tbuckley/cabot-search huggingface dataset:
Enhanced anti-inflammatory gene expression in humans following inhaled budesonide
Authors: Richard Leigh, Elizabeth King, Curtis Dumonceaux, Carol Gwozd, Suzanne Traves, Margaret Kelly, Anna Miller-Larsson, Robert Newton
Journal: European Respiratory Journal (2013)

RATIONALE:  Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment and act on the glucocorticoid receptor (GR) to repress inflammatory gene expression. Nevertheless, incomplete understanding of GR action hinders the development of improved anti-inflammatory ligands. While many studies focus on direct GR repression of inflammatory gene transcription ( transrepression ), corticosteroids also bind GR to enhance anti-inflammatory gene expression ( transactivation ). However, it is unclear whether a clinical dose of ICS elicits this effect in humans.   METHODS:  Twelve healthy, non-smoking, non-atopic males with normal lung function were recruited to a prospective double-blind, placebo-controlled, randomised, two-period cross-over study. A single dose of inhaled placebo or budesonide (1600 µg) was administered by Turbuhaler®. Bronchoscopy was performed after 5-6 h and endobronchial brushings and biopsies were obtained and processed for gene expression analysis.   RESULTS:  Inhaled budesonide significantly enhanced mRNA expression of multiple genes including;  FKBP5 / FKBP51 ,  TSC22D3 / GILZ ,  DUSP1 / MKP1 ,  ZFP36 / TTP ,  RGS2 ,  CDKN1C  / p57Kip2  and  NFKBIA / IKBA  in the biopsy samples. With the exception of  RGS2 , these mRNAs were also upregulated in cells obtained from brushings.   CONCLUSIONS:  This study confirms enhanced expression of multiple corticosteroid-induced genes by a single, clinical dose of inhaled budesonide. The data obtained illustrate the therapeutic importance of ICS-induced transactivation since  TSC22D3 ,  DUSP1 ,  ZFP36  and  NFKBIA  all repress inflammatory genes,  FKBP5  provides feedback control,  CDKN1C  (a cell-cycle inhibitor) may attenuate Jun N-terminal kinase activity while  RGS2  is bronchoprotective.
Harmonising spirometry education with HERMES: training a new generation of qualified spirometry practitioners across Europe
Authors: I. Steenbruggen, S. Mitchell, T. Severin, P. Palange, B.G. Cooper
Journal: European Respiratory Journal (2011)

“Hundreds of millions of people of all ages suffer from preventable chronic respiratory diseases and respiratory allergies in all countries of the world… accounting for 4 million deaths annually” 1.

The considerable toll of respiratory diseases in terms of quality of life, disability of patients and indeed premature death 2 underlines the importance of spirometry in the detection and monitoring during the management of respiratory disease. Yet, in the past two decades, there have been specific concerns of under-utilisation in screening 3, lack of training 4 and misdiagnosis based on inaccurate results 5, 6 which only serve to document the inadequacies in spirometry practice not only within Europe but on a world-wide scale.

An abundance of reports 2–8 has propelled quality issues in the practice of spirometry to centre stage and consequently introduced a number of quality improvement strategies. High-quality spirometry relies on three key determinants: 1) documented guidelines in spirometry, 2) access to quality spirometers, and finally, 3) trained and qualified spirometry practitioners 9. To some degree, the ERS/ATS guidelines in standardisation of spirometry 10 and availability of affordable spirometers across medical settings have directly addressed these first two factors. Further efforts implemented in the US by NIOSH (National Institute for Occupational Safety and Health), in several European countries, as well as across New Zealand and Australia through ANZSRS (Australian and New Zealand Society of Respiratory Science) have produced comprehensive training structures with supporting documents and certification criteria to endorse health professionals with a qualification to practice high-quality spirometry. There is some evidence which consistently shows that competence in spirometry is the key to quality services 7, 11, 12, but access to such training and assessment is relatively limited. Adopting HERMES (Harmonising Education in Respiratory Medicine for European Specialists) as …
Sustained Suppression of Neointimal Proliferation by Sirolimus-Eluting Stents
Authors: J. Eduardo Sousa, Marco A. Costa, Alexandre C. Abizaid, Benno J. Rensing, Andrea S. Abizaid, Luiz F. Tanajura, Ken Kozuma, Glenn Van Langenhove, Amanda G.M.R. Sousa, Robert Falotico, Judith Jaeger, Jeffrey J. Popma, Patrick W. Serruys
Journal: Circulation (2001)

Background We have previously reported a virtual absence of neointimal hyperplasia 4 months after implantation of sirolimus-eluting stents. The aim of the present investigation was to determine whether these results are sustained over a period of 1 year. Methods and Results Forty-five patients with de novo coronary disease were successfully treated with the implantation of a single sirolimus-eluting Bx VELOCITY stent in São Paulo, Brazil (n=30, 15 fast release [group I, GI] and 15 slow release [GII]) and Rotterdam, The Netherlands (15 slow release, GIII). Angiographic and volumetric intravascular ultrasound (IVUS) follow-up was obtained at 4 and 12 months (GI and GII) and 6 months (GIII). In-stent minimal lumen diameter and percent diameter stenosis remained essentially unchanged in all groups (at 12 months, GI and GII; at 6 months, GIII). Follow-up in-lesion minimal lumen diameter was 2.28 mm (GIII), 2.32 mm (GI), and 2.48 mm (GII). No patient approached the ≥50% diameter stenosis at 1 year by angiography or IVUS assessment, and no edge restenosis was observed. Neointimal hyperplasia, as detected by IVUS, was virtually absent at 6 months (2±5% obstruction volume, GIII) and at 12 months (GI=2±5% and GII=2±3%). Conclusions This study demonstrates a sustained suppression of neointimal proliferation by sirolimus-eluting Bx VELOCITY stents 1 year after implantation.
Abnormalities in Nitric Oxide and Its Derivatives in Lung Cancer
Authors: Fares A. Masri, Suzy A. A. Comhair, Thomas Koeck, Weiling Xu, Allison Janocha, Sudakshina Ghosh, Raed A. Dweik, Joseph Golish, Michael Kinter, Dennis J. Stuehr, Serpil C. Erzurum, Kulwant S. Aulak
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

A cellular prooxidant state promotes cells to neoplastic growth, in part because of modification of proteins and their functions. Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer.To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis.We analyzed levels of NO, nitrite (NO2-), nitrate (NO3-), and the location of the protein nitration and identified the proteins that are modified.Although exhaled NO and NO2- were increased, endothelial NO synthase or inducible NO synthase expression was similar in the tumor and tumor-free regions. However, immunohistochemistry showed that nitrotyrosine was increased in the tumor relative to non-tumor-bearing sections. We used proteomics to identify the modified proteins (two-dimensional polyacrylamide gel electrophoresis; mass spectrometry). Both the degree of nitration and the protein nitration profile were altered. We identified more than 25 nitrated proteins, including metabolic enzymes, structural proteins, and proteins involved in prevention of oxidative damage. Alterations of the biology of NO metabolites and nitration of proteins may contribute to the mutagenic processes and promote carcinogenesis.This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer.
Neoplastic Conversion &lt;italic&gt;In Vitro&lt;/italic&gt; of Mouse Cells: Cytologic, Chromosomal, Enzymatic, Glycolytic, and Growth Properties
Authors: Katherine K. Sanford, Barbara E. Barker, Ram Parshad, Benton B. Westfall, Mark W. Woods, Jay L. Jackson, Diana R. King, Ellison V. Peppers
Journal: JNCI Journal of the National Cancer Institute (1970)

We demonstrated that presumably virus-free cells from the germfree ALBM-2 mouse undergo “spontaneous” neoplastic conversions in vitro. With these cells we showed that a shift from diploidy to heteroploidy is not essential for spontaneous neoplastic conversion in vitro, that the neoplastic cells under the culture conditions used are less adherent to surface substrate than control non-neoplastic cells, and that the growth-pattern change associated with neoplastic conversion may result from a loss of surface-substrate dependency rather than from the hypothetical loss of contact inhibition of mitosis. We extended the serum effect on neoplastic conversion to these presumably virus-free cells. In addition to delaying neoplastic conversion, fetal calf serum (FCS) as compared with horse serum (HS) reduced the percentage of lines converted and increased the latent periods for development of tumors from the cells in vivo. By applying cytologic criteria of neoplastic conversion, we made diagnoses that were 100% consistent with results of in vivo assay. Electron microscope studies showed that the cytoplasmic basophilia in the neoplastic cells was associated with more numerous ribosomes than in non-neoplastic control cells, even when cell populations were increasing at similar rates. As observed earlier, the neoplastic cells increased in glycolytic capacity, with a reduced susceptibility to a glycolytic inhibitor, and had a slightly higher saturation density than non-neoplastic controls, although saturation density increased with time in culture. We extended to embryo cells the observation, made previously on adult and neonatal mouse cells, that alkaline phosphatase activity declines during long-term culture, whereas high acid phosphatase activity is maintained. Changes in arginase activity were not directly related to neoplastic change, but the activity declined in the cells on HS supplement and was maintained in cells on FCS.
DNA Methylation and Its Implications and Accessibility for Neuropsychiatric Therapeutics
Authors: Jeremy J. Day, Andrew J. Kennedy, J. David Sweatt
Journal: The Annual Review of Pharmacology and Toxicology (2014)

In this review, we discuss the potential pharmacological targeting of a set of powerful epigenetic mechanisms: DNA methylation control systems in the central nervous system (CNS). Specifically, we focus on the possible use of these targets for novel future treatments for learning and memory disorders. We first describe several unique pharmacological attributes of epigenetic mechanisms, especially DNA cytosine methylation, as potential drug targets. We then present an overview of the existing literature regarding DNA methylation control pathways and enzymes in the nervous system, particularly as related to synaptic function, plasticity, learning and memory. Lastly, we speculate upon potential categories of CNS cognitive disorders that might be amenable to methylomic targeting.
Increased Apoptosis in Cervical Intraepithelial Neoplasia Associated with HIV Infection: Implication of Oncogenic Human Papillomavirus, Caspases, and Langerhans Cells
Authors: Francine Walker, Homa Adle-Biassette, Patrick Madelenat, Dominique Hénin, Thérèse Lehy
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Increasing risk of squamous cervical intraepithelial neoplasia (CIN) exits in HIV-infected women. However, the relatively low incidence of invasive carcinoma in the untreated HIV-infected population suggests an imbalance between cell proliferation and apoptosis. We investigated apoptosis and caspases in cervical samples from this population comparatively to non-HIV-infected and control subjects. Experimental Design: Apoptotic terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling method, immunohistochemistry for caspase-2, caspase-3, caspase-8, caspase-9, and other apoptosis markers were done on 12 normal cervical samples and 103 low- and high-grade cervical lesions, containing human papillomavirus(es) from 35 HIV-negative and 33 HIV-positive women before tritherapy advent. Results: (a) The apoptotic index (AI) in epithelial cells did not vary between normal mucosa and condyloma acuminata infected or not with HIV. (b) AI augmented with the CIN severity in HIV-positive and HIV-negative women. (c) AI dramatically increased in oncogenic human papillomavirus-infected CIN of HIV-positive population compared with the CIN of similar grade in HIV-negative one. This was associated with a greater expression of caspase-8, active caspase-9, and active caspase-3 in those samples. Moreover, densities of Langerhans' cells, involved in apoptotic bodies engulfment, were greatly reduced in CIN of HIV-positive women. In samples, these densities were highly inversely correlated with AI (r = −0.88, P &amp;lt; 0.002). Conclusions: This study provides the first evidence for the strongly enhanced apoptosis levels and caspase expression in CIN of untreated HIV-infected women. We suggest that the reduction in Langerhans' cell number could contribute at least partly to apoptotic cell accumulation.
Inside Special Care
Authors: John C. Benson
Journal: Annals of Internal Medicine (2014)

On Being a Doctor19 August 2014Inside Special CareJohn C. Benson, MDJohn C. Benson, MDFrom University of Minnesota, St. Paul, Minnesota.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M14-0279 Audio Reading - “Inside Special Care” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Inside Special Care," by J.C. Benson. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail “We've got a spitter!” a nurse shouted. The police rolled the stretcher into the unit. Just midmorning, and already we were filling up.The police stopped at the nurses' station. Hands and feet, the patient was cuffed to the stretcher. He had been hooded with something like a fencing helmet to protect us from his projectile spitting. He was middle-aged, with an unkempt beard and an angry glare.“Let me out of here!” he screamed, straining against the handcuffs. The odor of alcohol and sweat was overpowering. He turned his head to the nurse. “I said let me loose, fatty!”... Author, Article, and Disclosure InformationAuthors: John C. Benson, MDAffiliations: From University of Minnesota, St. Paul, Minnesota.Corresponding Author: John C. Benson, MD, 367 Ramsey Street, St. Paul, MN 55102; e-mail, benso905@umn.edu. PreviousarticleNextarticle Advertisement Audio Reading - “Inside Special Care” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Inside Special Care," by J.C. Benson. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 19 August 2014Volume 161, Issue 4 Page: 302-303 Keywords Alcohols Myocardial infarction Nurses Shoulders Sleep Spine Swallowing Sweat Urination Urine ePublished: 19 August 2014 Issue Published: 19 August 2014 Copyright & PermissionsCopyright © 2014 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Blockade of the Ubiquitin Protease UBP43 Destabilizes Transcription Factor PML/RARα and Inhibits the Growth of Acute Promyelocytic Leukemia
Authors: Yongli Guo, Andrey V. Dolinko, Fadzai Chinyengetere, Bruce Stanton, Jennifer M. Bomberger, Eugene Demidenko, Da-Cheng Zhou, Robert Gallagher, Tian Ma, Fabrizio Galimberti, Xi Liu, David Sekula, Sarah Freemantle, Ethan Dmitrovsky
Journal: Cancer Research (2010)

More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative-acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation. RA treatment induced UBE1L, ISG15, and UBP43 expression in RA-sensitive but not RA-resistant APL cells. Similar in vivo findings were obtained in a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested directly from APL patients. UBP43 knockdown repressed PML/RARα protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARα. This inhibitory effect promoted apoptosis but did not affect the RA differentiation response in these APL cells. In contrast, elevation of UBP43 expression stabilized PML/RARα protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment.
THE INFLUENCE OF THE VAGUS NERVES UPON CONDUCTION BETWEEN AURICLES AND VENTRICLES IN THE DOG DURING AURICULAR FIBRILLATION
Authors: G. Canby Robinson
Journal: The Journal of Experimental Medicine (1916)

The experiments that have been reported indicate that stimulation of either the right vagus or the left vagus nerve is equally effectual in blocking impulses from the auricles to the ventricles when auricular fibrillation is present. Stimulation of the left vagus nerve is as effectual in blocking impulses from the normally beating auricles as from the auricles when in a state of fibrillation, and the type of auricular activity has apparently no influence on the effect which stimulation of the left vagus has on auriculoventricular conduction.
Prospective long-term follow-up of patients with localised Wegener's granulomatosis: does it occur as persistent disease stage?
Authors: Julia U Holle, Wolfgang L Gross, Konstanze Holl-Ulrich, Petra Ambrosch, Bernhard Noelle, Marcus Both, Elena Csernok, Frank Moosig, Susanne Schinke, Eva Reinhold-Keller
Journal: Annals of the Rheumatic Diseases (2010)

To identify patients with localised Wegener's granulomatosis (locWG) to assess whether it occurs as a long-term disease stage or phenotype and to characterise its outcome.Patients in a 'localised stage' with histological criteria compatible with WG and a follow-up period of ≥1 year were included. They were prospectively followed at the Vasculitis Center Schleswig-Holstein from 1989 to 2009 and the clinical manifestations, antineutrophil cytoplasmic autoantibodies (ANCA) status and damage were evaluated. Immunosuppression was adapted to disease activity and severity in a step-up regimen.Of 1024 patients with suspected WG, 99 were clinically diagnosed with locWG and 50 fulfilled the inclusion criteria (72% women, median age 43 years, 46% ANCA-positive). The median follow-up was 48 months. All achieved a response to treatment, 34% achieved complete remission, 1-4 relapses occurred in 46%, 5 (10%) had generalised disease (median 6 years after onset). ANCA status was not associated with relapse (p=0.98), transition to generalised disease (p=0.51) or refractory manifestations (p=0.60). 47% required cyclophosphamide for localised manifestations, 36% of them for pulmonary masses and 24% for orbital masses. 66% developed organ damage, mostly due to bony destruction or space obturation (28% saddle nose, 24% septal perforation, 10% orbital wall destruction). There were two deaths that were not related to WG.There is evidence that locWG is a long-term disease stage or phenotype (5% of all patients with WG), 46% of whom are ANCA-positive. LocWG is characterised by destructive and/or space-consuming lesions associated with high relapse rates (46%) and local damage.
Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism
Authors: Timo J. Laatikainen, Jari I. Peltonen, Pekka L. Nylander
Journal: Journal of Clinical Investigation (1974)

Estriol, estriol sulfate, progesterone, and 17 neutral steroid sulfates, including estriol precursors and progesterone metabolites, were determined in 27 cord plasma samples collected after pregnancies complicated by intrahepatic cholestasis of the mother. The levels of these steroids were compared with those in the cord plasma of 42 healthy controls. In the cord plasma, the steroid profile after pregnancies complicated by maternal intrahepatic cholestasis differed greatly from that seen after uncomplicated pregnancy. Two main differences were found. In the disulfate fraction, the concentrations of two pregnanediol isomers, 5alpha-pregnane-3alpha,20alpha-diol and 5beta-pregnane-3alpha,20alpha-diol, were high after cholestasis. Other investigators have shown that, as a result of cholestasis, these pregnanediol sulfates circulate in greatly elevated amounts in the maternal plasma. Our results indicate that in cholestasis these steroids cross the placenta into the fetal compartment, where they circulate in elevated amounts as disulfates. Secondly, the concentrations of several steroid sulfates known to be synthesized by the fetus were significantly lower in the cholestasis group than in the healthy controls. This was especially true of 16alpha-hydroxydehydroepiandrosterone sulfate and 16alpha-hydroxypregnenolone sulfate. These results suggest that, in pregnancies complicated by maternal intrahepatic cholestasis, impairment of fetal steroid synthesis, and especially of 16alpha-hydroxylation, occurs in the fetal compartment.Thus, the changes in maternal steroid metabolism caused by cholestasis are reflected in the steroid profile of the fetoplacental circulation. Furthermore, maternal intrahepatic cholestasis may result in the production of some substance which crosses the placenta and affects fetal steroid metabolism.
IgE‐mediated basophil releasability is influenced by intrinsic factors and by IgE on the cell surface
Authors: H. Mita, H. Yasueda, T. Ishii, K. Akiyama
Journal: Allergy (1995)

Experiments were done to clarify the mechanisms associated with releasability of histamine. First, washed leukocytes from 23 asthmatic patients sensitive to mite allergen were challenged with Der p 1, a major allergen isolated from Dermatophagoides pteronyssinus , or anti‐IgE. A significant correlation was observed between the ratio of Der p 1‐specific IgE liter to total IgE level (S/T) in the patient's plasma and either the reactivity (maximal percentage of histamine release; r s = 0.514, P = 0.016, n = 23) or the sensitivity (the minimum allergen concentration required to achieve 25% histamine release; r s = ‐0.790, P = 0.0002) to Der p 1. Additionally, the reactivity to Der p 1 was significantly correlated with that to anti‐IgE (r s = 0.690, P = 0.0012), indicating that an intrinsic cellular property may be one of the contributing factors in immunologic histamine release. In a second series of experiments, sinus mast cells were passively sensitized with immunoglobulins prepared from the patient's plasma. A statistically significant correlation was found between either the reactivity or the sensitivity to Der p 1 and S/T, thus indicating that S/T is an indicator of the releasability of histamine. When basophils or mast cells were passively sensitized with mouse IgE and subsequently stimulated with antimouse IgE, the reactivity to antihuman IgE was significantly correlated with that to antimouse IgE ( r s = 0.966, P = 0.0023, n = 11). These observations suggest that an intrinsic cellular property regulates reactivity in immunologic histamine release. Taken together, our results suggest that an intrinsic cellular property, as well as specific IgE antibody levels on the cell surface, is an important factor in determining histamine release in response to IgE‐dependent activation.