tbuckley/cabot-search huggingface dataset:
Active Albuterol or Placebo, Sham Acupuncture, or No Intervention in Asthma
Authors: Michael E. Wechsler, John M. Kelley, Ingrid O.E. Boyd, Stefanie Dutile, Gautham Marigowda, Irving Kirsch, Elliot Israel, Ted J. Kaptchuk
Journal: New England Journal of Medicine (2011)

In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma.In a double-blind, crossover pilot study, we randomly assigned 46 patients with asthma to active treatment with an albuterol inhaler, a placebo inhaler, sham acupuncture, or no intervention. Using a block design, we administered one each of these four interventions in random order during four sequential visits (3 to 7 days apart); this procedure was repeated in two more blocks of visits (for a total of 12 visits by each patient). At each visit, spirometry was performed repeatedly over a period of 2 hours. Maximum forced expiratory volume in 1 second (FEV(1)) was measured, and patients' self-reported improvement ratings were recorded.Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV(1), as compared with approximately 7% with each of the other three interventions (P<0.001). However, patients' reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P<0.001).Although albuterol, but not the two placebo interventions, improved FEV(1) in these patients with asthma, albuterol provided no incremental benefit with respect to the self-reported outcomes. Placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma. However, from a clinical-management and research-design perspective, patient self-reports can be unreliable. An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes. (Funded by the National Center for Complementary and Alternative Medicine.).
S8 Sensitivity of impulse oscillometry and spirometry in the assessment of beta-blocker induced bronchoconstriction and beta-agonist bronchodilatation in mild-to-moderate asthmatics
Authors: P. M. Short, P. A. Williamson, B. J. Lipworth
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> Impulse oscillometry (IOS) is known to be a sensitive marker of airway dysfunction, but is commonly associated with a wider variation than spirometry. The effects of β-blocker induced bronchoconstriction on IOS have not been studied. We compared the sensitivities of IOS and spirometry in the assessment of bronchoconstriction to propranolol and bronchodilatation to salbutamol. <h3>Methods</h3> Mild-to-moderate persistent stable asthmatics taking =1000 μg day budesonide or equivalent, received a single dose of 10 mg or 20 mg of oral propranolol followed by histamine bronchial challenge testing (PC10), with recovery to nebulised salbutamol (5 mg). Spirometry and IOS were measured pre and 2-h post β-blocker, post histamine and 20 min post salbutamol. Pre vs post % change (95% CI) values were compared and standardised response means (SRM) were calculated to assess the "signal to noise" of each test. <h3>Results</h3> Thirteen patients (mean age, 34 years) completed per protocol: 11 received 20 mg of oral propranolol. All IOS indices showed a greater magnitude of response to propranolol (ie, as % change) compared to spirometry. After adjustment for test variability, in response to propranolol, SRM9s for IOS outcomes were better than spirometry with the highest seen with R5 and <i>f</i>res. Likewise for the bronchodilator response to salbutamol the highest SRMs were also seen with R5 and <i>f</i>res (see Abstract S8 table 1). <h3>Conclusions</h3> IOS is a more sensitive response outcome than spirometry with respect to bronchoconstriction to oral propranolol and bronchodilatation post salbutamol in mild-to-moderate asthmatics.
Endobronchial ultrasound-guided transbronchial biopsy with thin bronchoscopy for peripheral pulmonary lesions
Authors: Masahide Oki, Hideo Saka, Chiyoe Kitagawa, Yoshihito Kogure, Shigehisa Kajikawa, Naohiko Murata, Takashi Adachi, Saori Oka, Rie Tsuboi
Journal: European Respiratory Journal (2011)

Introduction:  Endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) using a conventional bronchoscope has the limitation of poor bronchial selectivity because of its large size.   Aims and objectives:  The purpose of this study was to evaluate the diagnostic utility of EBUS-TBB using a thin bronchoscope for peripheral pulmonary lesions.   Methods:  Data prospectively collected from 188 patients with suspected peripheral lesions who underwent EBUS-TBB using a 3.4-mm thin bronchoscope with a 1.7-mm channel and a 1.4-mm radial ultrasonic probe under fluoroscopic guidance were retrospectively analyzed.   Results:  Thirteen patients with endobronchial lesions within the segmental bronchi that were defined as central lesions and 6 patients who did not return to follow-up were excluded from this analysis. Thus, a total of 169 patients (113 men and 56 women; median age, 67 years) with peripheral pulmonary lesions (median size, 28 mm; range, 8 to 70 mm) were included in the final analysis. The mean bronchus level reached with the thin bronchoscope was 4.6th generations. The lesion was localized with EBUS in 151 patients (91%). Diagnostic histologic specimens were obtained in 115 of 169 patients (68%: 48% [81% for lesions >30 mm, 50% for lesions >20 to ≤30 mm, and 17% for lesions ≤20 mm] for benign lesions and 76% [85% for lesions >30 mm, 70% for lesions >20 to ≤30 mm, and 65% for lesions ≤20 mm] for malignant lesions). Five complications (3%) occurred: 3 pneumothoraces, 1 pneumonia, and 1 moderate bleeding.   Conclusion:  EBUS-TBB using a thin bronchoscope is an accurate method for the diagnosis of peripheral pulmonary lesions, especially malignant lesions.
Age-specific and sex-specific mortality in 187 countries, 1970–2010: a systematic analysis for the Global Burden of Disease Study 2010
Authors: Haidong Wang, Laura Dwyer-Lindgren, Katherine T Lofgren, Julie Knoll Rajaratnam, Jacob R Marcus, Alison Levin-Rector, Carly E Levitz, Alan D Lopez, Christopher JL Murray
Journal: The Lancet (2012)
Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias
Authors: A Verkerk
Journal: Cardiovascular Research (2001)

Objective: The delayed phase of ventricular arrhythmias during acute ischemia (phase-1b arrhythmia) is associated with depletion of catecholamines and cell-to-cell uncoupling between depressed depolarized intramural ischemic region and surviving cells in subepicardium and subendocardium. In the present study we determined the effects of uncoupling and catecholamines on development of proarrhythmic afterdepolarizations. Methods: Depressed depolarized ischemic region was simulated by a passive electronic circuit with a potential of −73, −53, −33 or −13 mV. Using patch-clamp methodology, single sheep Purkinje and ventricular cells were coupled to the simulated ischemic region via a variable conductance. By varying coupling conductance, we were able to selectively study the effects of various degrees of uncoupling. Results: At strong coupling, cells were inexcitable and depolarized to potentials near those of the simulated ischemic region. Excitability, action potential duration and resting potential increased with progressive uncoupling. In a critical range of uncoupling, ventricular and 'high-plateau' Purkinje cells developed early afterdepolarizations when the potential of the simulated ischemic region was −13 mV. Norepinephrine (1 μM) frequently induced early and delayed afterdepolarizations in both ventricular and Purkinje cells, but these afterdepolarizations were only present during uncoupling when the potential of the simulated ischemic region was −33 mV or more positive. Conclusions: In a critical range of uncoupling, afterdepolarizations were present when the potential of the simulated ischemic region was −33 or −13 mV, suggesting that triggered activity plays a role in phase-1b arrhythmias when surviving layers uncouple from a highly depolarized intramural ischemic region.
Phase I Clinical and Pharmacokinetic Study of BMS-247550, a Novel Derivative of Epothilone B, in Solid Tumors
Authors: Sridhar Mani, Hayley McDaid, Anne Hamilton, Howard Hochster, Marvin B. Cohen, Dineo Khabelle, Tom Griffin, David E. Lebwohl, Leonard Liebes, Franco Muggia, Susan Band Horwitz
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks. Experimental Design: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550. Results: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m2. At 50 mg/m2, 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m2 (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3–4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m2, the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1–2 neuropathy was observed in all patients enrolled and treated at 40 mg/m2. Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naïve breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m2 (recommended Phase II dose) dose level were 21 liters/h/m2, 826 liters/m2, and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar. Conclusions: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m2, although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study.
Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib
Authors: Claudia Groß, Katja Steiger, Sufyan Sayyed, Irina Heid, Annette Feuchtinger, Axel Walch, Julia Heß, Kristian Unger, Horst Zitzelsberger, Marcus Settles, Anna Melissa Schlitter, Juliane Dworniczak, Jennifer Altomonte, Oliver Ebert, Markus Schwaiger, Ernst Rummeny, Andreas Steingötter, Irene Esposito, Rickmer Braren
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models. Experimental Design: DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors. Results: Histologically and biochemically confirmed liver damage resulted in increased 18F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1–3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only. Conclusions: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies. Clin Cancer Res; 21(19); 4440–50. ©2015 AACR. See related commentary by Weber et al., p. 4254
Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines
Authors: Denise Niewerth, Gertjan JL Kaspers, Yehuda G Assaraf, Johan van Meerloo, Christopher J Kirk, Janet Anderl, Jonathan L Blank, Peter M van de Ven, Sonja Zweegman, Gerrit Jansen, Jacqueline Cloos
Journal: Journal of Hematology & Oncology (2014)

Despite encouraging results with the proteasome inhibitor bortezomib in the treatment of hematologic malignancies, emergence of resistance can limit its efficacy, hence calling for novel strategies to overcome bortezomib-resistance. We previously showed that bortezomib-resistant human leukemia cell lines expressed significantly lower levels of immunoproteasome at the expense of constitutive proteasomes, which harbored point mutations in exon 2 of the PSMB5 gene encoding the β5 subunit. Here we investigated whether up-regulation of immunoproteasomes by exposure to interferon-γ restores sensitivity to bortezomib in myeloma and leukemia cell lines with acquired resistance to bortezomib. RPMI-8226 myeloma, THP1 monocytic/macrophage and CCRF-CEM (T) parental cells and sub lines with acquired resistance to bortezomib were exposed to Interferon-γ for 24-48 h where after the effects on proteasome subunit expression and activity were measured, next to sensitivity measurements to proteasome inhibitors bortezomib, carfilzomib, and the immunoproteasome selective inhibitor ONX 0914. At last, siRNA knockdown experiments of β5i and β1i were performed to identify the contribution of these subunits to sensitivity to proteasome inhibition. Statistical significance of the differences were determined using the Mann-Whitney U test. Interferon-γ exposure markedly increased immunoproteasome subunit mRNA to a significantly higher level in bortezomib-resistant cells (up to 30-fold, 10-fold, and 6-fold, in β1i, β5i, and β2i, respectively) than in parental cells. These increases were paralleled by elevated immunoproteasome protein levels and catalytic activity, as well as HLA class-I. Moreover, interferon-γ exposure reinforced sensitization of bortezomib-resistant tumor cells to bortezomib and carfilzomib, but most prominently to ONX 0914, as confirmed by cell growth inhibition studies, proteasome inhibitor-induced apoptosis, activation of PARP cleavage and accumulation of polyubiquitinated proteins. This sensitization was abrogated by siRNA silencing of β5i but not by β1i silencing, prior to pulse exposure to interferon-γ. Downregulation of β5i subunit expression is a major determinant in acquisition of bortezomib-resistance and enhancement of its proteasomal assembly after induction by interferon-γ facilitates restoration of sensitivity in bortezomib-resistant leukemia cells towards bortezomib and next generation (immuno) proteasome inhibitors.
Effective Reduction of Gastric Cancer Risk With Regular Use of Nonsteroidal Anti-Inflammatory Drugs in <i>Helicobacter Pylori</i>–Infected Patients
Authors: Chun-Ying Wu, Ming-Shiang Wu, Ken N. Kuo, Chang-Bi Wang, Yi-Ju Chen, Jaw-Town Lin
Journal: Journal of Clinical Oncology (2010)

Nonsteroidal anti-inflammatory drugs (NSAIDs) play protective roles in gastric carcinogenesis. However, the interaction between NSAIDs and Helicobacter pylori (H pylori) infection and the number needed to treat to prevent gastric cancer remains unclear.We conducted a nationwide retrospective cohort study based on data from the Taiwan National Health Insurance Database. Hospitalized patients with a primary diagnosis of peptic ulcer disease were selected. Overall, 52,161 patients were divided into non-NSAID user and regular NSAID user cohorts. Standardized incidence ratios (SIRs), cumulative incidences, and hazard ratios (HRs) were calculated.Patients with peptic ulcers who never used NSAIDs had higher risk of gastric cancer compared with the general population (SIR, 2.11; 95% CI, 2.07 to 2.15), but regular NSAID use conferred lower risk (SIR, 0.79; 95% CI, 0.77 to 0.81). The protective role of NSAID use was observed in patients with gastric ulcer, but not in patients with non-H pylori-associated duodenal ulcer. On multivariate analysis, regular NSAID use was an independent protective factor for gastric cancer development (HR, 0.79 for each incremental year; P < .001), especially in H pylori-associated patients (HR, 0.52 for each incremental year; P < .001). Among patients with H pylori-infected gastric ulcers, the NNT to prevent a gastric cancer was 50.Regular NSAID use may be a feasible way to prevent gastric cancer, at least in patients with gastric ulcers, and especially in H pylori-infected subjects.
Recruitment to a Clinical Trial Improves Glycemic Control in Patients With Diabetes
Authors: Edwin A.M. Gale, Scott D. Beattie, Jinghui Hu, Veikko Koivisto, Meng H. Tan
Journal: Diabetes Care (2007)

We assessed the effect upon A1C of recruitment to a clinical trial in patients with diabetes who had been screened and interviewed to determine eligibility but whose therapy was otherwise unchanged.Eligible trials were selected from the global program of an insulin manufacturer. Included were studies in which patients were seen on a single screening visit, pharmaceutical therapy was not altered before randomization, and A1C was measured in a central laboratory at both screening and randomization. Three trials involving patients with type 1 diabetes (n = 429) and three trials involving patients with type 2 diabetes (n = 611) were identified for analysis. The main outcome measure was change in A1C. Separate regression equations on the change in A1C were fitted for type 1 and type 2 diabetes and included effects of baseline A1C and the interval between the screening and randomization visits.A1C changed by -0.13% (range +0.09 to -0.26%) in those with type 1 diabetes at a median of 28 days and by -0.16% (-0.14 to -0.27%) for those with type 2 diabetes at a median of 14 days. The mean change in A1C in those with an interval of >or=28 days was -0.24% for those with type 1 diabetes and -0.23% for those with type 2 diabetes. The reduction was proportional to initial A1C, with large decreases in those with the poorest initial control but no overall change in those at or below the 10th percentile of A1C.Recruitment to a clinical trial, independent of any therapeutic intervention, produces improvements in glucose control.
Early assessment of severity in acute pancreatitis.
Authors: R C Williamson
Journal: Gut (1984)

Early assessment of severity in acute pancreatitisIn no other acute abdominal condition is the outcome so unpredictable at the outset.Of any four patients with acute pancreatitis, three will rapidly improve with simple supportive therapy, while the fourth develops one or more serious complications of the disease and stands about a one-in-three chance of dying.`Abetter understanding of the pathophysiology of pancreatitis, notably the fluid and oxygen requirements, has led to an overall mortality rate of around 10% in most prospective series.1 3 5 A recent study has shown, however, that a third of fatal cases are first diagnosed at necropsy.When these are included, the overall mortality rate is 20%.6Separation of patients with good and bad prognoses at the time of admission to hospital is valuable for at least three reasons.First, those with severe pancreatitis need much more vigorous resuscitation and monitoring, including admission to an intensive therapy area, urethral catheterisation and a central venous line.Acute pancreatitis is quite a common emergency and the routine adoption of these measures would be costly.Second, aggresive treatments such as peritoneal lavage, endoscopic papillotomy or urgent pancreatectomy might be justified in patients with a poor outlook, but scarcely so in the majority whose mild attacks quickly abort.Third, general acceptance of the criteria of severity would facilitate international comparisons of prospective studies.In the present issue a group of surgeons and statisticians report their success in predicting the severity of an attack of acute pancreatitis by means of laboratory tests performed within 48 hours of the-patients' arrival at the Glasgow Royal Infirmary.7In evaluating their work we need to define severe pancreatitis, to compare the many methods recommended for its detection and to determine whether the results repay the effort expended.As early operation is one option in treating acute gall stone pancreatitis, we must also consider the identification of this particular group of patients. DefinitionsAs pancreatic tissue is seldom available before death, the diagnosis of acute pancreatitis rests on appropriate clinical features with hyperamylasaemia in at least 80% of cases and on laparotomy findings in the remainder.1 3 8 There are several methods of measuring serum amylase, each with its own units; non-pancreatic isoenzymes can be excluded by electrophoresis.9The diagnostic threshold for serum amylase is controversial.It is generally set at a higher level in Britain (1000-2000 IU/1), where gall stones predominate,' 5 10 than in the United States 1331
Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis
Authors: Sabine Cepok, Dun Zhou, Rajneesh Srivastava, Stefan Nessler, Susanne Stei, Konrad Büssow, Norbert Sommer, Bernhard Hemmer
Journal: Journal of Clinical Investigation (2005)

MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8+ T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.