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm.This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.
Demonstration and quantitation of activation of the first complement in human serum
Authors: RJ Ziccardi, NR Cooper
Journal: The Journal of Experimental Medicine (1978)

Activation of the first component of human complement (C1) in human sera can be readily detected in double immunodiffusion studies with anti-C1q, anti- C1r, and anti-C1s as it produces a characteristic pattern quite different from that of precursor C1. Native macromolecular C1 gives a continuous line of precipitation with antisera to C1q, C1r, and C1s in double diffusion studies. After activation of C1 by incubation of serum with complement activators, three major changes occurred in the Ouchterlony pattern. First, spurring of the C1s precipitin line over that of macromolecular C1, indicating release of C1s from C1, was observed with low doses of activator. Release of C1s was quantitated by single radial diffusion and shown to be complete with the highest activator dose examined. Second, C1q was released with larger activator doses as shown also by spurring of the precipitin line due to this component over the remaining macromolecular C1. Third, and most surprising, C1r antigenicity was progressively lost as the activator dose was increased and no C1r line remained with the highest dose of activator tested. This was not true with C1s as there was no change in the total C1s concentration in serum incubated with various activator doses. These observations provide two approaches to the quantitation of C1 activation in human serum. First, C1r and C1s can be quantitated by single radial diffusion. A decrease in the C1r:C1s ratio correlates with activation. Second, C1s released by the activation can be quantitated by single radial diffusion if the agarose contains high concentrations of anti-C1q to confine C1, also containing C1s, to the area near the application well, and lesser concentrations of anti-C1s to permit free C1s to produce a measurable ring. The extent of release of C1s also correlates with activation. These immunochemical techniques to quantitate C1 activation directly inserum do not require specialized reagents. It is hoped that they will be useful in screening pathological sera and in monitoring the status of the complement system in patients.
Orange laser beams are not illusory: The need for a plurality of “real” color ontologies
Authors: Lieven Decock, Jaap van Brakel
Journal: Behavioral and Brain Sciences (2003)

Abstract Reflectance physicalism only provides a partial picture of the ontology of color. Byrne &amp; Hilbert’ account is unsatisfactory because the replacement of reflectance functions by productance functions is ad hoc, unclear, and only leads to new problems. Furthermore, the effects of color contrast and differences in illumination are not really taken seriously: Too many “real” colors are tacitly dismissed as illusory, and this for arbitrary reasons. We claim that there cannot be an all-embracing ontology for color.
Impaired Chronotropic Response to Exercise Stress Testing in Patients With Diabetes Predicts Future Cardiovascular Events
Authors: P. Michael Ho, Thomas M. Maddox, Colleen Ross, John S. Rumsfeld, David J. Magid
Journal: Diabetes Care (2008)

OBJECTIVES— To assess the association between impaired chronotropic response (CR) and adverse events among patients with diabetes referred for exercise treadmill testing (ETT). RESEARCH DESIGN AND METHODS— Impaired CR was defined as achievement of &amp;lt;80% of a patient's heart rate reserve. We used multivariable Cox proportional hazards regression to assess the independent association between impaired CR and adverse outcomes adjusting for demographics, comorbidities, and treadmill variables including the Duke Treadmill score. RESULTS— Of 1,341 patients with diabetes, 35.7% (n = 479) demonstrated impaired CR during ETT. Patients with impaired CR were at increased risk of all-cause mortality, myocardial infarction, or coronary revascularization procedures. In multivariable analyses, impaired CR remained significantly associated with adverse outcomes (hazard ratio 1.53 [95% CI 1.10–2.14]). CONCLUSIONS— Among patients with diabetes, impaired CR is common during ETT and is associated with adverse outcomes. Impaired CR can be used as another noninvasive tool to risk-stratify patients with diabetes following ETT.
Multimedia Medicine. Essentials in Gastroenterology I—Peptic Ulcer
Authors: R G SHIDRAWI
Journal: Gut (1999)

Multimedia Medicine. Essentials in Gastroenterology I—Peptic Ulcer . Harris A. Inflammatory Bowel Disease . Forbes A, Rowlands D. (CD-ROM; £95.00 plus VAT.) London: Royal Society of Medicine Press, 1998. ISBN 1-85315-336-2.

The first in the Multimedia Medicine series of interactive CD-ROMs developed jointly by The Royal Society of Medicine and the Royal College of Physicians, Essentials in Gastroenterology I offers …
Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids
Authors: M. Issar, S. Sahasranaman, P. Buchwald, G. Hochhaus
Journal: European Respiratory Journal (2006)

Due to the high affinity of new inhaled corticosteroids (ICS) towards the glucocorticoid receptor (GR), and because of the similarities between the binding domains of the GR and the progesterone receptor (PR), the present study focused on assessing the relative binding affinities (RBA) of glucocorticoids (systemic and ICS) to PR (RBA PR ). By comparison with the affinities towards the GR (RBA GR ) the binding selectivities were also assessed. In general, the selectivity of the investigated glucocorticoids showed a decreasing trend with increasing lipophilicity. When orally administered, less lipophilic glucocorticoids showed the highest selectivity, with RBA GR /RBA PR ratios of 1,375, 760 and 476 for betamethasone, beclomethasone and dexamethasone, respectively. For ICS, mometasone furoate, the most lipophilic steroid, was the least selective (1.1), followed by beclomethasone monopropionate (9), fluticasone propionate (12), triamcinolone acetonide (18), mometasone (25) and budesonide (44), which shows the highest selectivity among inhaled glucocorticoids. In conclusion, the present study revealed that there are differences in selectivity among commercially available glucocorticoids. Future clinical studies are needed to investigate whether the high affinity of some of the investigated glucocorticoids to the progesterone receptor is of clinical relevance.
Cardiac effects of salbutamol given by air driven nebuliser at home.
Authors: J J Gilmartin, D Veale, A Murray, P C Adams, G J Gibson
Journal: Thorax (1986)

Les resultats montrent l'innocuite du salbutamol nebulise par entrainement a l'air aux doses ordinaires chez des asthmatiques stables. Ceci n'exclut toutefois pas la possibilite d'effets cardiaques indesirables chez un malade qui se degrade et est hypoxique
Hearts From Rodents Exposed to Intermittent Hypoxia or Erythropoietin Are Protected Against Ischemia-Reperfusion Injury
Authors: Zheqing Cai, Dominador J. Manalo, Guo Wei, E. Rene Rodriguez, Karen Fox-Talbot, Huasheng Lu, Jay L. Zweier, Gregg L. Semenza
Journal: Circulation (2003)

Background— Preconditioning phenomena provide evidence for adaptive responses to ischemia that have important implications for treatment/prevention of myocardial infarction. Hypoxia-inducible factor 1 (HIF-1) mediates adaptive transcriptional responses to hypoxia/ischemia. Methods and Results— Exposure of wild-type mice to intermittent hypoxia resulted in protection of isolated hearts against ischemia-reperfusion injury 24 hours later. Cardiac protection induced by intermittent hypoxia was lost in Hif1a +/ − mice heterozygous for a knockout allele at the locus encoding HIF-1α. Erythropoietin (EPO) mRNA expression was induced in kidneys of wild-type mice subjected to intermittent hypoxia, resulting in increased plasma EPO levels. EPO mRNA expression was not induced in Hif1a +/ − mice. EPO administration to rats increased functional recovery and decreased apoptosis in isolated hearts subjected to ischemia-reperfusion 24 hours later. Conclusions— Hearts isolated from rodents subjected to intermittent hypoxia or EPO administration are protected against postischemic injury. Cardiac protection induced by intermittent hypoxia is critically dependent on Hif1a gene dosage. Our data suggest that additional studies to evaluate therapeutic applications of EPO administration are warranted.
Emergence of Smooth Muscle Cell Endothelin B–Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow
Authors: Stephen M. Black, Eugenia Mata-Greenwood, Robert W. Dettman, Boaz Ovadia, Robert K. Fitzgerald, Olaf Reinhartz, Stefan Thelitz, Robin H. Steinhorn, Rene Gerrets, Karen Hendricks-Munoz, Gregory A. Ross, Janine M. Bekker, Michael J. Johengen, Jeffrey R. Fineman
Journal: Circulation (2003)

Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.