tbuckley/cabot-search huggingface dataset:
Clinical Implications of Inflammation in Young Children
Authors: ANDREW BUSH, HARM TIDDENS, MICHAEL SILVERMAN
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The definition of asthma has changed from that of a clinical disease (wheeze and/or cough in a setting where asthma is likely and other, rarer conditions have been excluded) (1) to a combination of clinical symptoms and pathology, usually describing airway inflammation (2). The concept of including inflammation in the definition has been questioned (3). In young children it is impractical to include inflammation as a requirement for the diagnosis. We know that a large part of the asthma phenotype in young adults at least is related to helper T type 2 (Th2) lymphocyteand eosinophil-mediated airway inflammation, but even in atopic adult asthma other important mechanisms may be involved (4, 5). These may include noneosinophilic inflammation (neutrophils or other cells, chemical mediators acting directly on the airway, neurogenic inflammation, plasma extravasation) and the effect of a possible reduction in baseline airway caliber, either for developmental reasons or secondary to acquired remodeling (6). In the context of other childhood wheezing illness, both bronchoscopic (7) and blind (8) lavage studies suggest that pure virus-associated wheeze is not an eosinophilic disease and is not even due to or associated with chronic airway inflammation. Other evidence suggests that the eosinophil may not always be the main cell involved in airway inflammation. The neutrophil is an important component of the late-phase response (9) and of endotoxin-induced asthma (10). Furthermore, a subgroup of patients with asthma without elevated sputum eosinophil levels and who were poorly responsive to corticosteroids has been described (11). Finally, there may be significant differences in the pathology of severe and mild to moderate asthma (12). We also know that the treatment with inhaled or oral corticosteroids of what is presumed to be airway inflammation in children reduces blood markers of T cell activation and cytokine levels (13) and reduces sputum eosinophilia (14) and nitric oxide (NO) levels (15). This suggests that antiinflammatory treatment reduces some forms of airway inflammation. There is a poor correlation between these markers when they are used to measure the response to antiinflammatory therapy (16). Uncontrolled trials in children (17) and controlled studies in adults (18) indicate that a delay in the initiation of inhaled corticosteroid therapy for the treatment of chronic asthma results in poorer long-term lung function. This suggests that untreated inflammation leads to secondary airway remodeling, which becomes irreversible. However, there are few data on the relationship between early inflammatory processes and structural changes in the airways of patients with asthma. We also know that corticosteroids are not disease modifying in chronic childhood asthma, at least when started at the conventional time. Even after 2 yr, the plateau for bronchial hyperreactivity is not reached and relapse occurs if treatment is stopped (19).
Sphingosylphosphorylcholine-induced vasoconstriction of pulmonary artery: Activation of non-store-operated Ca entry
Authors: G THOMAS, V SNETKOV, R PATEL, R LEACH, P AARONSON, J WARD
Journal: Cardiovascular Research (2005)

Objective: Sphingosylphosphorylcholine (SPC) is an important lipid mediator that has been implicated in vascular disease. As it has not been studied in the pulmonary circulation, we examined its mechanisms of action in rat small intrapulmonary arteries (IPA).
Costimulation via OX40L Expressed by B Cells Is Sufficient to Determine the Extent of Primary CD4 Cell Expansion and Th2 Cytokine Secretion In Vivo
Authors: Phyllis-Jean Linton, Beverly Bautista, Elana Biederman, Evan S. Bradley, Judith Harbertson, Robyn M. Kondrack, Ryan C. Padrick, Linda M. Bradley
Journal: The Journal of Experimental Medicine (2003)

The development of effector and memory CD4 cell populations depends upon both T cell receptor (TCR) engagement of peptide/major histocompatibility complex (MHC) class II complexes and ligation of costimulatory molecules with counter receptors on antigen-presenting cells (APCs). We showed previously that sustained interactions with APCs could be crucial for optimal expansion of CD4 cells and for development of effectors that secrete cytokines associated with Th2 cells. Using an adoptive transfer model with TCR transgenic CD4 cells, we now show that responses of CD4 cells primed in B cell–deficient mice become aborted, but are fully restored upon the transfer of activated B cells. Although B cells have the capacity to secrete multiple cytokines that could affect CD4 priming, including IL-4, we were unable to distinguish a role for cytokines that are secreted by B cells. However, B cell costimulation via the OX40L/OX40 pathway that has been implicated in CD4 cell expansion, survival, and Th2 development was required. Th2 but not Th1 responses were impaired in OX40L-deficient recipients and normal responses were restored with OX40L sufficient B cells. The results suggest that without engagement of OX40L on B cells, CD4 cell responses to many protein Ag would be dominated by Th1 cytokines. These data have important implications for strategies to achieve optimal priming of CD4 subsets.
Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma
Authors: Toni K. Choueiri, Ulka Vaishampayan, Jonathan E. Rosenberg, Theodore F. Logan, Andrea L. Harzstark, Ronald M. Bukowski, Brian I. Rini, Sandy Srinivas, Mark N. Stein, Laurel M. Adams, Lone H. Ottesen, Kevin H. Laubscher, Laurie Sherman, David F. McDermott, Naomi B. Haas, Keith T. Flaherty, Robert Ross, Peter Eisenberg, Paul S. Meltzer, Maria J. Merino, Donald P. Bottaro, W. Marston Linehan, Ramaprasad Srinivasan
Journal: Journal of Clinical Oncology (2012)

Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.
Patients' adherence to treatment: How does it changes in 1 year after finishing of the participation in trial?
Authors: Nataliia Slepchenko, Yuriy Mostovoy, Andrii Sidorov
Journal: European Respiratory Journal (2013)

The aim of the study was to estimate how adherence to treatment of the chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) changes after participation in trial due to COPD and its influence on the quantity of acute episodes of both diseases.  Methods. The 45 patients (average age 53,7±5,9 yrs) with severe and very severe COPD and moderate AH were included. We ask patients to bring used inhalers to site in 1, 6 and 12 months after the trial completion. Using questionnaire and medical records we estimated the quantity of the COPD exacerbation, their total duration and quantity of hypertensive crisis during 1 year before the trial and during 1 year after its completion. Data were summarized, using mean, median and standard deviation and range for continuous parameters and using counts and percentages for categorical parameters.  Results. Before the trial only 23 (51%) patients had basis therapy due to COPD and only 20 (44%) of them had it due to AH. In 1 month after the trial completed these data were 40 (89%) and 38 (84%), in 6 months – 38 (84%) and 37 (82%), in 12 months – 30 (67%) and 29 (64%) respectively. The patients had 2,1±0,3 COPD exacerbations during the 1 year before trial and 1,5±0,2 during the 1 year after the trial (p=0,048). The total duration of COPD exacerbations were 20,5±3,7 days before and 15,9±2,9 days after the trial completion (p=0,04). The total quantity of hypertensive crisis became 4,2±0,5 vs 7,4±0,7 (p=0,044).  Conclusions. The participation in trial due to COPD improves the adherence to treatment of the COPD on 38% and AH on 40 %. It significantly decreases for both diseases in 1 year after the trial completion.
Differential Expression of Conserved Germ Line Markers and Delayed Segregation of Male and Female Primordial Germ Cells in a Hermaphrodite, the Leech Helobdella
Authors: Sung-Jin Cho, Yvonne Vallès, David A. Weisblat
Journal: Molecular Biology and Evolution (2013)

In sexually reproducing animals, primordial germ cells (PGCs) are often set aside early in embryogenesis, a strategy that minimizes the risk of genomic damage associated with replication and mitosis during the cell cycle. Here, we have used germ line markers (piwi, vasa, and nanos) and microinjected cell lineage tracers to show that PGC specification in the leech genus Helobdella follows a different scenario: in this hermaphrodite, the male and female PGCs segregate from somatic lineages only after more than 20 rounds of zygotic mitosis; the male and female PGCs share the same (mesodermal) cell lineage for 19 rounds of zygotic mitosis. Moreover, while all three markers are expressed in both male and female reproductive tissues of the adult, they are expressed differentially between the male and female PGCs of the developing embryo: piwi and vasa are expressed preferentially in female PGCs at a time when nanos is expressed preferentially in male PGCs. A priori, the delayed segregation of male and female PGCs from somatic tissues and from one another increases the probability of mutations affecting both male and female PGCs of a given individual. We speculate that this suite of features, combined with a capacity for self-fertilization, may contribute to the dramatically rearranged genome of Helobdella robusta relative to other animals.
Mechanisms responsible for surfactant changes in sepsis-induced lung injury
Authors: W. Huang, L. A. McCaig, R. A. W. Veldhuizen, L-J. Yao, J. F. Lewis
Journal: European Respiratory Journal (2005)

Pulmonary surfactant is altered in sepsis, and these changes contribute to the predisposition of septic lungs to subsequent insults, ultimately leading to acute lung injury. Specifically, the total amount of surfactant is lower in sepsis, mainly due to decreased small aggregate (SA) surfactant pools. The amount of large aggregate (LA) surfactant is not altered. To evaluate the mechanisms responsible for these alterations, trace doses of tritium-labelled dipalmitoylphosphatidylcholine ( 3 H-DPPC)-labelled LA were instilled intratracheally into adult rats 20 hrs after caecal ligation and perforation (CLP) or sham surgery. Animals were sacrificed at 0, 1 and 4 h after instillation and recovery of 3 H-DPPC in alveolar macrophages (AM), LA and SA was measured. In separate in vitro experiments, AM isolated from CLP/sham rats were incubated with LA or SA isolated from normal animals to evaluate the uptake of these aggregates into the AM. Results showed increased surfactant radioactivity associated with AM of CLP animals compared with sham animals both in vivo and in vitro . In addition, more 3 H-DPPC label remained in LA forms in the CLP animals in vivo compared with sham. These findings indicate that differences in surfactant aggregate uptake and large aggregate conversion occur in septic lungs, resulting in changes in surfactant pools.
Where the magic breaks down: Boundaries and the “focus-of-attention” in schizophrenia
Authors: Robert D. Oades, Boutheina Jemel
Journal: Behavioral and Brain Sciences (2001)

The boundaries, the influences on, and consequences of a short-term memory (STM) capacity of 4 leads us to consider global versus local processing. We argue that in schizophrenia cognitive problems can lie partly in pre-conscious automatic selective attention and partly with the speed of processing in later controlled processes (including compound STM). The influence of automatic attentional mechanisms may be under-estimated in normal psychology and explain the loss of the magic 4 in schizophrenia.
Role of flies and provision of latrines in trachoma control: cluster-randomised controlled trial
Authors: Paul M Emerson, Steve W Lindsay, Neal Alexander, Momodou Bah, Sheik-Mafuji Dibba, Hannah B Faal, KebbaO Lowe, Keith PWJ McAdam, Amy A Ratcliffe, Gijs EL Walraven, Robin L Bailey
Journal: The Lancet (2004)
How to quantify coughing: correlations with quality of life in chronic cough
Authors: A. Kelsall, S. Decalmer, D. Webster, N. Brown, K. McGuinness, A. Woodcock, J. Smith
Journal: European Respiratory Journal (2008)

Different methods are used for quantifying coughing in sound recordings, but as yet no method has been shown to be more valid than any other. In the present study, the relationships between three different units of cough were examined and their ability to predict subjective ratings of cough and cough-related quality of life were evaluated. In total, 70 subjects (mean±sd age 55±11.7 yrs, 51 (73%) females) with chronic unexplained cough (median duration 4.8 yrs, interquartile range 2.5–10.1 yrs) performed fully ambulatory 24-h sound recordings, which were manually counted by trained observers and quantified by 1) explosive phases, 2) cough seconds and 3) cough epochs. Subjects also completed cough visual analogue scales (VAS) and the Leicester Cough Questionnaire (LCQ). All units of cough were strongly correlated; explosive phases and cough seconds correlated slightly more strongly than cough seconds with cough epochs or explosive phases with cough epochs. LCQ scores correlated moderately with explosive phases and seconds; epochs correlated slightly less well. Cough VAS scores showed a similar pattern. Explosive phases and seconds are interchangeable units of cough, moderately related to subjective measures and cough-related quality of life; epochs are a less satisfactory alternative.
13-cis-Retinoic Acid and Interferon -2a: Effective Combination. Therapy for Advanced Squamous Cell Carcinoma of the Skin
Authors: S. M. Lippman, D. R. Parkinson, L. M. Itri, R. S. Weber, S. P. Schantz, D. M. Ota, M. A. Schusterman, I. H. Krakoff, J. U. Gutterman, W. K. Hong
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article 13- cis -Retinoic Acid and Interferon α -2a: Effective Combination. Therapy for Advanced Squamous Cell Carcinoma of the Skin Get access Scott M. Lippman, Scott M. Lippman * Department of Medical Oncology, The University of Texas M. D. Anderson Cancer CenterHouston *Correspendence to : Scott M. Lippman, M.D., Department of Medical Oncology, Box 80, The University to Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 Search for other works by this author on: Oxford Academic PubMed Google Scholar David R. Parkinson, David R. Parkinson Department of Clinical Immunology, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar Loretta M. Itri, Loretta M. Itri Department of Clinical Development, Hoffmann-La RocheNutley, N. J. Search for other works by this author on: Oxford Academic PubMed Google Scholar Randal S. Weber, Randal S. Weber Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar Stimson P. Schantz, Stimson P. Schantz Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar David M. Ota, David M. Ota Department of General Surgery, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark A. Schusterman, Mark A. Schusterman Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar Irwin H. Krakoff, Irwin H. Krakoff Department of Medical Oncology, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar Jordan U. Gutterman, Jordan U. Gutterman Department of Clinical Immunology, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar Waun Ki Hong Waun Ki Hong Department of Medical Oncology, The University of Texas M. D. Anderson Cancer CenterHouston Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 4, 19 February 1992, Pages 235–241, https://doi.org/10.1093/jnci/84.4.235 Published: 19 February 1992 Article history Received: 22 August 1991 Revision received: 09 December 1991 Accepted: 09 December 1991 Published: 19 February 1992
Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer
Authors: Tong Li, Yak-Nam Wang, Tatiana D. Khokhlova, Samantha D'Andrea, Frank Starr, Hong Chen, Jeannine S. McCune, Linda J. Risler, Afshin Mashadi-Hossein, Sunil R. Hingorani, Amy Chang, Joo Ha Hwang
Journal: Cancer Research (2015)

Pancreatic cancer is characterized by extensive stromal desmoplasia, which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity-cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high-intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active vs. passive drug diffusion). For both types, the pHIFU exposures that were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized doxorubicin concentration by up to 4.5-fold compared with controls. Furthermore, normalized doxorubicin concentration was associated with the cavitation metrics (P < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, that is, doxorubicin infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors. .
New CQC chairman plans changes to sharpen the regulator's performance
Authors: A. O'Dowd
Journal: BMJ (2012)

The man set to chair the main watchdog for NHS organisations in England has promised to sharpen its performance and ensure no more scandals such as those at Mid Staffordshire NHS Foundation Trust or the Winterbourne View care home.1 2

David Prior, who has been named as the government’s preferred candidate for the post of chairman of the Care Quality Commission, appeared before the parliamentary health select committee as part of a pre-appointment hearing on 5 December.

Prior is chairman of Norfolk and Norwich University Hospitals NHS Foundation Trust and is also a qualified barrister, spent 10 years in the steel industry, and was a Conservative MP …
Comparison of Site-Specific Rate-Inference Methods for Protein Sequences: Empirical Bayesian Methods Are Superior
Authors: I. Mayrose
Journal: Molecular Biology and Evolution (2004)

The degree to which an amino acid site is free to vary is strongly dependent on its structural and functional importance. An amino acid that plays an essential role is unlikely to change over evolutionary time. Hence, the evolutionary rate at an amino acid site is indicative of how conserved this site is and, in turn, allows evaluation of its importance in maintaining the structure/function of the protein. When using probabilistic methods for site-specific rate inference, few alternatives are possible. In this study we use simulations to compare the maximum-likelihood and Bayesian paradigms. We study the dependence of inference accuracy on such parameters as number of sequences, branch lengths, the shape of the rate distribution, and sequence length. We also study the possibility of simultaneously estimating branch lengths and site-specific rates. Our results show that a Bayesian approach is superior to maximum-likelihood under a wide range of conditions, indicating that the prior that is incorporated into the Bayesian computation significantly improves performance. We show that when branch lengths are unknown, it is better first to estimate branch lengths and then to estimate site-specific rates. This procedure was found to be superior to estimating both the branch lengths and site-specific rates simultaneously. Finally, we illustrate the difference between maximum-likelihood and Bayesian methods when analyzing site-conservation for the apoptosis regulator protein Bcl-xL.
Lipoxins Are Potential Endogenous Antiinflammatory Mediators in Asthma
Authors: Caroline Bonnans, Isabelle Vachier, Claude Chavis, Philippe Godard, Jean Bousquet, Pascal Chanez
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Lipoxins, endogenous eicosanoids biosynthetized in vivo at inflammation sites, are potential antiinflammatory mediators. Subjects with severe asthma present chronic inflammation of the airways despite long-term treatment with oral glucocorticoids. Therefore it is of interest to investigate the potential antiinflammatory effects of lipoxin A4 (LXA4) and lipoxin B4 (LXB4) that could attenuate chronic inflammation. In a first time, we detected interleukin (IL)-8 and LXA4 in supernatants of induced sputum. IL-8 was heightened in severe asthma (p = 0.001), whereas high concentrations of lipoxin A4 were present in mild asthma (p = 0.001). We then studied the effects of LXA4 on IL-8 released in vitro. Nanomolar concentrations of LXA4 and LXB4 inhibited the IL-8 released by peripheral blood mononuclear cells from the two groups of patients with asthma: a maximal inhibition of 29.4% (p < 0.01) was observed for patients with mild asthma, and 41.5% inhibition (p < 0.001) for patients with severe asthma at 1 nM and 100 nM LXA4 concentrations, respectively. Polymerase chain reaction analysis indicated that peripheral blood mononuclear cells from patients with asthma expressed the LXA4 receptor mRNA. Moreover, pertussis toxin reversed LXA4- and LXB4-inhibited IL-8 release. These findings suggest that lipoxins have potential antiinflammatory action in asthma.