tbuckley/cabot-search huggingface dataset:
Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events
Authors: Eric Bateman, Harold Nelson, Jean Bousquet, Kenneth Kral, Laura Sutton, Hector Ortega, Steven Yancey
Journal: Annals of Internal Medicine (2008)

Background: Recent analyses have suggested an increased risk for serious asthma-related adverse events in patients receiving long-acting β-agonists. Purpose: To examine whether the incidences of severe asthma-related events (hospitalizations, intubations, deaths, and severe exacerbations) differ in persons receiving salmeterol plus inhaled corticosteroids compared with inhaled corticosteroids alone. Data Sources: The GlaxoSmithKline (Research Triangle Park, North Carolina) database, MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systemic Reviews (1982 to September 2007) were searched without language restriction. Study Selection: Randomized, controlled trials reported in any language that compared inhaled corticosteroids plus salmeterol (administered as fluticasone propionate/salmeterol by means of a single device or concomitant administration of inhaled corticosteroids and salmeterol) versus inhaled corticosteroids alone in participants with asthma. Data Extraction: Three physicians independently reviewed and adjudicated blinded case narratives on serious adverse events that were reported in the GlaxoSmithKline trials. Data Synthesis: Data from 66 GlaxoSmithKline trials involving a total of 20 966 participants with persistent asthma were summarized quantitatively. The summary risk difference for asthma-related hospitalizations from these trials was 0.0002 (95% CI, −0.0019 to 0.00231; P = 0.84) for participants receiving inhaled corticosteroids plus salmeterol (n = 35 events) versus those receiving inhaled corticosteroids alone (n = 34 events). One asthma-related intubation and 1 asthma-related death occurred among participants receiving inhaled corticosteroids with salmeterol; no such events occurred among participants receiving inhaled corticosteroids alone. A subset of 24 trials showed a decreased risk for severe asthma-related exacerbations for inhaled corticosteroids plus salmeterol versus inhaled corticosteroids alone (risk difference, −0.025 [CI, −0.036 to −0.014]; P <0.001). Limitations: The included trials involved selected patients who received careful follow-up. Only 26 trials were longer than 12 weeks. Few deaths and intubations limited the ability to measure risk for these outcomes. Conclusion: Salmeterol combined with inhaled corticosteroids decreases the risk for severe exacerbations, does not seem to alter the risk for asthma-related hospitalizations, and may not alter the risk for asthma-related deaths or intubations compared with inhaled corticosteroids alone.
Mouse Models of Nitric Oxide Synthase Deficiency
Authors: PAUL L. HUANG
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Knockout mice for each of the three nitric oxide (NO) synthase (NOS) genes have been generated. Their phenotypes reflect the roles of each NOS isoform in physiologic and pathologic processes. This article reviews how neuronal NOS (nNOS) and endothelial NOS (eNOS) knockout mice have contributed to our knowledge of the roles of NO in cerebral ischemia, cardiovascular processes, and the autonomic nervous system. In some instances, the effects of NO produced by one isoform antagonize the effects of NO produced by another isoform. For example, after cerebral ischemia, the nNOS isoform is involved in tissue injury, whereas the eNOS isoform is important in maintaining blood flow. All three isoforms are expressed in the respiratory tract, but only the nNOS isoform appears to be involved in modulating airway responsiveness and only the inducible NOS isoform appears to respond to antigen stimulation. In the cardiovascular system, endothelial NO is important for vascular tone, systolic and diastolic cardiac function, vascular proliferative responses to injury, platelet aggregation, and hemostasis.
How Large a Training Set is Needed to Develop a Classifier for Microarray Data?
Authors: Kevin K. Dobbin, Yingdong Zhao, Richard M. Simon
Journal: Clinical Cancer Research (2008)

A common goal of gene expression microarray studies is the development of a classifier that can be used to divide patients into groups with different prognoses, or with different expected responses to a therapy. These types of classifiers are developed on a training set, which is the set of samples used to train a classifier. The question of how many samples are needed in the training set to produce a good classifier from high-dimensional microarray data is challenging.We present a model-based approach to determining the sample size required to adequately train a classifier.It is shown that sample size can be determined from three quantities: standardized fold change, class prevalence, and number of genes or features on the arrays. Numerous examples and important experimental design issues are discussed. The method is adapted to address ex post facto determination of whether the size of a training set used to develop a classifier was adequate. An interactive web site for performing the sample size calculations is provided.We showed that sample size calculations for classifier development from high-dimensional microarray data are feasible, discussed numerous important considerations, and presented examples.
Microbial aetiology of community-acquired pneumonia and its relation to severity
Authors: C. Cilloniz, S. Ewig, E. Polverino, M. A. Marcos, C. Esquinas, A. Gabarrus, J. Mensa, A. Torres
Journal: Thorax (2011)

<h3>Background</h3> The distribution of the microbial aetiology and mortality of community-acquired pneumonia (CAP) was investigated in relation to the clinical setting and severity scores (pneumonia severity index (PSI) and confusion, blood urea nitrogen, respiratory rate, blood pressure, age (CURB-65)). <h3>Methods</h3> 3523 patients with CAP were included (15% outpatients, 85% inpatients). The distribution of the microbial aetiology in relation to the clinical setting and severity scores (PSI, CURB-65) and the relative mortality of different aetiologies across the severity scores were analysed. <h3>Results</h3> The aetiology was established in 1463 patients (42%), of whom 257 died (7%). The ranking of aetiologies varied according to site of care, with increasing frequency of <i>Streptococcus pneumoniae</i> and mixed aetiologies and decreasing frequency of atypical pathogens in hospitalised patients and those in ICUs. The distribution of aetiologies according to severity scores showed corresponding patterns; however, the severity scores were more sensitive to Gram-negative enteric bacilli (GNEB) and <i>Pseudomonas aeruginosa</i> and less sensitive in identifying mixed aetiologies as moderate- and high-risk conditions. Mortality rates according to aetiology and severity scoring showed increasing mortality rates for all pathogens except atypical pathogens. <i>S pneumoniae</i> had the highest number of deaths while GNEB, <i>P aeruginosa</i>, <i>Staphylococcus aureus</i> and mixed aetiologies had the highest mortality rates. <i>Legionella pneumophila</i> was similarly distributed according to site of care and prognostic scores. <h3>Conclusions</h3> CAP due to atypical bacterial pathogens is recognised both clinically and by severity scoring as a low-risk condition. Severity scores are more sensitive in identifying patients with GNEB and <i>P aeruginosa</i> as moderate- and high-risk aetiologies whereas mixed aetiologies may be underestimated.
In Vivo Tracking of Stem Cells for Clinical Trials in Cardiovascular Disease
Authors: John V. Frangioni, Roger J. Hajjar
Journal: Circulation (2004)

Various stem cells hold promise for the treatment of human cardiovascular disease. Regardless of stem cell origin, future clinical trials will require that the location and number of such cells be tracked in vivo, over long periods of time. The problem of tracking small numbers of cells in the body is a difficult one, and an optimal solution does not yet exist. We review the many contrast agents and detectors that have been proposed for stem cell tracking during clinical trials, define the characteristics of an ideal imaging technology, and suggest future directions for research.
The lung in the antiphospholipid syndrome
Authors: G Espinosa, R Cervera, J Font, R A Asherson
Journal: Annals of the Rheumatic Diseases (2002)

Patients with antiphospholipid syndrome (APS) may develop a broad spectrum of pulmonary disease. Pulmonary thromboembolism and pulmonary hypertension are the most common complications, but microvascular pulmonary thrombosis, pulmonary capillaritis, and alveolar haemorrhage have also been reported. Clinicians should seriously consider these types of vascular injury when evaluating patients with APS who present with dyspnoea, fever, and infiltrates on chest radiography.
Alternatively Spliced IS6 Segments of the α <sub>1C</sub> Gene Determine the Tissue-Specific Dihydropyridine Sensitivity of Cardiac and Vascular Smooth Muscle L-Type Ca <sup>2+</sup> Channels
Authors: Andrea Welling, Andreas Ludwig, Stephanie Zimmer, Norbert Klugbauer, Veit Flockerzi, Franz Hofmann
Journal: Circulation Research (1997)

Dihydropyridines (DHPs) block the vascular smooth muscle L-type Ca2+ channel at lower concentrations than the cardiac Ca2+ channel, although their alpha 1 subunit, which binds the DHPs, is derived from the same gene. This alpha 1C gene gives rise to several splice variants, among which the alpha 1C-b variant is affected by lower concentrations of nisoldipine than the alpha 1C-a variant. Functional expression of chimeras of alpha 1C-a and alpha 1C-b subunits demonstrated that the transmembrane segment IS6 is responsible for the different dihydropyridine sensitivity. Northern blot analysis showed that transcripts coding for the IS6 segment of the alpha 1C-a subunit were expressed in heart but not in aorta, whereas the IS6 segment of the alpha 1C-b subunit was expressed predominantly in vascular smooth muscle. In situ hybridization of rat heart sections confirmed this expression pattern of IS6 alpha 1C-a and IS6 alpha 1C-b in ventricular and smooth muscle myocytes, respectively. These results suggest that the different dihydropyridine sensitivities of cardiac and vascular L-type Ca2+ channels are caused at least partially by the tissue-specific expression of alternatively spliced IS6 segments of the alpha 1C gene.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral MAPK/ERK Kinase Inhibitor PD-0325901 in Patients with Advanced Cancers
Authors: Patricia M. LoRusso, Smitha S. Krishnamurthi, John J. Rinehart, Lisle M. Nabell, Lisa Malburg, Paul B. Chapman, Samuel E. DePrimo, Steven Bentivegna, Keith D. Wilner, Weiwei Tan, Alejandro D. Ricart
Journal: Clinical Cancer Research (2010)

To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients.Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics.Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving >or=15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the dose-limiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease >or=4 months. PD-0325901 exposure was generally dose proportional. Doses >or=2 mg BID consistently caused >or=60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (>or=50%) in Ki-67.PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use.
Circulating Eosinophil/Basophil (Eo/B) Progenitors at One Year of Age Positively Correlate with Atopic Eczema and Indoor Chemical Exposure in the LINA Study
Authors: K. Weisse, I. Lehmann, G. Herberth, T. Kohajda, S. Röder, M. Borte, D. Heroux, J. Denburg
Journal: Journal of Allergy and Clinical Immunology (2011)
Benefits of Modest Weight Loss in Improving Cardiovascular Risk Factors in Overweight and Obese Individuals With Type 2 Diabetes
Authors: Rena R. Wing, Wei Lang, Thomas A. Wadden, Monika Safford, William C. Knowler, Alain G. Bertoni, James O. Hill, Frederick L. Brancati, Anne Peters, Lynne Wagenknecht
Journal: Diabetes Care (2011)

Overweight and obese individuals are encouraged to lose 5-10% of their body weight to improve cardiovascular disease (CVD) risk, but data supporting this recommendation are limited, particularly for individuals with type 2 diabetes.We conducted an observational analysis of participants in the Look AHEAD (Action For Health in Diabetes) study (n=5,145, 40.5% male, 37% from ethnic/racial minorities) and examined the association between the magnitude of weight loss and changes in CVD risk factors at 1 year and the odds of meeting predefined criteria for clinically significant improvements in risk factors in individuals with type 2 diabetes.The magnitude of weight loss at 1 year was strongly (P<0.0001) associated with improvements in glycemia, blood pressure, triglycerides, and HDL cholesterol but not with LDL cholesterol (P=0.79). Compared with weight-stable participants, those who lost 5 to <10% ([means±SD] 7.25±2.1 kg) of their body weight had increased odds of achieving a 0.5% point reduction in HbA1c (odds ratio 3.52 [95% CI 2.81-4.40]), a 5-mmHg decrease in diastolic blood pressure (1.48 [1.20-1.82]), a 5-mmHg decrease in systolic blood pressure (1.56 [1.27-1.91]), a 5 mg/dL increase in HDL cholesterol (1.69 [1.37-2.07]), and a 40 mg/dL decrease in triglycerides (2.20 [1.71-2.83]). The odds of clinically significant improvements in most risk factors were even greater in those who lost 10-15% of their body weight.Modest weight losses of 5 to <10% were associated with significant improvements in CVD risk factors at 1 year, but larger weight losses had greater benefits.
The role of surface IgD in the response to thymic-independent antigens.
Authors: I M Zitron, D E Mosier, W E Paul
Journal: The Journal of Experimental Medicine (1977)

An alloanti-delta antibody was prepared by immunizing C57BL/Ka mice with BALB/c spleen cells. Its specificity for delta-chain was demonstrated by immunoprecipitation and SDS-PAGE of 125I-labeled membrane proteins from BC8 spleen cells. BC8 mice possess C57BL/Ka "background" genes and BALB/c IgH genes. The anti-delta reagent without complement inhibited the primary in vitro anti-TNP antibody response to TNP-AECM-Ficoll by BC8 spleen cells, although it had no effect of the anti-TNP response of congenic C57BL/Ka spleen cells, which lack the delta-allotype identified by this antibody. On the other hand, the anti-delta antibody had no effect on the anti-TNP response of BC8 spleen cells to TNP-BA, except at limiting antigen concentrations. Both TNP-AECM-Ficoll and TNP-BA are T-I antigens, but they differ in that TNP-AECM-Ficoll fails to stimulate in vitro responses by immunologically defective CBA/N and neonatal spleen cells whereas TNP-BA can cause responses from both these animals. These results suggest that the IgD receptor is critical to T-I antibody responses initiated by TNP-AECM-Ficoll but that it is not required for T-I responses stimulated by TNP-BA.
Tandem Mass Spectrometry: The Competitive Edge for Pharmacology
Authors: C Fenselau
Journal: The Annual Review of Pharmacology and Toxicology (1992)

The notion of connecting two mass spectrometers to examine the chemistry of purified ion species was realized experimentally as early as 1954 (1), and ten years later instruments of this complexity had been constructed in five labora­ tories worldwide (2). The utility of collisions of fast-moving ionswith neutral target atoms to promote fragmentation was introduced by Jennings in 1968 (3). The analytical value of collisional activation and tandem mass spec­ trometry for components of mixtures received attention through the next decade (e. g. 4-6), and was demonstrated with a variety of instrumental configurations. The commercial availability around 1980 of tandem mass spectrometers based on three-sector analyzers and on three quadrupole an­ alyzers, and around 1985 of four-sector tandem instruments and of hybrids comprising two sectors and two quadrupole modules, rapidly increased the use of tandem (MSMS) techniques in analytical applications (7-14). Simply stated, these provide (a) a separation technique based on mass that removes chemical contamination (e. g. coelutants in HPLC peaks or matrix ions desorbed by fast atom bombardment) and separates components of mixtures, (b) reproducible and extensive fragmentation, and (c) increased selectivity through selected reaction monitoring. The selectivity and reliability provided by these powerful hyphenated instruments are compellingly relevant to prob­ lems in pharmacology. Applications of MSMS were included in about 100 papers in pharmacological journals in 1990.
Asymptomatic Reactivation of Herpes Simplex Virus in Women after the First Episode of Genital Herpes
Authors: David M. Koelle, Jacqueline Benedetti, Andria Langenberg, Lawrence Corey
Journal: Annals of Internal Medicine (1992)

Objective: To determine frequency, anatomic site, and host factors associated with asymptomatic shedding of herpes simplex virus after initial episodes of genital herpes. Design: Cohort study with follow-up for a median of 63 weeks. Setting: Referral clinic. Patients: Women (306) with first episode of herpes; 43 had primary herpes simplex virus type 1, and 227 and 36 had primary and nonprimary herpes simplex virus type 2, respectively. Measurements: Cultures were obtained for herpes simplex virus every 4 to 6 weeks at times in which genital lesions and symptoms were not present. Main Results: Asymptomatic shedding was detected among 11.9%, 18.3%, and 22.9% of women with primary herpes simplex virus type 1, primary HSV type 2, and nonprimary HSV type 2, respectively. Among patients with type 2 infection, previous type 1 antibody was associated with a lower rate of asymptomatic vulvar shedding. Asymptomatic cervical shedding was 3 times more frequent during the first three months after resolution of primary type 2 disease than during later time periods. In contrast, the rate of symptomatic recurrent herpes did not change over time. Conclusions: Asymptomatic genital herpes simplex type 2 is more common than type 1. Asymptomatic genital shedding occurs more often during the first 3 months after acquisition of primary type 2 disease than during later periods. Patients with HSV type 2 should be advised of this high early rate of asymptomatic shedding and of potential transmission to sexual partners.
Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants
Authors: Rajesh A. Shenoi, Manu Thomas Kalathottukaren, Richard J. Travers, Benjamin F. L. Lai, A. Louise Creagh, Dirk Lange, Kai Yu, Marie Weinhart, Ben H. Chew, Caigan Du, Donald E. Brooks, Cedric J. Carter, James H. Morrissey, Charles A. Haynes, Jayachandran N. Kizhakkedathu
Journal: Science Translational Medicine (2014)

Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the only clinically approved antidote to heparin, has shown adverse effects and ineffectiveness against low-molecular weight heparins and fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules and recombinant proteins have several drawbacks including limited efficacy, toxicity, immunogenicity, and high cost. Thus, there is an unmet clinical need for safer, rapid, predictable, and cost-effective anticoagulant-reversal agents for all clinically used heparins. We report a design strategy for a fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use of multivalent presentation of branched cationic heparin binding groups (HBGs). Optimization of the UHRA design was aided by isothermal titration calorimetry studies, biocompatibility evaluation, and heparin neutralization analysis. By controlling the scaffold's molecular weight, the nature of the protective shell, and the presentation of HBGs on the polymer scaffold, we arrived at lead UHRA molecules that completely neutralized the activity of all clinically used heparins. The optimized UHRA molecules demonstrated superior efficacy and safety profiles and mitigated heparin-induced bleeding in animal models. This new polymer therapeutic may benefit patients undergoing high-risk surgical procedures and has potential for the treatment of anticoagulant-related bleeding problems.
Parenteral Nutrition in Low-Birth-Weight Infants
Authors: W C Heird, M R Gomez
Journal: Annual Review of Nutrition (1996)

Parenteral nutrition has been used in the nutritional management of low-birth-weight infants for the past 25 years. Nonetheless, many aspects of the technique still are not completely understood. Further, Other aspects that are reasonably well understood frequently are not applied in clinical practice. As a result, infants requiring this therapy frequently do not benefit maximally from it. Some of the important issues concerning this technique are discussed, and some of the important questions that need to be addressed are identified. Answers to many of these important questions are necessary to further enhance the benefits and diminish the undesired consequences of this therapy for infants who require it.