tbuckley/cabot-search huggingface dataset:
Impact of airflow obstruction severity on the course of COPD during follow-up
Authors: Nikolay Yanev, Nikolay Kyuchukov, Ilia Krachunov, Zlatina Ivanova, Pavlina Nikolova, Plamen Pavlov, Tsania Popova, Yavor Ivanov
Journal: European Respiratory Journal (2014)

Introduction  Chronic obstructive pulmonary disease (COPD) is characterised by slow progressive deterioration in airflow in most patients enhanced by exacerbations, many of which require hospitalisation and are associated with higher mortality rate.  Aim  This prospective 2-year, follow-up study attempted to explore the changes in five parameters: spirometry, symptoms, hospitalisations, exacerbations and mortality during the period.  Methods  A total of 267 (215 male and 52 female, mean age 66±9 ) COPD outpatients were recruited. They were divided in four groups according to the stage of airway obstruction (GOLD 2007). Study procedures were performed at baseline and on 6 months thereafter. Assessments include clinical examination, pulmonary function test, breathlessness scale (mMRC). Health outcomes were tracked down - number of COPD related hospitalisations, exacerbations and mortality.  Results  Patients in stage I (FEV1 87,6±8,7) and stage II (FEV1 62,9±8,7) showed a mean decline in FEV1 (2,8%) at the end of the study. They had more exacerbations (1,0±0,7; 0,7±0,8) and hospitalisations (0,4±0,5; 0,2±0,4) respectively compared to baseline. Patients in stage III (FEV1 39,5 ± 5,7) and IV (FEV1 24,8±3,1) were rather stable according to FEV1 decline, but had more exacerbations (1,0±0,8; 1,7±0,9), hospitalisations (0,4±0,7; 0,5±0,9) and higher mortality rate (8.5%). Symptoms measured by mMRC were found to be higher in stage III (2,2±0,8; p  Conclusion  The severity and worsening of airflow obstruction is found to negatively impact all of the measured parameters causing increase of symptoms.
Abstract 234: Quantifying the Effect of CPR Quality on Cardiac Arrest Outcome: A Meta-analysis
Authors: Sarah Wallace, Benjamin S Abella, Lance Becker
Journal: Circulation (2012)

Objective : While evidence has accrued that CPR quality impacts cardiac arrest outcome, the effect size of variation in CPR quality remains poorly characterized. Furthermore, the relative contributions of chest compression (CC) components (such as rate and depth) to successful resuscitation remain unclear. We sought to measure the effect of CPR quality on cardiac arrest outcome through systematic review and meta-analysis. Methods: A comprehensive search was performed for English-language articles using PubMed, MEDLINE, Cochrane Library, and direct author contact. We included any clinical study assessing CPR performance on adult cardiac arrest patients where survival was a reported outcome, either return of spontaneous circulation (ROSC) or survival to admission or discharge. Effect sizes were reported as mean differences. Missing data were resolved by author contact. Estimates were segregated by CPR metric (CC rate, depth, no-flow fraction, and ventilation rate), and a random-effects model was applied to estimate an overall pooled effect. Evidence for statistical heterogeneity between studies was tested via goodness of fit (X 2 ). Results: Of 603 abstracts evaluated, 8 studies published between 2005 and 2012 met inclusion criteria. These 8 studies included 2113 unique arrest cases (1937 out-of-hospital, 176 in-hospital). Mean age was 68.0 years, 64.1% of the cohort was male, overall ROSC was 31.2%, and survival to discharge was 4.9%. Arrest survivors were significantly more likely to have received deeper CCs than non-survivors (mean difference 2.44 mm, 95% CI 1.19 to 3.69 [p&lt;0.001], n=6 studies, p for heterogeneity=0.9). Survivors were also significantly more likely to have received CC rates closer to 85-100 cpm than non-survivors (absolute mean difference from 100 cpm -5.04 cpm, 95% CI -8.44 to -1.65 cpm [p=0.004], n=6 studies, p for heterogeneity=0.2). Findings for depth and rate did not vary by arrest location, CPR performer, study quality, or outcome type. No significant difference in no-flow fraction (n=5 studies) or ventilation rate (n=3 studies) between survivors and non-survivors was observed. Conclusions: Deeper chest compressions and rates closer to 85-100 cpm are significantly associated with improved survival from cardiac arrest.
Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts
Authors: S Ajeganova, J H Humphreys, M K Verheul, H W van Steenbergen, J A B van Nies, I Hafström, B Svensson, T W J Huizinga, L A Trouw, S M M Verstappen, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2016)

Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.
Trastuzumab-resistant HER2-positive metastatic breast cancer: Comparing results of lapatinib and capecitabine in brain and other metastatic sites.
Authors: E. J. Cortes, M. Bomfim, B. V. Freitas, F. Muller, E. R. Silva, B. da Silva
Journal: Journal of Clinical Oncology (2010)

e11505 Background: Trastuzumab, anthracycline, and taxane resistant HER2-positive metastatic breast cancer has poor prognosis. Progression in brain metastasis (BM) commonly leads to difficult diagnostic interpretation and treatment decisions, poor quality of life, and death. Methods: Consented patients (pts) with HER2-positive metastatic breast cancer, ECOG ≤2, with resistance to trastuzumab, taxane, and anthracyclines, were recruited for treatment with daily lapatinib (L) (1,250 mg daily) and capecitabine (C) (2,000 mg/m2/day days 1-14) in a 21 day cycle. Progression was evaluated by RECIST and statistics by SPSS. Results: We enrolled 10 pts (median age 44), median follow up was 19.51 months (M). One patient had grade 3 toxicity due to C and was kept with L only; no other patient discontinued L nor C due to toxicity. Nine (90%) pts had ≥2 metastatic sites, one pt had BM only, and 6 pts had BM in addition to other sites. Median time to progression (TTP) was 9.10 M for the 10 pts, 13.86 M for BM as site of first progression, and 5.90 M for non-BM progression (p<0.05). BM was the most common site for first progression, seen in 4 pts. There was no new BM lesion during treatment. Overall BM response to Tx was 50% (1 complete response, 2 partial responses). In all 4 patients that progressed in central nervous system, head NMR showed enlarged metastatic lesions with central liquefied images, and were interpreted initially as radio/chemo necrosis. Two pts had neurological symptoms and discontinued L and C. The last two pts that progressed in brain had their metastatic images interpreted as necrosis also. However, specific NMR vascular analysis revealed higher perfusion/permeability image patterns, interpreted as caused by tumor activity. They went to BM surgical resection and histology showed tumor cells and 40% of necrosis. Both patients are well and without signs or symptoms after surgery. Conclusions: Brain was the most common metastatic site in this pts, and BM had a longer TTP than the other metastasis. Surgical removal of BM appears to help patients and should be considered in earlier stage of enlargement of lesions. NMR perfusion-permeability studies may facilitate medical decisions. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Inhibition of glycogen synthase kinase 3beta reduces GC function in human monocytes via modulation of HDAC2 activity
Authors: Anta Ngkelo, Laurie Stevens, Mike Yeadon, Iain Kilty, Ian Adcock, Paul Kirkham
Journal: European Respiratory Journal (2011)

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterized by insensitivity to glucocorticoids (GCs). Reactive oxygen species (ROS) are an etiologic factor in the pathogenesis of COPD and contribute to the reduced GC action. Insensitivity to GCs has been associated with impaired catalytic activity of HDAC2 in the lungs of COPD patients. GSK3beta is a constitutively active kinase that regulates cell cycle and gene expression. Phosphorylation of Ser9 on GSK3beta leads to its inactivation and elevated levels of the phospho-GSK3beta have been documented in the peripheral lung of COPD patients.  Monocytes from healthy volunteers were treated with H2O2 which induced GSK3beta Ser9 phosphorylation in a concentration- and time-dependant manner. Use of selective inhibitors showed that the ERK pathway mediates the ROS induced GSK3beta phosphorylation. To examine how inactivation of GSK3beta regulates GC function, we assessed the effect of a selective inhibitor (CT99021) on GC-mediated inhibition of GM-CSF release. The data showed that inhibition of GSK3beta alone had no significant effect on LPS induced GM-CSF release but it attenuated the ability of dexamethasone to suppress GM-CSF release by up to 50%. Selective inhibition of GSK3beta also significantly decreased HDAC2 activity suggesting that HDAC2 is an important mediator in this pathway.  Our results indicate that ROS induces inhibition of GSK3beta via the ERK pathway leading to decreased HDAC2 activity and GC insensitivity. This pathway should be considered in evaluating the therapeutic potentials of GSK3beta activators in restoring GC sensitivity in COPD.
Factors that predict for positive GeneXpert MTB/RIF on bronchoalveolar lavage samples in children with suspected tuberculosis
Authors: Pierre Goussard, E. Walters, C. Bosch, P.R. Gie, Anneke Hesseling
Journal: European Respiratory Journal (2014)

Background

Pilot studies have reported that GeneXpert MTB/RIF (Xpert) testing of bronchoalveolar lavage (BAL) samples improves diagnostic yield and the rapid detection of drug resistance in children undergoing bronchoscopy for complicated intrathoracic tuberculosis (TB).

Aim: To determine factors predictive of positive Xpert on BAL in children with suspected tuberculosis.

Methods

Children < 13 years undergoing bronchoscopy for suspected complicated intrathoracic TB, October 2012 to January 2014 were studied. Clinical data, including duration of TB treatment prior to bronchoscopy and chest x-ray changes, were collected. During bronchoscopy airways were evaluated for compression, severity of obstruction and lymph gland ulceration into the airways. BAL samples obtained were analysed by fluorescent smear microscopy, automated liquid culture and Xpert.

Results

Forty children ( median age 18 months) were studied. The median duration of TB treatment prior to bronchoscopy was 8 days . TB was confirmed in 31 (78%) by either BAL Xpert or culture. Xpert and culture were positive in 29 (73%) and 23 (58%) cases respectively. In 21 (53%) both Xpert and culture were positive. Incremental value of Xpert was 8 cases (35%); only 2 cases were culture positive but Xpert negative. The median time to culture positivity was 14 days (7-44 days). Positive Xpert was associated with lymph nodes ulcerating into the airway (p = 0.03) but not with airway obstruction , chest x-ray changes or duration of treatment <14 days .

Conclusion

In children with complicated pulmonary TB, Xpert on BAL increases the diagnostic yield by >35% and is associated with lymph node ulceration into the airways.
Phase II study of omacetaxine (OM) and low-dose AraC (LDAC) in older patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
Authors: Tapan M. Kadia, Elias Jabbour, Naveen Pemmaraju, Stefan Faderl, Gautam Borthakur, Deborah A. Thomas, Naval Guastad Daver, Farhad Ravandi, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2012)

6592 Background: Treatment of AML in patients (pts) &gt; 70 yrs of age with intensive chemotherapy is associated with high rates of early mortality and little benefit. Newer, lower-intensity approaches with novel mechanisms are needed. OM is a semisynthetic plant alkaloid which has demonstrated activity in AML as a single agent and with chemotherapy. Methods: We studied a low intensity program combining subcutaneous (SQ) OM with SQ LDAC in pts &gt;/= 60 yrs, with AML or MDS, a performance status (PS) of &lt;/=2, and adequate organ function. Initially, 6 pts were enrolled at the following doses: OM 1.25 mg/m2 SQ Q12 hrs x 3 days with AraC 20 mg SQ Q12 hrs x 7 days on a 4 week cycle. If safety is confirmed, the phase II portion would commence at the safe dose levels. Up to 12 courses can be given. The primary endpoint was to determine the complete remission (CR) rate. Secondary endpoints were: CR duration, DFS, OS, safety, and early mortality. Results: 17 pts were enrolled on study so far. The median age was 74 yrs (range, 64-81); the median PS was 1 (0-1). The karyotypes in these pts were: diploid in 6 (35%), complex with chromosome (chr) 5 and/or 7 abnormality (abnl) in 4 (24%), complex without chr 5 and/or 7 abnl in 2 (12%), 11q abnl in 1 (6%), poor metaphases in 1 (6%), and other in 3 (18%). Four pts with prior MDS were treated with a median of 2 prior therapies (1-3). Median bone marrow blast % at the start of therapy was 40 (15-87). The median WBC, hemoglobin, and platelets were 2.1 (0.4–24.8), 8.9 (7.7–10.7), and 45 (14–104), respectively. These pts have received a median of 1 (1-3) cycle of therapy. Of the 11 pts evaluable for response, there were 2(18%) CR, 1(9%) CRp, 1(9%) PR for an ORR of 4/11 (36%). Five pts had no response and were taken off study. Two pts died on study: 1 on day 6 and 1 on day 27. Both pts were 74 yrs with a complex karyotype. One died of pneumonia and multi-organ failure and the 2 nd died from cardiac arrest. Other than the deaths, serious adverse events included grade 3 transaminitis in 1 and grade 3 heart failure in 1. Conclusions: OM and LDAC appears to be tolerable in older pts with AML. The combination appears to have activity. Stopping boundaries for futility and safety have not been breached. Enrollment is ongoing.
Abstract 16451: Left Ventricular Sphericity Predicts Left Ventricular Thrombus Formation After Acute Anterior Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention
Authors: Shinichi Okino, Nobuyuki Kuroiwa, Shigeru Fukuzawa, Masayuki Inagaki
Journal: Circulation (2013)

Introduction: The aim of this study is to investigate whether left ventricular sphericity index (LVSI) is associated with left ventricular thrombus (LVT) formation in patients with acute anterior m...
Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells
Authors: R. Keaney Rathbun, Gregory R. Faulkner, Marika H. Ostroski, Tracy A. Christianson, Grant Hughes, Gary Jones, Robert Cahn, Richard Maziarz, Gordon Royle, Winifred Keeble, Michael C. Heinrich, Markus Grompe, Paula A. Tower, Grover C. Bagby
Journal: Blood (1997)
A retrospective study of lung cancer in young women
Authors: Haifa Zaibi, Hajer ben Abdelghaffar, Leila Fekih, Dorra Greb, Ines Akrout, Hela Hassene, Soraya Fenniche, Dalenda Belhabib, Mohamed Lamine Megdiche
Journal: European Respiratory Journal (2012)

Introduction:   Less advanced disease staging at presentation, better performance status and better survival figures have been noticed in younger (≤50 years) lung cancer women W1 as compared to older (>50 years) patients with the disease W2.   Aim:   To compare clinico-pathological features of lung cancer in young and elderly women and to determine any existing difference between the two groups.   Patients and methods:   It9s a retrospective study, including 44 women admitted in our department with lung cancer.   Results:   There were 15 young women with a mean age of 41 years (20-50 years) and 29 elderly patients with a mean age of 64 years (51-85 years). 26% of first group were current smoker.  26% of W1 had family history of lung cancer vs 3% of W2 (p=0.02). Comorbidities were not found in any case of W1 and in 45% of W2 (p    Conclusion:   Majority of these patients presented with early stage disease. 26% had positive family history suggesting a possible genetic factor. Favourable performance status resulted in higher resection rate and active treatment, which lead to better survival.
Abstract 13255: Angiotensin-II and MARCKS: a Hydrogen Peroxide- and Rac1-Dependent Signaling Pathway in Vascular Endothelium
Authors: Hermann Kalwa, Juliano Sartoretto, Simone Sartoretto, Thomas Michel
Journal: Circulation (2012)

MARCKS is an actin-binding protein that modulates vascular endothelial cell migration and cytoskeleton signaling. Angiotensin-II (Ang-II) is implicated both in physiological responses and in vascul...
Use of circulating and tumor-infiltrating myelomonocytic cells to predict survival in human malignant pleural mesothelioma (MPM).
Authors: B. Burt, T. Tilleman, R. Bueno, D. Sugarbaker
Journal: Journal of Clinical Oncology (2010)

10578 Background: MPM is a devastating cancer with limited effective therapies. Mesothelioma tumor cells produce high levels of monocyte stimulating factors that can be found in the serum and effusions of patients with MPM. We hypothesized that an increased number of myeloid cells in MPM patients correlates with advanced disease and has a negative influence on clinical outcome. Methods: We analyzed preoperative WBC and absolute monocyte count in 896 patients with MPM that were treated surgically at a single institution from 1991 to 2009. Separately, an immunohistochemical analysis of the macrophage antigen CD68 was performed on MPM tissues from 60 patients who underwent cytoreductive surgery. Data were analyzed via t-tests, Spearman correlation coefficients, and survival analyses. Results: 80% of patients were male and 66% of cases were of the epithelial histologic subtype. Preoperatively, 21% of patients had a high WBC (> 10,000 cells/uL) and 8.5% had a high monocyte count (> 800 cells/uL). Patients with epithelial histology survived significantly longer than those with non-epithelial histology (16.7 v 8.9 mo; p < 0.0001). Patients with a normal WBC survived significantly longer than those with a high WBC (14.6 v 8.3 mo, p < 0.0001) and patients with a normal monocyte count survived significantly longer than those with a high monocyte count (18.6 v 9.6 mo, p < 0.0001). Patients with non-epithelial histology were more likely to have a higher WBC (p < 0.001) and a higher number of circulating monocytes (p = 0.0003) than those with epithelial histology. In MPM tissue sections, macrophages were a striking component of the inflammatory infiltrate representing 27 ± 9% (5%-50%) of all nucleated cells. The number of tumor-infiltrating macrophages inversely correlated with survival (p = 0.009). Present in both tumor nests and stroma, a high presence of macrophages in either compartment was associated with worse outcome (p = 0.02 tumor nest, p = 0.01 stroma). Conclusions: An increased number of circulating monocytes or tumor-infiltrating macrophages portends poor overall survival in MPM. This may overlie a systemic immune response to this malignancy and provides a potential target for intervention. No significant financial relationships to disclose.
Abstract 181: β-Adrenergic Preconditioning Is Adenosine Mediated
Authors: Amanda Lochner, Ruduwaan Salie, Johan A Moolman
Journal: Circulation Research (2012)

This study investigated the roles of adenosine, oxygen free radicals (ROS), the K + ATP channels and the PI 3 K/PKB/Akt and ERK signal transduction pathways during the triggering and mediation phases of beta-adrenergic preconditioning (BPC) Methods : Using the isolated working rat heart, BPC was elicited by administration of denopamine (B 1 receptor agonist, 10 -7 M), isoproterenol (B 1 /B 2 receptor agonist, 10 -7 M) or formoterol (B 2 receptor agonist, 10 -9 M) for 5 min followed by 5 min washout. Index ischemia was 35 min regional ischemia followed by 2h reperfusion and infarct size was determined with the tetrazolium method. The role of adenosine was studied using selective adenosine receptor antagonists. Involvement of ROS, PKC, the mitochondrial K + ATP channels, endogenous opioids and bradykinin was studied by using N-acetyl cysteine (NAC), bisindolylmaleimide, 5-HD, naloxone or HOE140, respectively. Wortmannin and PD98,059 were used to inhibit PI 3 K and ERK respectively. Phosphorylation of these kinases was determined by Western blot. Results: Preconditioning with all three B-adrenergic receptor agonists caused a significant (40-60%) reduction in infarct size and improvement in postischemic function. BPC with isoproterenol and denopamine was abolished by the adenosine A 3 receptor antagonist MRS1191 during both the triggering and mediation phases, while being effective during reperfusion only in formoterol preconditioned heart s. B 1 /B 2 PC was attenuated by MRS1754 (adenosine A 2B receptor antagonist) during the triggering and mediation phases. The mediation phase of B 1 /B 2 PC was also abolished by ZM241385 (A 2A receptor blocker). The adenosine A 1 receptor blocker, DPCPX, was without effect. The ROS scavenger NAC caused a significant attenuation of cardioprotection induced by all three B-adrenergic receptor agonists. 5-HD, naloxone and Hoe140 were without effect on BPC. Activation of ERK and PI3K/PKB/Akt during both triggering and reperfusion phases are required for cardioprotection. Conclusion: BPC in rat hearts is dependent on activation of the A 3 adenosine receptors by endogenous adenosine and production of free radicals during the triggering and mediation phases while the A 2A and A 2B receptors participate mainly during reperfusion.