tbuckley/cabot-search huggingface dataset:
Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
Authors: Larry Mansouri, Lesley-Ann Sutton, Viktor Ljungström, Sina Bondza, Linda Arngården, Sujata Bhoi, Jimmy Larsson, Diego Cortese, Antonia Kalushkova, Karla Plevova, Emma Young, Rebeqa Gunnarsson, Elin Falk-Sörqvist, Peter Lönn, Alice F. Muggen, Xiao-Jie Yan, Birgitta Sander, Gunilla Enblad, Karin E. Smedby, Gunnar Juliusson, Chrysoula Belessi, Johan Rung, Nicholas Chiorazzi, Jonathan C. Strefford, Anton W. Langerak, Sarka Pospisilova, Frederic Davi, Mats Hellström, Helena Jernberg-Wiklund, Paolo Ghia, Ola Söderberg, Kostas Stamatopoulos, Mats Nilsson, Richard Rosenquist
Journal: The Journal of Experimental Medicine (2015)

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.
Comparison of measures of ventilation heterogeneity derived from multiple breath inert gas washout
Authors: Sherif Gonem, Steven Corkill, Amisha Singapuri, Dhananjay Desai, Per Gustafsson, Christopher Brightling, Salman Siddiqui
Journal: European Respiratory Journal (2012)

Introduction:  Multiple breath inert gas washout (MBW) is a technique for quantifying ventilation heterogeneity (VH). We compared four measures of VH with regard to repeatability, ability to discriminate between healthy subjects and patients with asthma, and robustness to variations in tidal volume (Vt), anatomical dead space (Vd) and functional residual capacity (FRC).   Methods:  MBW was performed in triplicate on 13 healthy subjects and 22 patients with moderate to severe asthma, using a previously published method (Horsley  et al .  Thorax . 2008; 63(2): 135-140). Lung clearance index (LCI), mixing ratio (MiR) and moment ratio (MoR) were calculated. A novel marker of VH, the rate constant ratio (RCR), was calculated by fitting the washout data to a two-phase decay model and calculating the ratio between the fast and slow rate constants. Repeatability and discriminatory ability were assessed using intraclass correlation coefficients (ICC) and receiver operating characteristic (ROC) curves, respectively. Robustness of the parameters was assessed by calculating the signal-to-noise ratio (SNR), using simulated MBW data to determine the noise caused by variations in FRC, Vt and Vd.   Results:  LCI, MoR and MiR exhibited good repeatability, with ICC values of 0.899, 0.888 and 0.885 respectively, but RCR was less repeatable (ICC = 0.783). The parameters all had areas under the ROC curve between 0.7 and 0.75. The most robust parameter was the RCR (SNR = ∞), followed by the MiR (SNR = 6.8), LCI (SNR = 3.4) and MoR (SNR = 1.2).   Conclusion:  MiR appears to be the most favourable measure of VH. We recommend that it is reported alongside the LCI.
Evaluation of patients admitted to our outpatient smoking cessation clinic
Authors: Mine Atun Dikici, Bedriye Atay Yayla, Fatma Evyapan
Journal: European Respiratory Journal (2013)

Aim: Majority of the smokers intend to stop smoking. However success rate is low and is affected by many factors. In a previous report (February 2009-January 2011) we found that he rate of smoking cessation rate was 21,8 % for 2 years. We further assessed the properties of patients admitted to our cigarette smoking cessattion setting between 2009-2013  Material and Methods: In this retrospective cohort study we evaluated 621 people admitted to our smoking cessation clinic between February 2009- February 2013.  Results: Patients mean age was: 41,11±13 (min:16, max: 75) ; 71 % male,29% were female with mean 26,42 ± 20,542 pack-years of smoking status. Almost all patients (87.1%) had complaints related to cigarette consumption: halithosis (64.1%), dyspnea (58,8%), sputum (56.1%), and 85,5 % of patients had already unsuccessful attempt to quit. Fagerstrom tests showed that 64.9 % our patients had   6. The most common comorbidities in patients were dyslipidemia (11.6%), hypertension (10.8%), DM (9.8%), COPD (%9.5).  Conclusions: Between February 2009 –January 2011 medical treatment was started 47.7% of the patients. Between January 2011 and January 2013 this ratio had increased to 72.8%.  This may be a result of smoking cessation drugs (bupropion and varenicline) had been distributed free by the Ministry of Health in February 2012.
Identification of Anaplasma phagocytophilum in tick populations in Estonia, the European part of Russia and Belarus
Authors: O. Katargina, J. Geller, A. Alekseev, H. Dubinina, G. Efremova, N. Mishaeva, V. Vasilenko, T. Kuznetsova, L. Järvekülg, S. Vene, Å. Lundkvist, I. Golovljova
Journal: Clinical Microbiology and Infection (2011)
Prospective assessment of menstrually related mood disorders
Authors: David R Rubinow, Peter Roy-Byrne, M. Christine Hoban, Philip W. Gold, Robert M. Post
Journal: American Journal of Psychiatry (1984)

For prospective longitudinal confirmation of menstrually related mood changes, the authors selected a 100-mm visual analogue scale for twice-daily self-rating of mood. The advantages of this method are simplicity; increased compliance; ease of graphic presentation, allowing evaluation of severity and relationship to menstruation; and greater uniformity among studies of menstrually related syndromes. In a preliminary application of this measure to 20 women with self-diagnosed premenstrual syndrome, eight (40%) had a mean depression rating during the week before menstruation that was 30% higher than during the week after cessation of menstruation.
Prospective, Multicenter Evaluation of Risk Factors Associated With Invasive Bacterial Infection in Children With Cancer, Neutropenia, and Fever
Authors: M. E. Santolaya, A. M. Alvarez, A. Becker, J. Cofré, N. Enríquez, M. O’Ryan, E. Payá, J. Pilorget, C. Salgado, J. Tordecilla, M. Varas, M. Villarroel, T. Viviani, M. Zubieta
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To identify clinical and laboratory parameters present at the time of a first evaluation that could help predict which children with cancer, fever, and neutropenia were at high risk or low risk for an invasive bacterial infection. PATIENTS AND METHODS: Over a 17-month period, all children with cancer, fever, and neutropenia admitted to five hospitals in Santiago, Chile, were enrolled onto a prospective protocol. Associations between admission parameters and risk for invasive bacterial infection were assessed by univariate and logistic regression analyses. RESULTS: A total of 447 febrile neutropenic episodes occurred in 257 children. Five parameters were statistically independent risk factors for an invasive bacterial infection. Ranked by order of significance, they were as follows: C-reactive protein levels of 90 mg/L or higher (relative risk [RR], 4.2; 95% confidence interval [CI], 3.6 to 4.8); presence of hypotension (RR, 2.7; 95% CI, 2.3 to 3.2); relapse of leukemia as cancer type (RR, 1.8, 95% CI, 1.7 to 2.3); platelet count less than or equal to 50,000/mm 3 (RR, 1.7; 95% CI, 1.4 to 2.2); and recent (≤ 7 days) chemotherapy (RR, 1.3; 95% CI, 1.1 to 1.6). Other previously postulated risk factors (magnitude of fever, monocyte count) were not independent risk factors in this study population. CONCLUSION: In a large population of children, common clinical and laboratory admission parameters were identified that can help predict the risk for an invasive bacterial infection. These results encourage the possibility of a more selective management strategy for these children.
LSC 2014 abstract - Proteinase activated receptor-1 (PAR1) plays a key role in the early inflammatory response to streptococcus pneumoniae pulmonary infection
Authors: Ricardo José, Andrew Williams, Michal Sulikowski, Natalia Smoktunowicz, Paul Mercer, Jeremy Brown, Rachel Chambers
Journal: European Respiratory Journal (2014)

Introduction:  S. pneumoniae  is the most common cause of community acquired pneumonia and may result in an exaggerated inflammatory response associated with lung injury. PAR1 has been implicated in coagulation-inflammation cross-talk but its role in pneumococcal-induced pulmonary inflammation is poorly understood.   Methods:  BALB/c mice were challenged intranasally with  S. pneumoniae  (D39) or PBS followed by an intraperitoneal injection of a highly selective PAR 1  antagonist SCH530348 (or vehicle) every 12 h. Mice were culled at 4, 24 and 48 h. In separate experiments paraffin embeded lung slices were immunostained for PAR 1 , Ly6G and  S. pneumoniae .   Results:  S. pneumoniae  infection resulted in increased bronchoalveolar lavage fluid (BALF) neutrophil counts and albumin levels, as well as increased levels of whole lung TNF-α, IL-1β, IL-6, IFNγ, KC, CCL2 and CCL7. On immunohistochemical analysis, areas of Ly6G staining correlated with areas of  S. pneumoniae  staining. PAR 1  antagonism significantly reduced BALF neutrophil counts at 4 and 24 h, and attenuated the increase in IL-1β, CCL2 and CCL7 levels at 4 h following  S. pneumoniae  challenge. Bacterial counts in BALF, lung homogenates and blood were not affected by PAR1 antagonism at any of the time points examined. Additionally, PAR 1  antagonism attenuated albumin levels from recovered BALF at 24 h.   Conclusion:  PAR 1  antagonism attenuates  S. pneumoniae -induced early neutrophilic inflammation and alveolar barrier disruption without compromising host defence.
Bispectral index (BIS®) in hypercapnic encephalopathy caused by COPD exacerbation
Authors: Roberto Chalela Rengifo, Sergi Pascual Guardia, Joaquin Gea Guiral, Lluis Gallart Gallego, Mauricio Orozco Levi
Journal: European Respiratory Journal (2013)

Introduction : hypercapnic encephalopathy (HE) is frequently observed in COPD exacerbations and no scale is validated to measure its intensity. Bispectral Index (BIS), is an electronic tool that uses algorithmic analyses of electroencephalogram and is used to measure the depth of anesthesia

Objective : to evaluate the relationship between the values of the BIS and the sedation/awareness scales most frequently used (Glasgow Coma Scale, GCS; Ramsay Sedation Scale; and Richmond Scale) in patients with COPD exacerbation and HE

Methods : we selected 10 patients with COPD exacerbation, respiratory acidosis, neurological alterations (as expression of HE) and candidates for non-invasive mechanical ventilation (NMV). BIS Monitor and NMV were started at the same time. Gas exchange and neurological alertness scales were measured, as well as brain activity using the continuous BIS system (scale 0-100). 35 measurements were performed

Results : there is a significant correlation between the clinical scales and BIS values (Ramsay-BIS, r2=-0.812; GCS-BIS, r2=0.707, and Richmond-BIS, r2=0.594, p <0.001 all 3). Analysed per categories, we found that lesser degrees of HE (Ramsay 2) had an average BIS of 92 (95% CI 90-94), whereas in Ramsay 3 was 66 (95% CI 55-78) and Ramsay 4 was 59 (95% CI 49-69). In stable phases it was 95±3.

Conclusions : the clinical scales are subjective and not necessarily applicable to discriminate levels of HE. The BIS monitor displays quantitative, continuous information and it is equipped with alarms that could be used to warn about severe HE; it provides more detailed information than the offered by other scales and could be useful to monitor the progress of patients with NMV.
Immunotoxins to a Human Melanoma-Associated Antigen: Resistance to Pokeweed Antiviral Protein Conjugates In Vitro
Authors: A C Morgan, J Bordonaro, J W Pearson, G Sivam
Journal: JNCI Journal of the National Cancer Institute (1987)

Pokeweed antiviral protein (PAP) from the summer leaves of Phytolacca americana was purified and conjugated via N-succinimidyl-3-(2-pyridyldithio)propionate to 9.2.27 anti-melanoma antibody to a glycoprotein-proteoglycan complex. The conjugate was highly potent (50% inhibition dose of 5 X 10(-11)-10(-13) M on antigen-positive melanoma) and highly selective (5 X 10(-8) on antigen-negative melanoma). Human melanoma cells were selected for resistance to in vitro killing of the PAP conjugate by cycling through a killing and recovery sequence. Resultant cultures were shown to be more than 2 logs less sensitive to the killing of the PAP conjugate than untreated cultures. Isolation of clones by limiting dilution and reanalysis indicated that the resistant polyclonal culture contained clones with a range of sensitivities. Resistant cultures were also resistant to other A-chain conjugates of 9.2.27, but not to intact toxins like ricin and abrin. Resistant cultures showed no change in antigen expression after selection with the PAP conjugate of 9.2.27. Thus, just as with many other chemotherapeutic agents, tumor cells can become resistant to agents inhibiting protein synthesis even when targeted with monoclonal antibody. The mechanisms of this resistance and modalities to minimize resistance are currently being explored.
Association between information provision and decisional conflict in cancer patients
Authors: J.A. Sim, J.S. Shin, S.M. Park, Y.J. Chang, A. Shin, D.Y. Noh, W. Han, H.K. Yang, H.J. Lee, Y.W. Kim, Y.T. Kim, S.Y. Jeong, J.H. Yoon, Y.J. Kim, D.S. Heo, T.Y. Kim, D.Y. Oh, H.G. Wu, H.J. Kim, E.K. Chie, K.W. Kang, Y.H. Yun
Journal: Annals of Oncology (2015)
Higher rates of streptococcal colonization among children in the Pacific Rim Region correlates with higher rates of group A streptococcal disease and sequelae
Authors: G. Erdem, S. Sinclair, J.R. Marrone, T.F. I'atala, A. Tuua, B. Tuua, F. Tuumua, A. Dodd, C. Mizumoto, L. Medina
Journal: Clinical Microbiology and Infection (2009)
Increased oxidized methionine residues in BAL fluid proteins in acute or chronic bronchitis
Authors: KL Maier, L Leuschel, U Costabel
Journal: European Respiratory Journal (1992)

Phagocytic cells such as alveolar macrophages (AM) or polymorphonuclear neutrophils (PMN) in the bronchoalveolar tract are a potential source of the oxygen-derived free radicals which are presumed to be involved in lung tissue damage. Previous results have shown that the methionine sulphoxide (MET(O)) content of bronchoalveolar lavage fluid (BALF) protein is a reliable parameter to indicate oxidative processes in idiopathic pulmonary fibrosis (IPF). We measured the molar ratio between MET(O) and methionine (MET) in the BALF protein from healthy nonsmokers (control group), healthy smokers and patients with acute or chronic bronchitis (AB or CB). The MET(O)/MET ratio of the nonsmoking group (n = 11) was 0.046 +/- 0.008 (mean +/- SEM). Healthy smokers (n = 8) had similar values (0.042 +/- 0.008), even though they had strongly increased AM counts in BALF. Patients with AB (n = 12) showed an increased MET(O)/MET ratio (0.191 +/- 0.031) and had high PMN but normal AM counts in BALF. Patients with CB (n = 13) showed an increase in the MET(O)/MET ratio (0.086 +/- 0.010) and moderately increased PMN and markedly increased AM counts. Taking all results together, the MET(O)/MET ratio correlated positively with the relative PMN number (r = 0.70; p less than 0.0002) and inversely with the relative AM number (r = 0.67; p less than 0.0002). In the group with CB, the MET(O)/MET ratio correlated inversely with forced expiratory volume in one second (FEV1) % pred. (r = -0.77) and FEV1/inspiratory vital capacity (IVC) % pred. (r = -0.89).(ABSTRACT TRUNCATED AT 250 WORDS)
Induced sputum differential gene expression implicates increased p38 signalling activity in severe asthma
Authors: Katherine Baines, Jodie Simpson, Lisa Wood, Rodney Scott, Peter Gibson
Journal: European Respiratory Journal (2011)

Rationale: There is an urgent need for further insight into the characteristics and classifications of severe asthma. A thorough understanding of the mechanisms underlying the disease processes is essential to this.

Objective: To investigate the mechanisms of severe asthma through differential gene expression and pathways analysis of sputum gene expression profiles.

Methods: Induced sputum was collected from participants with severe asthma (n=12), defined by the presence of poor asthma control (ACQ>1) or airflow obstruction (FEV1%predicted 1000μg) and long-acting β-agonist, and compared to mild and moderate asthma (uncontrolled (n=21) and controlled (n=21)) and healthy controls (n=13). Gene expression profiles were generated (Illumina Humanref-8 V2) from sputum RNA and analysed using GeneSpring GX11.

Results: In severe asthma, 1236 genes were altered compared to controlled asthma, and 1723 genes were altered compared to healthy controls. Only 48 genes were altered between uncontrolled and controlled asthma. There was enrichment of genes in the p38 signalling pathway associated with severe asthma compared to both controlled asthma and healthy controls. The transforming growth factor-β receptor, interleukin-2 and epidermal growth factor receptor 1 pathways were also enriched in severe asthma when compared to healthy controls.

Conclusions: Severe asthma is associated with substantial differences in sputum gene expression that underlie unique cellular mechanisms that are not just associated with loss of asthma control. The p38 signalling pathway may be important in the pathogenesis of severe asthma.
Cyclic AMP mediates the anti-asthma properties of the lidocaine analog JMF2-1
Authors: Priscilla Olsen, Luciana Coelho, Jorge Costa, Renato Cordeiro, Patricia Silva, Marco Martins
Journal: European Respiratory Journal (2012)

Inhalation of JMF2-1, an analog of lidocaine with reduced anesthetic activity, prevents airway contraction and lung inflammation in experimental asthma models. We sought to test if JMF2-1 effects are a consequence of increased intracellular cAMP levels in asthma cell targets, such as smooth muscle cells and T cells. Apoptosis of T cells treated with JMF2-1 in vitro was assessed by flow cytometry. The spasmolytic effect of JMF2-1 was tested on isolated rat tracheal rings. Intracellular levels of cAMP from T cells and airway smooth muscle cells treated with JMF2-1 were detected by radioimmunoassay. We found that JMF2-1 inhibited tracheal ring contraction induced by carbachol. The antispasmodic effect remained unaltered following epithelium removal or pretreatment with L-NAME, but it was clearly sensitive to 9-(tetrahydro-2-furyl) adenine (SQ22,536), an adenylate cyclase inhibitor. JMF2-1 induced apoptosis of anti-CD3 activated T cells in a mechanism sensitive to zIETD, indicating that JMF2-1 mediates caspase-8-dependent apoptosis. JMF2-1 significantly increased cAMP intracellular levels ( P < 0.05) of cultured airway smooth muscle cells (from 2.3 ± 0.7 to 44.1 ± 1.9) and T lymphocytes (from 36.3 ± 5.9 to 208.3 ± 25.8 pMol/mg of protein) (mean ± SEM, n=3). This effect was consistently abrogated by SQ22,536 and reproduced by forskolin in both systems. Our results suggest that JMF2-1 inhibits respiratory smooth muscle contraction as well as T cell survival through enhancement of intracellular cAMP levels. These findings may help to explain the anti-inflammatory and antispasmodic effects of JMF2-1 observed in previous studies.
How did the tuberculosis patients reach to a tuberculosis dispensary and how long did it take
Authors: Dilek Karadogan, Betül Abduloglu, Göksel Kiter
Journal: European Respiratory Journal (2011)

The aim of this study is to evaluate the patients diagnosed as tuberculosis and registered to a Tuberculosis dispensary in year 2010 according to the health care units which they applied beforehand and the time period since first symptom of tuberculosis has occurred.  For this descriptive study, the questionnaires which consist of questions about enrolled tuberculosis patients9 characteristics, symptoms, duration between the first symptom and diagnosis,and health care units they applied before coming to tuberculosis dispensary have been filled with face to face interviews.  Total 127 questionnaires were completed, the majority of patients were male (59.1%). Mean age was 51±20 years. The rate of lung tuberculosis was 59.1% and the rest were extrapulmonary tuberculosis. City center was declared as residency place in 54.3% of patients. By the time of tuberculosis diagnosis, 5.5% of patients have no health insurrance. The most common symptoms were cough (55%), weakness (52.8%) and night sweat (44.9%). At least one symptom has started more than one month before the diagnosis in 47.2% of patients, while in 19.7% less than one month. First application rates were found as 7.9%, 59% and 29.1% to primary, secondary and tertiary care units, respectively. The rate to be sent to another health care unit after first application was 66.1%. Tuberculosis was diagnosed mostly in university hospital (35.0%), the rate for tuberculosis dispensary was 23.6%.  A strategy targeted to improve the role and efficacy of primary care units in referral of the patients with highly suggestive symptoms to the tuberculosis dispensaries should have the priority to avoid the time lag in diagnosis.
Tear gas causes small airway obstruction in women
Authors: Eda Uslu, Gulcihan Ozkan, Cagla Uyanusta Kucuk, Hilal Onaran, Cagla Pinar Tastan Uzunmehmetoglu, Aslihan Ilgaz, Gamze Ayar, Makbule Ozlem Akbay, Hikmet Firat, Tansu Ulukavak Ciftci, Serdar Akpinar, Bulent Ciftci, Selma Firat Guven, Selen Bilekli, Arif Muezzinoglu, Fatih Torlak, Peri Arbak, Elif Dagli
Journal: European Respiratory Journal (2014)

Objective:  There is little known about effects of tear gas on different genders. This study was carried out to investigate the respiratory complaints and lung functions in women and men exposed to tear gas.   Methods:  During the June 2013 public demonstrations questionnaire survey was performed and lung function measuremenst were done in 460 demonstrators from Istanbul and 86 from Ankara.   Findings:  283 males (age:31.2±11.1) and 262 females (aged:31.2±9.9) participated in the study. Smoking rates were found to be 62.3% in females, and 64.1 % among males. Females exposed to gas indoors were significantly higher than males 31.5 % vs 20.4 % p=0.015). Among females , compared to males chest tightness (79.4% vs 66.3%,p=0.001), cough (87.3% vs 77.8%, p=0.003), chest pain (51.7% vs 41.8%) , nasal discharge (78.8% vs 70.3%, p=0.016) and skin irritation (54.2% vs 40.8%, p=0.002) were significantly morefrequent. Duration of symptoms in males compared to females such as chest tightness (4.9 hrs vs 5.6 hrs), cough (6.0 hrs vs 7.0 hrs), sputum production (18.2 hrs vs 23.7 hrs) were significantly shorter (p >0.05). Lung function measurements showed %FVC of 99.0 % in females and 98.5 % males (p>0.05) ; FEV1 96.0 % in females and 101.5 % in males (p>0.05). FEV1/FVC were similar in both genders (102.4% vs 102.3However MMFR values in females were significantly lower than males (89.8 % vs 97.4 % p=0.005).   Conclusion :  Higher rates of respiratory symptoms and lower small airway funcitons in females may be due to exposure indoors. Neverthless the possibility of gender response variability must be researched.