tbuckley/cabot-search huggingface dataset:
Alpha-1-antitrypsin phenotype and endotoxin exposure are related to BHR but not to change in lung function in a 15 year follow up of young Danish farmers
Authors: Torben Sigsgaard, Anneli C.S. Bolund, Ioannis Basinas, Grethe Elholm, Øyvind Omland, Martin Miller, Vivi Schlünssen
Journal: European Respiratory Journal (2013)

We have earlier shown that farming exposure interacs with rare Alpha-1-antitrypsin (α1-AT) phenotypes in relation to BHR*. We studied 1,964 farming students and 407 controls in 1992/4, and 963 and 172 of these again in 2007/8. Spirometry, a health questionnaire, smoking and occupational history were collected each time. Cumulative dust and endotoxin exposures were estimated from job-exposure matrices based on personal dust measurements. Lung function change was expressed as Δz-scores using the LMS equations (Stanojevic S, et al. AJRCCM 2008; 177: 253-60). We also studied bronchial hyperresponsiveness using the Yan method with Metacholine. People with an α1-AT serum concentration   Table 1 shows the OR (95% c.i.) for BHR at follow up according to Pi-group, endotoxin exposure and smoking in the cohort.  It can be seen, that all three variables were significantly associated to an increased OR for BHR. This confirms our earlier finding in the cohort. However we were not able to show any significant interaction between Pi-types and exposure. No effect of the Pi types were found on lung function change, neither for FEV1 nor for FVC.  *Sigsgaard et al ERJ 2000.
Abstract 102: Acute Mechanical Unloading of the Left Ventricle Promotes Cardioprotective Signaling and Limits Myocardial Infarct Size
Authors: Navin K Kapur, Vikram Paruchuri, Xiaoying Qiao, Kevin Morine, Wajih Syed, Hamid Salehi, Sam Dow, Nimish Shah, Michele Esposito, Natesa Pandian, Richard H Karas
Journal: Circulation Research (2014)

Management of an acute myocardial infarction (AMI) focuses on restoring oxygen supply to limit myocardial damage, however ischemia-reperfusion injury (IRI) remains a major determinant of mortality in AMI. No studies have targeted initially reducing left ventricular stroke work (LVSW) to limit IRI in AMI. The Impella CP axial-flow pump reduces LVSW. We tested the hypothesis that first reducing myocardial work and delaying coronary reperfusion reduces infarct size by activating cardioprotective signaling pathways. Methods: AMI was induced by occlusion of the left anterior descending artery (LAD) via angioplasty for 90 minutes in 50kg male Yorkshire swine (n=5/group). In Group 1, the LAD was reperfused for 120 minutes. In Group 2, after 90 minutes of ischemia the Impella CP device was activated and the LAD left occluded for an additional 60 minutes (150 minutes of LAD occlusion total), followed by 120 minutes of reperfusion. The Impella CP was active throughout reperfusion. Western blot analysis quantified myocardial kinase activity. Results: Compared to Group 1, Group 2 had a reduced LVSW, LV end-diastolic volume and end-diastolic pressure after reperfusion [Fig A]. Group 2 showed increased myocardial phosphorylation of cardioprotective kinases: AKT, ERK, GSK3β and STAT-3 [Fig B]. Compared to Group 1, the percent myocardial infarct size normalized to the area at risk (AAR) was reduced in Group 2 (73+13% vs 42+15%, p=0.02). Conclusion: We report the potential benefit of primarily unloading the heart and delaying coronary reperfusion to salvage myocardium in AMI. This is the first report to examine the impact of the Impella CP on cardioprotective signaling in the heart.
30 day mortality and eosinopenia in patients with pneumonia
Authors: Carlos Echevarria, Tom Hartley, Thapas Nagarajan, Hilary Tedd, John Steer, Gerald John Gibson, Stephen Christopher Bourke
Journal: European Respiratory Journal (2014)

Introduction   Blood eosinophil count is an independent predictor of mortality in patients: with bacteraemia; requiring intensive care; and with acute exacerbations of COPD (AECOPD). In AECOPD eosinopenia may be related to steroid use prior to admission. We describe eosinopenia and mortality in patients with pneumonia and no chronic lung disease or maintenance steroid use.   Methods   198 patients, mean (SD) age 74 (16) years, were identified and data for mortality, eosinopenia ( 7 mmol/l, Respiratory rate >30/min, low systolic ( 65 years) were collected. Odds ratios (OR) for death at 30 days were calculated.   Results   A higher proportion of patients with eosinopenia had a raised CRP (>50mg/l) compared with those without eosinopenia (81.3% vs. 62.7% p   Discussion   Blood eosinopenia  50mg/l was weak.
Epicutaneous immunotherapy with a hypoallergenic Bet v 1 suppresses allergic asthma in a murine model
Authors: S. Siebeneicher, S. Reuter, A. Wangorsch, M. Krause, K. Foetisch, A. Heinz, S. Naito, A. Reuter, C. Taube, S. Vieths, S. Scheurer, M. Toda
Journal: Allergy (2015)

Due to reduced allergic potency, hypoallergenic variants have been suggested as safer and potentially more efficacious alternative to the corresponding wild-type allergens in allergen-specific immunotherapy. Here, we aimed at investigating the efficacy of recombinant Bet v 1B2, a hypoallergenic folding variant of Bet v 1, in epicutaneous immunotherapy to suppress asthmatic features using a murine model of birch pollen allergy.Before, or after sensitization with rBet v 1 plus ALUMW and intranasal challenges with birch pollen extract, BALB/c mice received epicutaneous immunization (EPI) with rBet v 1, or rBet v 1B2 on their depilated back. Prophylactic EPI with rBet v 1B2, but not with rBet v 1, suppressed serum levels of Bet v 1-specific IgE antibodies and reduced the number of eosinophils and the concentrations of Th2 cytokines in bronchoalveolar lavage. In an established allergic condition, serum levels of Bet v 1-specific IgE antibodies were similar between PBS-treated control mice and EPI-treated mice. However, therapeutic EPI with rBet v 1B2, but not with rBet v 1, significantly suppressed the development of airway inflammation and lung function impairment.This study is the first to show the effect of therapeutic EPI with a recombinant form of a hypoallergenic folding variant on the suppression of asthmatic features. Our results suggest that rBet v 1B2 along with its reduced IgE-binding capacity could be a preferred therapeutic allergen than wild-type rBet v 1 in epicutaneous immunotherapy of birch pollen-induced allergic asthma, in particular due to a lower risk of allergic side effect.
Intrinsic Resistance to Methotrexate of Cultured Mammalian Cells in Relation to the Inhibition Kinetics of Their Dihydrofolate Reductases
Authors: Robert C. Jackson, Leigh I. Hart, Kenneth R. Harrap
Journal: Cancer Research (1976)

Four cultured mammalian cell lines, differing in intrinsic resistance to methotrexate over a 70-fold range, have been compared with respect to several biochemical factors that might influence response to the drug. Cellular activity of the enzymes dihydrofolate reductase and thymidylate synthetase and the total levels of folate cofactors did not vary by more than a factor of 2 among the cell lines. All the cell types were able to transport extracellular methotrexate efficiently across the cell membrane, and at comparable rates. A kinetic study of highly purified dihydrofolate reductases from the four sources revealed small differences in the Km values for dihydrofolate and reduced nicotinamide adenine dinucleotide phosphate. A study was made of the inhibition of the four dihydrofolate reductases by methotrexate, and Ki values were obtained by fitting the Zone B equation of Goldstein (Goldstein, A., J. Gen. Physiol., 27: 529–580, 1944) to the resulting data. Values of Ki determined by this method correlated with intrinsic resistance of the cell lines and showed a 25-fold range from the most sensitive to the most resistant line. It is concluded that the response of a cell to methotrexate is significantly influenced by the dissociation constant of its dihydrofolate reductase-methotrexate complex.
The relationship between<i>Helicobacter pylori</i>seropositivity and COPD
Authors: Marc A Sze, Yu-Wei Roy Chen, Sheena Tam, Donald Tashkin, Robert A Wise, John E Connett, SF Paul Man, Don D Sin
Journal: Thorax (2015)

<h3>Rationale</h3> Chronic systemic infections such as those with <i>Helicobacter pylori (H. pylori)</i> may contribute to the evolution and progression of chronic obstructive pulmonary disease (COPD). Using data from the Lung Health Study (LHS), we determined the relationship of <i>H. pylori</i> infection with the severity and progression of COPD. <h3>Methods</h3> Using an immunoassay, we measured <i>H. pylori</i> immunoglobulin G (IgG) antibody titres in serum samples of 4765 patients with mild-to-moderate COPD. We then determined their relationship with the individual9s FEV<sub>1</sub> and the rate of decline in FEV<sub>1</sub> and mortality over 11 years using multiple regression analysis. <h3>Results</h3> Approximately 18% of the patients were seropositive to <i>H. pylori</i> and these individuals demonstrated lower FEV<sub>1</sub> (L) values at every study visit compared with individuals who were seronegative for <i>H. pylori</i> (p value=0.00012). However, patients with seropositivity to <i>H. pylori</i> were on average 0.012 m shorter than those with seronegativity (p value=0.0015). The significant relationship between FEV<sub>1</sub> and <i>H. pylori</i> seropositivity disappeared when FEV<sub>1</sub> per cent predicted (FEV<sub>1</sub>pp) was used (p value=0.45). <i>H. pylori</i> seropositive individuals had greater circulating C reactive protein (CRP) levels compared with <i>H. pylori</i> seronegative individuals (p value=0.012), and had increased risk of cardiovascular mortality (relative risk 1.61, p=0.05). <h3>Conclusions</h3> <i>H. pylori</i> infection was associated with reduced lung function that is most likely due to the effect of the bacterium on lung growth earlier in life. It is also associated with systemic inflammation and increased risk of cardiovascular mortality in patients with COPD. <h3>Trial registration numbers</h3> NCT00000568 and NCT00000569.
Pharyngeal Critical Pressure in Patients with Obstructive Sleep Apnea Syndrome
Authors: EMILIA SFORZA, CHRISTOPHE PETIAU, THOMAS WEISS, ANNE THIBAULT, JEAN KRIEGER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Current evidence suggests that patients with obstructive sleep apnea (OSA) may have greater pharyngeal critical pressure (Pcrit), which reflects the increase in upper airway collapsibility. The contribution of Pcrit to the severity of OSA and to the efficacious continuous positive pressure (nCPAPeff) therapy has never been extensively described and no data are available about the interaction of Pcrit, age, and anthropometric variables. To determine the relationship between Pcrit, severity of the disease, nCPAPeff, and anthropometric variables we measured Pcrit in a group of 106 patients with OSA. Pharyngeal critical pressure was derived from the relationship between maximal inspiratory flow and nasal pressure, Pcrit representing the extrapolated pressure at zero flow. Upper airway resistance (Rus) was determined as the reciprocal of the slope (DeltaPn/DeltaVImax cm H2O/L/s) in the regression equation. In a subgroup of 68 patients, during the diagnostic night, we measured as indices of respiratory effort, the maximal inspiratory esophageal pressure (Pes) at the end of apnea (Pesmax), the overall increase from the minimum to the maximum (DeltaPes), and the rate of increase of Pes during apnea (RPes). As a group, the mean Pcrit was 2.09 +/- 0.1 cm H2O (range, 0 to 4.5) and the mean Rus was 11.1 +/- 0.5 cm H2O/L/s. Although men have greater Pcrit, pharyngeal collapsibility was influenced neither by neck size nor by body mass index (BMI). Although there was a significant relationship between Pcrit and apnea plus hypopnea index (AHI) (r = 0.23, p = 0.02), neck circumference was the stronger predictor of apnea frequency, with Pcrit contributing only to the 3% of the variance. In the group of patients as a whole, a model including AHI, BMI, Rus, and Pcrit explained the 36% of the variance in nCPAPeff, with a greater contribution of AHI, Pcrit accounting for only 3% of the variation. In patients for whom the measure of respiratory effort was obtained, 42% of the variance in nCPAPeff was explained by RPes (33%) and BMI. From these results we conclude that Pcrit alone does not yield a diagnostically accurate estimation of OSA severity and nCPAPeff. Although individual collapsibility may predispose to pharyngeal collapse, upper airway occlusion may require the combination of several factors, including obesity, upper airway structure, and abnormalities in muscle control.
Incidence of Ocular Injuries from Road Traffic Accidents after Introduction of Seat Belt Legislation
Authors: S A Vernon, D B Yorston
Journal: Journal of the Royal Society of Medicine (1984)

A prospective study was performed to characterize any change in the pattern of ocular injuries following the introduction of compulsory front seat belt wear on 1 February 1983. During a 24-week period in 1981 (1 February to 31 July), 24 patients with eye and adnexal injuries as a result of motor car road traffic accidents (RTAs) were seen at the Bristol Eye Hospital: 12 of these patients required emergency surgery. In the identical period two years later (1 February to 31 July 1983), only 6 patients suffered ocular injury from RTAs: 3 of these required emergency surgery. All patients in the latter series obeying the legislation on seat belt use were injured by flying glass, indicating a possible change in pattern of injury. The decrease in incidence of ocular injuries from RTAs between the two series was shown to be statistically significant. The compulsory fitting of laminated glass to all new cars in Great Britain and Europe is strongly advised.
A new method to determine the site of upper airway obstruction using sleep induced endoscopy in patients with obstructive sleep apnea
Authors: Marcelo G. Gregorio, Marcia Jacomelli, Naury Danzi-Soares, Fabiola Schorr, Pedro R. Genta, Geraldo Lorenzi-Filho
Journal: European Respiratory Journal (2011)

We evaluated 12 male OSA patients, age= 54±10y; body mass index = 28.8±3.5 kg/m2 and apnea hypopnea-index = 39±18 events/h. The patients were monitored by full polysomnography and sleep was induced by midazolam drip infusion. The patients slept with a nasal mask attached to a flow generator capable of producing positive and negative pressures. After obtaining stable breathing, mask pressure was dialed down for 5 breaths to pre-established levels that induced flow restriction and apnea. Obstruction of the upper airway at the retropalatal (PAL) and retroglossal (GLOS) sites were classified as partial or complete by direct endoscopy visualization.  Results: The midazolam dose used was 3.7±2,25 mg and the mask pressure used to obtain flow restriction and apnea was 3.4±2.8 and 0.8±2.9 cmH2O, respectively. The behavior of the upper airways of all patients during flow restriction and apnea is presented below.  Five patients (42%) presented exclusively retropalatal (n=2) or retroglossal (n=3) obstruction during apena, suggesting that the site of obstruction is variable during obstructive events. We conclude that this is a promising method that may help to understand the mechanisms leading to OSA.
Ultrastructural Cell Patterns in Human Gastric Carcinoma Compared With Non-Neoplastic Gastric Mucosa—Histogenetic Analysis of Carcinoma by Mucin Histochemistry&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Nobuaki Sasano, Katsuhiro Nakamura, Motonobu Arai, Kaneyoshi Akazaki
Journal: JNCI Journal of the National Cancer Institute (1969)

Surgically removed specimens from 415 human stomachs, 16 without cancer and 399 with carcinomas, were studied cytologically for a comparison between benign epithelia and carcinoma cells. Of these, 69 were studied by electron microscopy. In noncancerous stomachs, mucus-bearing cells, especially mucous neck cells, are described in detail. The foveolar cells, especially those in the pyloric antrum, seemed most significant in the cytogenesis of gastric cancer. Gastric carcinoma cells were markedly variable, but they were conveniently divided into four groups: 1) undifferentiated carcinoma cells, 2) carcinoma cells resembling intestinal epithelium, 3) those resembling gastric cells proper, and 4) those resembling epidermoid cells. Electron microscopically, almost all gastric cancers revealed intestinalization. Carcinoma cells similar to the gastric epithelium proper were rarely observed. Among them, surface epithelial cell and foveolar cell types occurred most often. Carcinoma cells bearing zymogen granules were sparse. Twenty-nine adenoacanthomas, including nineteen additional subtypes, showed a histologic transition from “adenocarcinoma papillare medullare,” and nine of these showed intestinalization at the same time. So-called signet-ring cells could be divided into two groups. Almost all resembled goblet cells, but a few were similar to pyloric gland cells.
Clonality of slime-producing methicillin-resistant coagulase-negative staphylococci disseminated in the neonatal intensive care unit of a university hospital
Authors: A. Foka, V. Chini, E. Petinaki, F. Kolonitsiou, E.D. Anastassiou, G. Dimitracopoulos, I. Spiliopoulou
Journal: Clinical Microbiology and Infection (2006)
Inhibition of Spermidine/Spermine N1‐Acetyltransferase Activity: A New Therapeutic Concept in Rheumatoid Arthritis
Authors: Michel Neidhart, Emmanuel Karouzakis, Astrid Jüngel, Renate E. Gay, Steffen Gay
Journal: Arthritis & Rheumatology (2014)

Objective Changes in polyamine‐modulated factor 1 (PMF‐1) promoter methylation might favor the expression of spermidine/spermine N1‐acetyltransferase 1 (SSAT‐1), causing excessive consumption of S ‐adenosyl methionine (SAM). This study was undertaken to evaluate the effect of SSAT‐1 activity inhibition, either alone or in combination with SAM. Methods Synovial fibroblasts were isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). PMF‐1 promoter methylation was determined by pyrosequencing. Small interfering RNAs (siRNAs) against SSAT‐1 were transfected weekly in RA synovial fibroblasts (RASFs). In addition, synovial fibroblasts were treated with diminazene aceturate (DA), an inhibitor of SSAT‐1. SSAT‐1, 5‐methylcytosine (5‐MeC), adenosyl methionine decarboxylase (AMD), PMF‐1, DNA methyltransferase 1 (DNMT‐1), CXCL12, β1 integrin, and CD44 levels were measured by flow cytometry. Putrescine levels were determined by colorimetry. Levels of matrix metalloproteinases were measured by enzyme‐linked immunosorbent assay. Cell adhesion was tested. The SCID mouse model of RA was used to monitor the invasiveness of RASFs. Results RASFs showed elevated SSAT‐1, AMD, and PMF‐1 levels. However, PMF‐1 promoter methylation was unchanged. Transfection of siRNA targeting SSAT‐1 increased 5‐MeC levels within 21 days. Similarly, DA increased 5‐MeC levels in RASFs. In addition, DA increased the levels of DNMT‐1, decreased the levels of AMD, putrescine, activation markers, and MMP‐1, and altered the adhesion of RASFs. DA was more efficient in RASFs with higher levels of SSAT‐1. Most interestingly, the combination of DA and SAM reduced the invasiveness of RASFs by 70%. Conclusion The use of DA alone or in combination with SAM/ l ‐methionine might introduce a new therapeutic concept in RA. This is the first therapy that would directly target RASFs and thereby inhibit ongoing joint destruction.
Multivalent Forms of the Notch Ligand DLL-1 Enhance Antitumor T-cell Immunity in Lung Cancer and Improve Efficacy of EGFR-Targeted Therapy
Authors: Asel K. Biktasova, Duafalia F. Dudimah, Roman V. Uzhachenko, Kyungho Park, Anwari Akhter, Rajeswara R. Arasada, Jason V. Evans, Sergey V. Novitskiy, Elena E. Tchekneva, David P. Carbone, Anil Shanker, Mikhail M. Dikov
Journal: Cancer Research (2015)

Activation of Notch signaling in hematopoietic cells by tumors contributes to immune escape. T-cell defects in tumors can be reversed by treating tumor-bearing mice with multivalent forms of the Notch receptor ligand DLL-1, but the immunologic correlates of this effect have not been elucidated. Here, we report mechanistic insights along with the efficacy of combinational treatments of multivalent DLL-1 with oncoprotein targeting drugs in preclinical mouse models of lung cancer. Systemic DLL-1 administration increased T-cell infiltration into tumors and elevated numbers of CD44(+)CD62L(+)CD8(+) memory T cells while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells enhanced expression of T-bet and phosphorylation of Stat1/2. Adoptive transfer of T cells from DLL1-treated tumor-bearing immunocompetent hosts into tumor-bearing SCID-NOD immunocompromised mice attenuated tumor growth and extended tumor-free survival in the recipients. When combined with the EGFR-targeted drug erlotinib, DLL-1 significantly improved progression-free survival by inducing robust tumor-specific T-cell immunity. In tissue culture, DLL1 induced proliferation of human peripheral T cells, but lacked proliferative or clonogenic effects on lung cancer cells. Our findings offer preclinical mechanistic support for the development of multivalent DLL1 to stimulate antitumor immunity.
Utilization of FIXED combination (FC) in the treatment of asthma patients in real life condition in the Czech Republic (UFO)
Authors: Viktor Kasak, Eva Kasakova, Jana Vinklerova
Journal: European Respiratory Journal (2012)

Moderate and severe asthma is treated by FC of BUD/FOR, SAL/FP and BDP/FOR in the Czech Republic (CR). We do not have any data about real life utilization of FC in asthma treatment in the CR.  Primary obj.: Utilization of FC in the treatment of asthma pts. per year 2010. Secondary obj.: To describe asthma treatment in the CR in pts. who were prescribed a FC therapy.  Our study looking into the pts. records kept by specialist - allergists (132) and pulmologists (144). Every participating investigator recruited 10 pts. for the study.  Asthmatic outpatients older than 6 years (n = 2786) who come to a regular visit were treated with one of three FC for at least 18 months. There were 1,8% pts. with intermittent asthma, 18,8% pts. with mild persistent, 67,6% pts. with moderate persistent, 12,2% pts. with severe persistent including 3,4% pts. with asthma difficult to treat.  60.8% pts. were treated with BUD/FOR (55.9% pts. in convectional regime, 44.1% pts. in the SMART regime), 37.3% pts. were treated with SAL/FP, 1.9% pts. were treated with BDP/FOR). Median of number of pack prescribed per year to pts. with asthma for BUD/FOR in convectional regime was 7 and in SMART regime was 7, for SAL/FP 12, for BDP/FOR 6. Total compliance of using FC was 53%, compliance of using FC in convectional regimes was 48.5%, compliance of using BUD/FOR in the SMART regime was 68%.  The utilization of BUD/FOR in SMART regime in the treatment of asthma pts. per year was the same as the utilization of BUD/FOR in convectional regime. Therapy of BUD/FOR in SMART regime increased compliance in comparison with convectional regimes of the other FC.