tbuckley/cabot-search huggingface dataset:
The role of the bronchial provocation challenge tests in the diagnosis of exercise-induced bronchoconstriction in elite swimmers
Authors: A Castricum, K Holzer, P Brukner, L Irving
Journal: British Journal of Sports Medicine (2008)

The International Olympic Committee-Medical Commission (IOC-MC) accepts a number of bronchial provocation tests for the diagnosis of exercise-induced bronchoconstriction (EIB) in elite athletes, none of which have been studied in elite swimmers. With the suggestion of a different pathogenesis involved in the development of EIB in swimmers, there is a possibility that the recommended test for EIB in elite athletes, the eucapnic voluntary hyperpnoea (EVH) challenge, may be missing the diagnosis in elite swimmers.The aim of this study was to assess the effectiveness of the EVH challenge, the field swim challenge and the laboratory cycle challenge in the diagnosis of EIB in elite swimmers.33 elite swimmers were evaluated on separate days for the presence of EIB using 3 different bronchial provocation challenge tests: an 8 minute field swim challenge, a 6 minute laboratory EVH challenge, and an 8 minute laboratory cycle challenge.Change in forced expiratory volume in 1 second (FEV(1)) pre and post test protocol. A fall in FEV(1) from baseline of > or =10% post challenge was diagnostic of EIB.Only 1 of the 33 subjects (3%) had a positive field swim challenge with a fall in FEV(1) of 16% from baseline. 18 of the 33 subjects (55%) had a positive EVH challenge, with a mean fall in FEV(1) of 20.4 (SD 11.7)% from baseline. 4 of the subjects (12%) had a positive laboratory cycle challenge, with a mean fall in FEV(1) of 14.8 (4.7)% from baseline. Only 1 of the 33 subjects was positive to all 3 challenges.These results suggest that the EVH challenge is a highly sensitive challenge for identifying EIB in elite swimmers, in contrast to the laboratory and field-based exercise challenge tests, which significantly underdiagnose the condition. The EVH challenge, a well-established and standardised test for EIB in elite winter and summer land-based athletes, should thus be used for the diagnosis of EIB in elite swimmers, as recommended by the IOC-MC.
Lebrikizumab reduces serum periostin in asthma patients with elevated baseline periostin
Authors: Heleen Scheerens, Joseph Arron, David Choy, Sofia Mosesova, Preeti Lal, John Matthews
Journal: European Respiratory Journal (2012)

Background:  Periostin is a matricellular protein induced in airway epithelia by interleukin-13 (IL13) and a good systemic biomarker for IL13 activity. Lebrikizumab, a humanized monoclonal antibody, binds IL13 and improved lung function in moderate-to-severe asthma patients (pts) with elevated baseline serum periostin in a Phase II study.   Aims:  To examine the effect of blocking IL13 on systemic periostin levels in pts with uncontrolled asthma, despite inhaled corticosteriods.   Methods:  Pts (n=218) were randomized to lebrikizumab 250 mg (n=106) or placebo (PB) (n=112) SC every 4 weeks for 6 doses, with 12 weeks follow-up (NCT00930163). Serum periostin was measured at baseline and throughout the study. Pts were classified as periostin-high (≥median) or periostin-low (   Results:  PB-corrected reductions in periostin were evident after 1 week of lebrikizumab treatment: 5.4% baseline reduction across all pts and 7.3% baseline reduction in periostin-high pts (p 90%) who were periostin-low at baseline maintained the periostin levels    Conclusions:  Lebrikizumab reduced serum periostin in periostin-high, but not periostin-low pts, vs placebo. These data suggest that in asthma pts, elevated serum periostin levels are dependent on IL13 activity.
Direct thrombin inhibitors in cardiovascular medicine.
Authors: J Lefkovits, E J Topol
Journal: Circulation (1994)

Currently used antithrombotics such as heparin have a number of potential limitations that may be overcome by the new class of agents that directly inhibit thrombin. These agents variously block the active catalytic and/or the anion binding exosites of the thrombin molecule and are potent and specific inhibitors of thrombin's many biological actions, as demonstrated by in vitro and animal models of thrombosis. Preliminary data indicate that the direct antithrombins are safe and efficacious in humans, and their use in acute coronary syndromes and coronary angioplasty in place of heparin has yielded promising early results. Phase III trials in these clinical settings are currently under way. Newer antithrombotics that inhibit thrombin generation and thrombin activity at various strategic points within the coagulation cascade are also in the early stages of development.
A novel TAT–Mitochondrial signal sequence fusion protein is processed, stays in mitochondria, and crosses the placenta
Authors: Victoria Del Gaizo, R Mark Payne
Journal: Molecular Therapy (2003)

Mutations in nuclear and mitochondrial genomes can lead to defects in mitochondrial function. To date, repair of these defects with exogenous proteins or gene transfer has been difficult with either viral or nonviral vectors. We hypothesized that TAT fusion proteins would cross both mitochondrial membranes and that incorporation of a mitochondrial signal sequence into a TAT fusion protein would allow processing and localization of exogenous proteins in mitochondria. A TAT-mitochondrial malate dehydrogenase signal sequence (mMDH)-enhanced green fluorescent protein (eGFP) fusion protein was constructed. TAT-mMDH-eGFP allowed rapid transduction and localization of fusion protein into mitochondria of multiple cell types. In contrast, TAT-GFP, without a mitochondrial signal sequence, rapidly transduced into cells and mitochondria, displayed pseudo-first-order kinetics, but did not remain there. Mice injected 5 days prior with TAT-mMDH-eGFP had detectable eGFP activity in multiple tissue types. Western blotting of cytosolic and mitochondrial fractions isolated from their livers confirmed eGFP localization to mitochondria and that the mMDH transit peptide was recognized and processed. Furthermore, TAT-mMDH-eGFP fusion protein injected into pregnant mice crossed the placenta and was detectable in both the fetus and the newborn pups. TAT fusion proteins containing a mitochondrial signal sequence are a viable method to localize proteins to mitochondria.
The 6-min walking distance: long-term follow up in patients with COPD
Authors: C. Casanova, C. G. Cote, J. M. Marin, J. P. de Torres, A. Aguirre-Jaime, R. Mendez, L. Dordelly, B. R. Celli
Journal: European Respiratory Journal (2006)

The 6-min walking distance (6MWD) test is used in clinical practice and research into patients with chronic obstructive pulmonary disease (COPD). However, little is known about natural long-term change in this parameter. The 6MWD was measured at baseline and then annually for 5 yrs in 294 patients with COPD and its annual rate of decline was determined. Forced expiratory volume in one second (FEV1) was also measured and the relationship between changes in both markers was explored. At baseline, the median 6MWD was 380 m (range 160-600 m). It declined by 19% (16 m.yr(-1)) over the 5 yrs compared with baseline in patients with American Thoracic Society/European Respiratory Society stage III COPD (FEV1 30-50% predicted) and by 26% (15 m.yr(-1)) in patients with stage IV COPD (FEV1 <30% pred). Over the 5-yr follow-up, the proportion of patients with a minimal clinically significant decline of 54 m increased with the severity of the disease. It was 24% in stage II, 45% in stage III, and 63% in stage IV disease. In contrast, the rate of decline of FEV1 was greater in patients with milder airflow obstruction and lesser in patients with lower absolute FEV1 values. In conclusion, the 6-min walking distance test provides increasingly useful information as the severity of chronic obstructive pulmonary disease increases.
Left Cardiac Sympathetic Denervation for Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Arthur A.M. Wilde, Zahurul A. Bhuiyan, Lia Crotti, Mario Facchini, Gaetano M. De Ferrari, Thomas Paul, Chiara Ferrandi, Dave R. Koolbergen, Attilio Odero, Peter J. Schwartz
Journal: New England Journal of Medicine (2008)

Catecholaminergic polymorphic ventricular tachycardia is a potentially lethal disease characterized by adrenergically mediated ventricular arrhythmias manifested especially in children and teenagers. Beta-blockers are the cornerstone of therapy, but some patients do not have a complete response to this therapy and receive an implantable cardioverter-defibrillator (ICD). Given the nature of catecholaminergic polymorphic ventricular tachycardia, ICD shocks may trigger new arrhythmias, leading to the administration of multiple shocks. We describe the long-term efficacy of surgical left cardiac sympathetic denervation in three young adults with catecholaminergic polymorphic ventricular tachycardia, all of whom had symptoms before the procedure and were symptom-free afterward.
Molecular and immunological characterization of Pen ch 18, the vacuolar serine protease major allergen of <i>Penicillium chrysogenum</i>
Authors: H.‐D. Shen, H. Chou, M. F. Tam, C.‐Y. Chang, H.‐Y. Lai, S.‐R. Wang
Journal: Allergy (2003)

Background: We have suggested previously that the 32 and 34 kDa major allergens of Penicillium chrysogenum (also known as P. notatum ) are the vacuolar (Pen ch 18) and the alkaline (Pen ch 13) serine proteases, respectively, of P. chrysogenum . The purpose of this study is to characterize the 32 kDa allergen of P. chrysogenum and its immunoglobulin E (IgE)cross‐reactivity with Pen ch 13 allergen. Methods: The full‐length cDNA of Pen ch 18 was isolated by reverse transcriptase‐polymerase chain reaction and the 5′‐rapid amplification cDNA end reaction. Recombinant Pen ch 18 was expressed as his‐tagged proteins in Escherichia coli . Its reactivity with IgE and monoclonal antibodies against fungal serine protease allergens was analyzed by immunoblotting. The IgE cross‐reactivity between Pen ch 18 and Pen ch 13 was analyzed by immunoblot inhibition. Overlapping recombinant fragments and synthetic peptides were used to map the B cell epitopes on Pen ch 18. Results: In this study, we isolated a 1857 bp cDNA fragment containing an open reading frame of 494 amino acids that encodes the preproenzyme of Pen ch 18. Similar to other vacuolar serine proteases, this precursor appears to undergo N‐ and possibly C‐terminal cleavage upon maturation. The his‐tagged recombinant Pen ch 18 containing the putative sequence of the mature protein reacted with IgE antibodies in serum samples from asthmatic patients. In addition, IgE‐binding to the 32 kDa major allergen of P. chrysogenum was inhibited when a positive serum sample was absorbed with recombinant Pen ch 18 before immunoblotting. Both inhibition and almost no inhibition of IgE‐binding to the 32 kDa major allergen of Pen ch 18 were detected when eight positive serum samples were preabsorbed individually with purified Pen ch 13 before immunoblotting. The major IgE binding region was located in a fragment (PN1) encompassing the N‐terminal 102 amino acid residues of the recombinant Pen ch 18. A dominant linear IgE epitope was further mapped within residues 73–95 (peptide PN1‐e) of the N‐terminally processed allergen. Monoclonal antibody FUM20 that reacts with Pen ch 18 but not with Pen ch 13 binds a synthetic peptide with sequence encompassing the N‐terminal 23 residues of the recombinant Pen ch 18. Monoclonal antibody PCM39 that reacts with both Pen ch 13 and Pen ch 18 recognizes a peptide containing residues 132–154 of the allergen. Conclusions: Our results confirm that the Pen ch 18 allergen is a vacuolar serine protease of P. chrysogenum that matures through N‐ and possibly C‐terminal processing. The finding that there are cross‐reactive and allergen‐specific IgE epitopes for Pen ch 18 and Pen ch 13 suggests that both major allergens should be included in clinically diagnostic P. chrysogenum extracts.
In vivo measurement of colonic butyrate metabolism in patients with quiescent ulcerative colitis
Authors: E J Simpson
Journal: Gut (2000)

<h3>BACKGROUND</h3> Butyrate, a short chain fatty acid produced by bacterial fermentation, is a major fuel source for the colonocyte. In vitro work has shown that ulcerative colitis may be characterised by a metabolic defect in colonocyte butyrate oxidation. <h3>AIMS</h3> To investigate the rate of metabolism of rectally administered butyrate in patients with quiescent colitis. <h3>METHODS</h3> [1-<sup>13</sup>C]-butyrate enemas were administered to 11 patients with long standing quiescent ulcerative colitis and to 10 control patients. The rate of production of <sup>13</sup>CO<sub>2</sub> in exhaled breath over four hours was measured by isotope ratio mass spectrometry combined with indirect calorimetry in order to measure CO<sub>2</sub> production. This allowed calculation of the patients9 resting energy expenditure and respiratory quotient. <h3>RESULTS</h3> Over a four hour period, 325 (SEM 21) μmol <sup>13</sup>CO<sub>2</sub> was recovered in breath samples from the colitis group compared with 322 (17) μmol from the control group (NS). The respiratory quotient of the colitic group was significantly lower than that of the control group. <h3>CONCLUSION</h3> There was no difference in the rate of metabolism of butyrate between the two groups. It is unlikely that there is a primary metabolic defect of butyrate metabolism in patients with quiescent ulcerative colitis.
Pulmonary Artery Catheterization
Authors: C. David Naylor
Journal: JAMA (1993)

<h3>Objectives.</h3> —To review the evidence regarding indications for pulmonary artery catheterization (PAC) in critically ill patients, and to propose a guideline-generating process that would encourage randomized controlled trials of PAC. <h3>Data Sources.</h3> —Computerized and manual search for randomized trials involving PAC as an integral part of the protocol, published as of October 1992. Manual search for guidelines endorsed by specialty societies and/or proposed by expert panels following an explicit group process. <h3>Data Synthesis.</h3> —Four trials suggest benefit from PAC for pre- or perioperative management of high-risk surgical patients. Two others indicate that PAC for low-risk aortic aneurysm surgery confers no advantages. Use of PAC to guide therapy aimed at improved mixed venous oxygen saturation was beneficial compared with usual care with PAC in two small trials among patients with septic shock and severe trauma. Other PAC indications are either untested or inadequately tested by small trials. Large trials are needed, but trials to date have been impeded by clinicians' uncertainty about PAC and unwillingness to randomize critically ill patients. No published guidelines for PAC have used a formal group process and/or a hierarchical review of evidence to demarcate proven from unproven indications. <h3>Conclusions.</h3> —We propose a research-promoting expert panel on indications for PAC. Aided by a critical literature review, experts would rate case scenarios on the need for routine PAC with or without a specified intervention strategy. Future trials should test indications where there is either consensus about the uncertainty of need for PAC, or interpanelist disagreement owing to inconclusive evidence. This process could facilitate practice guideline development, utilization management, and large trials of PAC and related interventions. (<i>JAMA</i>. 1993;269:2407-2411)
Pathogen-specific IgG antibody levels in immunodeficient patients receiving immunoglobulin replacement do not provide additional benefit to therapeutic management over total serum IgG
Authors: Ignatius Chua, Macarena Lagos, Bambos M. Charalambous, Sarita Workman, Ronnie Chee, Bodo Grimbacher
Journal: Journal of Allergy and Clinical Immunology (2011)
Long-term remission of Kaposi sarcoma–associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy
Authors: Mario Corbellino, Giovanna Bestetti, Chiara Scalamogna, Sara Calattini, Morena Galazzi, Luca Meroni, Daniele Manganaro, Marco Fasan, Mauro Moroni, Massimo Galli, Carlo Parravicini
Journal: Blood (2001)
Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke
Authors: Javier Milara, Teresa Peiró, Adela Serrano, Julio Cortijo
Journal: Thorax (2013)

<h3>Background</h3> Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of remodelling, peribronchiolar fibrosis is observed in the small airways of patients with COPD and contributes to airway obstruction. Epithelial to mesenchymal transition (EMT) appears to be involved in the formation of peribronchiolar fibrosis. This study examines the EMT process in human bronchial epithelial cells (HBECs) from non-smokers, smokers and patients with COPD as well as the in vitro effect of cigarette smoke extract (CSE) on EMT. <h3>Methods</h3> HBECs from non-smokers (n=5), smokers (n=12) and patients with COPD (n=15) were collected to measure the mesenchymal markers α-smooth muscle actin, vimentin and collagen type I and the epithelial markers E-cadherin, ZO-1 and cytokeratin 5 and 18 by real time-PCR and protein array. In vitro differentiated bronchial epithelial cells were stimulated with CSE. <h3>Results</h3> Mesenchymal markers were upregulated in HBECs of smokers and patients with COPD compared with non-smokers. In contrast, epithelial cell markers were downregulated. In vitro differentiated HBECs underwent EMT after 72 h of CSE exposure through the activation of intracellular reactive oxygen species, the release and autocrine action of transforming growth factor β<sub>1</sub>, the phosphorylation of ERK1/2 and Smad3 and by the downregulation of cyclic monophosphate. <h3>Conclusions</h3> The EMT process is present in bronchial epithelial cells of the small bronchi of smokers and patients with COPD and is activated by cigarette smoke in vitro.
The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer
Authors: Maria H Traka, Caroline A Spinks, Joanne F Doleman, Antonietta Melchini, Richard Y Ball, Robert D Mills, Richard F Mithen
Journal: Molecular Cancer (2010)

Abstract Background Dietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue. Results We initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing. Conclusion To our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.
Hepatocellular codistribution of c100, c33, c22, and NS5 hepatitis C virus antigens detected by using immunopurified polyclonal spontaneous human antibodies
Authors: Giorgio Ballardini, Paolo Groff, Fabrizio Giostra, Raffaella Francesconi, Rita Miniero, Sabrina Ghetti, Daniela Zauli, Francesco B. Bianchi
Journal: Hepatology (1995)

Hepatitis C virus (HCV) antigens in liver biopsy have been detected by immunohistochemistry using both spontaneous human IgG and murine monoclonal or rabbit polyclonal monospecific reagents. Conflicting results have been obtained in different studies. This was probably because of the incapacity of single experimental antibodies, raised against synthetic or recombinant peptides, to recognize native tissue antigens. To overcome this possibility, we immunopurified monospecific spontaneous polyclonal human Ig, therefore induced by native antigens, from the single antigen-containing bands of RIBA 3 strips. Antibodies to c100, c33, c22, and NS5 antigens were obtained from the serum of a patient affected by chronic hepatitis C. The IgG fraction of this serum had proved to stain tissue HCV antigens. Eight biopsies were selected on the basis of strong hepatocellular reactivity with the whole IgG fraction in a variable number (from 5% to 75%) of cells. The four antigens were detected in all biopsies; a clear cellular codistribution was observed on serial sections. These data demonstrate that the possibility to identify HCV antigens in liver biopsies is higher when using human antibodies induced by native antigens rather than experimental antibodies. The approach of immunopurification of human antibodies can be extended to other HCV-related epitopes to obtain reagents useful for the selection and optimization of monoclonal or polyclonal antibodies.
Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression
Authors: Motoyuki Igata, Hiroyuki Motoshima, Kaku Tsuruzoe, Kanou Kojima, Takeshi Matsumura, Tatsuya Kondo, Tetsuya Taguchi, Kazuhiko Nakamaru, Miyuki Yano, Daisuke Kukidome, Kazuya Matsumoto, Tetsushi Toyonaga, Tomoichiro Asano, Takeshi Nishikawa, Eiichi Araki
Journal: Circulation Research (2005)

Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21 CIP but not that of p27 KIP . Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.