tbuckley/cabot-search huggingface dataset:
Strategies for reducing treatment in mild persistent asthma
Authors: Andrew R L Medford
Journal: Thorax (2007)

▴ American Lung Association Asthma Clinical Research Centers, Peters SP, Anthonisen N, et al . Randomised comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med2007;356:2027–39.

[OpenUrl][1][CrossRef][2][PubMed][3]



Inhaled corticosteroids (ICS) are standard treatment for persistent asthma but it is important to “step down” treatment when possible to minimise adverse effects. The optimal strategy for reducing treatment in mild asthma has not yet been determined.

Five hundred patients with mild asthma (pre-bronchodilator FEV1 >60% predicted) well controlled on 4–6 weeks fluticasone 100 μg twice …

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Taurocholate induced gastric mucosal injuries in experimental portal hypertension.
Authors: W J Angerson, J G Geraghty, D C Carter
Journal: Gut (1992)

The susceptibility of the gastric mucosa to injury by topical sodium taurocholate (40 mmol/l) in hydrochloric acid (150 mmol/l) was studied in prehepatic and cirrhotic rat models of portal hypertension. Portal venous pressure was increased in rats who had undergone partial portal vein ligation compared with rats that had undergone sham operation on days 3, 7, and 28 after operation (20.6 (0.9), 14.8 (0.8), and 11.3 (0.5) mm Hg v 7.3 (0.7), 7.3 (0.6), and 8.2 (0.2) mmHg respectively (mean (SEM)). At day 3 gastric mucosal injuries were increased in rats with partial portal vein ligation compared with sham operated rats (55.3 (9.4) vs 22.3 (10.5) mm2, p = 0.006), but at the later time intervals there was no significant difference in injuries between the two groups. In rats with carbon tetrachloride induced hepatic cirrhosis, portal pressure was increased (15.6 (1.0) v 6.7 (0.6) mmHg), but again there was no significant difference in mucosal injuries relative to control animals. We conclude that gastric mucosal defence mechanisms are impaired in acute but not chronic experimental portal hypertension.
An fMRI Auditory Oddball Study of Combined-Subtype Attention Deficit Hyperactivity Disorder
Authors: Michael C. Stevens, Godfrey D. Pearlson, Kent A. Kiehl
Journal: American Journal of Psychiatry (2007)

Studies of attention deficit hyperactivity disorder (ADHD) have reliably found reduced amplitude event-related potentials (ERPs) measuring attention-related brain function, indicating impairment in the brain's ability to automatically orient attention to odd or novel environmental stimuli and to represent that information in working memory. However, the relationship between abnormal neurocognition and dysfunction in specific brain regions in ADHD remains unclear.The authors used functional magnetic resonance imaging (fMRI) to identify brain regions with abnormal hemodynamic activity during processing of target and novelty oddball stimuli that engage attention. Forty-six boys 11-18 years of age participated in the study, including 23 diagnosed as having ADHD with hyperactivity and impulsivity (combined type) and 23 demographically matched control subjects. Event-related fMRI data were collected while participants performed a three-stimulus auditory oddball task. Hemodynamic activity was compared between ADHD participants and control subjects in brain regions previously linked to P3 ERPs.Participants with ADHD showed deficits in brain activity elicited by infrequent attentionally engaging stimuli in regions associated with attentional orienting and working-memory cognitive processes. These deficits co-occurred with highly variable and slow task performance.This study links ADHD attentional orienting and working-memory deficits to dysfunction in specific cortical brain regions. The results indicate that ADHD pathophysiology impairs brain systems that are important for allocating attention and using cognitive representations to guide cognition and behavior. Attention-related neural dysfunction is thus an important factor to consider in neurobiological theories of ADHD.
Targeting Stat3 Abrogates EGFR Inhibitor Resistance in Cancer
Authors: Malabika Sen, Sonali Joyce, Mary Panahandeh, Changyou Li, Sufi M. Thomas, Jessica Maxwell, Lin Wang, William E. Gooding, Daniel E. Johnson, Jennifer R. Grandis
Journal: Clinical Cancer Research (2012)

Abstract Purpose: EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and -independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor–resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting. Experimental Design: pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab-sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC50 concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression. Results: Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies. Conclusions: These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy. Clin Cancer Res; 18(18); 4986–96. ©2012 AACR.
A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer
Authors: Thomas Powles, Matthew Wheater, Omar Din, Thomas Geldart, Ekaterini Boleti, Andrew Stockdale, Santhanam Sundar, Angus Robinson, Imtiaz Ahmed, Akhila Wimalasingham, Wendy Burke, Shah-Jalal Sarker, Syed Hussain, Christy Ralph
Journal: European Urology (2015)
Artificial neural networks: Current status in cardiovascular medicine
Authors: Dipti Itchhaporia, Peter B. Snow, Robert J. Almassy, William J. Oetgen
Journal: Journal of the American College of Cardiology (1996)

Artificial neural networks are a form of artificial computer intelligence that have been the subject of renewed research interest in the last 10 years. Although they have been used extensively for problems in engineering, they have only recently been applied to medical problems, particularly in the fields of radiology, urology, laboratory medicine and cardiology. An artificial neural network is a distributed network of computing elements that is modeled after a biologic neural system and may be implemented as a computer software program. It is capable of identifying relations in input data that are not easily apparent with current common analytic techniques. The functioning artificial neural network's knowledge is built on learning and experience from previous input data. On the basis of this prior knowledge, the artificial neural network can predict relations found in newly presented data sets. In cardiology, artificial neural networks have been successfully applied to problems in the diagnosis and treatment of coronary artery disease and myocardial infarction, in electrocardiographic interpretation and detection of arrhythmias and in image analysis in cardiac radiography and sonography. This report focuses on the current status of artificial neural network technology in cardiovascular medical research.
Estimating Synonymous and Nonsynonymous Substitution Rates Under Realistic Evolutionary Models
Authors: Ziheng Yang, Rasmus Nielsen
Journal: Molecular Biology and Evolution (2000)

Approximate methods for estimating the numbers of synonymous and nonsynonymous substitutions between two DNA sequences involve three steps: counting of synonymous and nonsynonymous sites in the two sequences, counting of synonymous and nonsynonymous differences between the two sequences, and correcting for multiple substitutions at the same site. We examine complexities involved in those steps and propose a new approximate method that takes into account two major features of DNA sequence evolution: transition/transversion rate bias and base/codon frequency bias. We compare the new method with maximum likelihood, as well as several other approximate methods, by examining infinitely long sequences, performing computer simulations, and analyzing a real data set. The results suggest that when there are transition/transversion rate biases and base/codon frequency biases, previously described approximate methods for estimating the nonsynonymous/synonymous rate ratio may involve serious biases, and the bias can be both positive and negative. The new method is, in general, superior to earlier approximate methods and may be useful for analyzing large data sets, although maximum likelihood appears to always be the method of choice.
British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary
Authors: Bryan Williams, Neil R Poulter, Morris J Brown, Mark Davis, Gordon T McInnes, John F Potter, Peter S Sever, Simon McG Thom
Journal: BMJ (2004)

Much new evidence has emerged on the importance of blood pressure as a risk factor for cardiovascular disease; the importance of lifestyle measures for the prevention and treatment of hypertension; the efficacy and safety of different drug classes; management of hypertension in groups at higher risk, including people with diabetes; the importance of assessing the total risk of cardiovascular disease; and additional benefits associated with the use of statins.

Concern remains that national surveys continue to show substantial underdiagnosis, undertreatment, and poor rates of blood pressure control in the United Kingdom.1 A key reason for this is the predominant use of monotherapy by most doctors.1 To improve this suboptimal treatment, the British Hypertension Society recommends a treatment algorithm based on the AB/CD rule.2

Treatment of blood pressure alone will leave many hypertensive patients at unacceptably high risk of cardiovascular complications and death. This guideline reinforces the view that doctors should not focus solely on blood pressure but must also formally assess total risk of cardiovascular disease and use multifactorial interventions, including statins and aspirin, to reduce it. Most management of blood pressure and risk of cardiovascular disease will take place in primary care, and these guidelines are intended for general practitioners, practice nurses, and generalists in hospital practice. Detailed advice on implementation and the implications of the national service frameworks and the general medical services contract are contained in the full document (http://www.bhsoc.org/).3

These guidelines have been prepared by the guidelines working party of the British Hypertension Society on behalf of the society. The working party reviewed new data that have become available since the previous guidelines were published4 and amended the recommendations accordingly. Drafts of the full document were improved by consultation with …
Lymphocyte destruction by antibody-dependent cellular cytotoxicity mediated in vitro by antibodies in serum from patients with systemic lupus erythematosus.
Authors: M L Mahowald, A P Dalmasso
Journal: Annals of the Rheumatic Diseases (1982)

Sera from patients with systemic lupus erythematosus (SLE) were tested for the presence of IgG antilymphocyte antibodies that are capable of mediating antibody-dependent cellular cytotoxicity (ADCC) of peripheral blood lymphocytes (PBL) from normal donors. The effector cells employed were PBL autologous with the target PBL. Positive ADCC responses were obtained with serum from 5 SLE patients with severe active diseases. It is possible that ADCC is a mechanism by which IgG antilymphocyte antibodies in patients with SLE may mediate in-vivo lymphocytolysis.
Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia
Authors: Joseph Cheriyan, Andrew J. Webb, Lea Sarov-Blat, Maysoon Elkhawad, Sharon M.L. Wallace, Kaisa M. Mäki-Petäjä, David J. Collier, John Morgan, Zixing Fang, Robert N. Willette, John J. Lepore, John R. Cockcroft, Dennis L. Sprecher, Ian B. Wilkinson
Journal: Circulation (2011)

Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen-activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38α/β MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia.Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol >4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (n=27) or placebo (n=29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (P=0.01 and P=0.03) compared with responses in control subjects (n=12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; P=0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; P=0.02), and to L-NMMA by 10% (95% confidence interval, -1 to 23; P=0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, -81 to -6%; P<0.05) in patients treated with losmapimod compared with placebo.Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease.
Pharmacokinetics and Pharmacodynamic Effects of a New Antibody Glycoprotein IIb/IIIa Inhibitor (YM337) in Healthy Subjects
Authors: Sebastian Harder, Carl M. Kirchmaier, Hans Jürgen Krzywanek, Dagmar Westrup, Jin-Woo Bae, Hans Klaus Breddin
Journal: Circulation (1999)

This study describes the first administration of YM337, the Fab fragment of a humanized monoclonal antibody against the fibrinogen GP IIb/IIIa receptor, in healthy male humans.Platelet aggregation (20 micromol/L ADP), platelet adhesion, fibrinogen binding, bleeding time, and YM337 concentrations in plasma were studied in substudy 1 after single boluses of 0.025, 0. 05, 0.1, 0.2, and 0.4 mg/kg YM337 and in substudy 2 after a bolus (0. 35 mg/kg) plus 6 hours of infusion at different dose levels of YM337 (0.5, 0.75, 1.0, 1.5 microg. kg(-1) x min(-1)), with abciximab as reference drug (n=5 or 6 subjects per group). After the 0.2-mg/kg and 0.4-mg/kg boluses, fibrinogen binding was reduced by >80% and bleeding time was prolonged to approximately 60 minutes. Bolus followed by infusion of 1.0 and 1.5 microg x kg(-1) x min(-1) YM337 maintained inhibition of platelet aggregation >80%. Aggregation and bleeding time returned to normal within 24 hours. A bolus of 0.25 mg/kg of abciximab followed by an infusion of 0.125 microg x kg(-1) x min(-1) showed effects similar to those observed with the 0.5- and 0. 75-microg x kg(-1) x min(-1) infusion of YM337. In 53 subjects exposed to YM337, 1 case of transient thrombocytopenia and 3 minor bleeding events occurred. No human anti-chimeric antibodies were detected 2 weeks and 2 months after administration.YM337 effectively inhibits IIb/IIIa-mediated platelet aggregation and adhesion in humans. The results of this phase 1 study will give rise to further clinical evaluation of YM337.
Dissection of a DNA-damage-induced transcriptional network using a combination of microarrays, RNA interference and computational promoter analysis.
Authors: Ran Elkon, Sharon Rashi-Elkeles, Yaniv Lerenthal, Chaim Linhart, Tamar Tenne, Ninette Amariglio, Gideon Rechavi, Ron Shamir, Yosef Shiloh
Journal: Genome biology (2005)

Gene-expression microarrays and RNA interferences (RNAi) are among the most prominent techniques in functional genomics. The combination of the two holds promise for systematic, large-scale dissection of transcriptional networks. Recent studies, however, raise the concern that nonspecific responses to small interfering RNAs (siRNAs) might obscure the consequences of silencing the gene of interest, throwing into question the ability of this experimental strategy to achieve precise network dissections.We used microarrays and RNAi to dissect a transcriptional network induced by DNA damage in a human cellular system. We recorded expression profiles with and without exposure of the cells to a radiomimetic drug that induces DNA double-strand breaks (DSBs). Profiles were measured in control cells and in cells knocked-down for the Rel-A subunit of NFkappaB and for p53, two pivotal stress-induced transcription factors, and for the protein kinase ATM, the major transducer of the cellular responses to DSBs. We observed that NFkappaB and p53 mediated most of the damage-induced gene activation; that they controlled the activation of largely disjoint sets of genes; and that ATM was required for the activation of both pathways. Applying computational promoter analysis, we demonstrated that the dissection of the network into ATM/NFkappaB and ATM/p53-mediated arms was highly accurate.Our results demonstrate that the combined experimental strategy of expression arrays and RNAi is indeed a powerful method for the dissection of complex transcriptional networks, and that computational promoter analysis can provide a strong complementary means for assessing the accuracy of this dissection.
Prognostic indicators of early and late death in children admitted to district hospital in Kenya: cohort study
Authors: J A Berkley
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objectives:</b> To identify clinical indicators of immediate, early, and late mortality in children at admission to a sub-Saharan district hospital and to develop prognostic scores. <b>Design:</b> Prospective cohort study. <b>Setting:</b> One district hospital in Kenya. <b>Participants:</b> Children aged over 90 days admitted to hospital from 1 July 1998 to 30 June 2001. <b>Main outcome measures:</b> Prognostic indicators of mortality. <b>Results:</b> Of 8091 children admitted up to 1 June 2000, 436 (5%) died. Sixty (14%) died within four hours after admission (immediate), 193 (44%) after 4-48 hours (early), and 183 (42%) after 48 hours (late). There were marked differences in the clinical features associated with immediate, early, and late death. Seven indicators (neurological status, respiratory distress (subcostal indrawing or deep breathing), nutritional status (wasting or kwashiorkor), severe anaemia, jaundice, axillary temperature, and length of history) were included in simplified prognostic scores. Data from 4802 children admitted from 1 July 2000 to 30 June 2001 were used to validate the scores. For simplified prognostic scores the areas under the receiver operating characteristic curves were 0.93 (95% confidence interval 0.92 to 0.94), 0.82 (0.80 to 0.83), and 0.82 (0.81 to 0.84) for immediate, early, and late death, respectively. <b>Conclusion:</b> In children admitted to a sub-Saharan hospital, the prognostic indicators of early and late deaths differ but a small number of simple clinical signs predict outcome well.
Magnetic Resonance Imaging Permits In Vivo Monitoring of Catheter-Based Vascular Gene Delivery
Authors: Xiaoming Yang, Ergin Atalar, Dechun Li, Jean-Michel Serfaty, Danming Wang, Ananda Kumar, Linzhao Cheng
Journal: Circulation (2001)

Background Gene therapy is an exciting frontier in modern medicine. To date, most investigations about the imaging of gene therapy have primarily focused on noncardiovascular systems, and no in vivo imaging modalities are currently available for monitoring vascular gene therapy. The purpose of this study was to develop an in vivo imaging tool to monitor a catheter-based vascular gene delivery procedure. Methods and Results We produced gadolinium/blue dye and gadolinium/gene-vector media by mixing Magnevist with a trypan-blue or a lentiviral vector carrying a green fluorescent protein (GFP) gene. The gadolinium was used as an imaging marker for magnetic resonance (MR) imaging to visualize vessel wall enhancement, and the blue dye/GFP was used as a tissue stain marker for histology/immunohistochemistry to confirm the success of the transfer. Using Remedy gene delivery catheters, we transferred the gadolinium/blue dye (n=8) or gadolinium/GFP lentivirus (n=4) into the arteries of 12 pigs, that were monitored under high-resolution MR imaging. The results showed, in all 12 pigs, the gadolinium enhancement of the target vessel walls on MR imaging and the blue/GFP staining of the target vessel tissues with histology/immunohistochemistry. This study shows the potential of using MR imaging to dynamically visualize (1) where the gadolinium/genes are delivered; (2) how the target portion is marked; and (3) whether the gene transfer procedure causes complications. Conclusions We present a technical development that uses high-resolution MR imaging as an in vivo imaging tool to monitor catheter-based vascular gene delivery.