tbuckley/cabot-search huggingface dataset:
Impact of exacerbations on pulmonary arterial enlargement in patients with chronic obstructive pulmonary disease
Authors: Hirofumi Kiyokawa, Susumu Sato, Motokazu Kato, Shigeo Muro, Toyohiro Hirai, Michiaki Mishima
Journal: European Respiratory Journal (2013)

RATIONALE. Pulmonary hypertension is one of the most important abnormalities in COPD patients because it is associated with poor prognosis and impaired quality of life. In the recent study1) it is reported that pulmonary artery enlargement (PA/A ratio: the ratio pulmonary artery diameter (PA) to aortic artery diameter (A)) is associated with severe exacerbations of COPD. However the association between exacerbations and longitudinal changes in PA/A ratio is still unclear. Thus we analyzed the time course of PA/A ratio in relationship to exacerbations in COPD patients.  METHOD. Exacerbations were prospectively recorded for 2 years. Exacerbations were defined as symptomatic deterioration requiring additional medical treatment. Baseline and 2-year follow-up CT scans were performed under stable condition. Annual changes of PA/A ratio (ΔPA/A ratio) were compared between patients with and without a history of exacerbations.  RESULTS. 66 patients were included. Twenty-nine patients had a history of exacerbations during 2-year follow-up while 37 patients didn’t. In patients with exacerbations ΔPA/A ratio were greater than in patients without exacerbations (1.31 versus 1.11, p=0.03). Multivariate regression analysis showed that a history of exacerbations was an independent predictor of pulmonary artery enlargement (R2=0.10, p=0.02).  CONCLUSION. This is the first longitudinal study to demonstrate that exacerbations are associated with pulmonary enlargement in COPD. This study suggested that exacerbations were the cause of the progression in pulmonary hypertension and increase of risk of further exacerbation.  1. Wells, J.M. et al. N Engl J Med 2012; 367:913-21.
Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis
Authors: Pierre Blanchard, Anne Lee, Sophie Marguet, Julie Leclercq, Wai Tong Ng, Jun Ma, Anthony T C Chan, Pei-Yu Huang, Ellen Benhamou, Guopei Zhu, Daniel T T Chua, Yong Chen, Hai-Qiang Mai, Dora L W Kwong, Shie Lee Cheah, James Moon, Yuk Tung, Kwan-Hwa Chi, George Fountzilas, Li Zhang, Edwin Pun Hui, Tai-Xiang Lu, Jean Bourhis, Jean Pierre Pignon
Journal: The Lancet Oncology (2015)
Conserved developmental transcriptomes in evolutionarily divergent species
Authors: Anup Parikh, Edward Roshan Miranda, Mariko Katoh-Kurasawa, Danny Fuller, Gregor Rot, Lan Zagar, Tomaz Curk, Richard Sucgang, Rui Chen, Blaz Zupan, William F Loomis, Adam Kuspa, Gad Shaulsky
Journal: Genome biology (2010)

Abstract Background Evolutionarily divergent organisms often share developmental anatomies despite vast differences between their genome sequences. The social amoebae Dictyostelium discoideum and Dictyostelium purpureum have similar developmental morphologies although their genomes are as divergent as those of man and jawed fish. Results Here we show that the anatomical similarities are accompanied by extensive transcriptome conservation. Using RNA sequencing we compared the abundance and developmental regulation of all the transcripts in the two species. In both species, most genes are developmentally regulated and the greatest expression changes occur during the transition from unicellularity to multicellularity. The developmental regulation of transcription is highly conserved between orthologs in the two species. In addition to timing of expression, the level of mRNA production is also conserved between orthologs and is consistent with the intuitive notion that transcript abundance correlates with the amount of protein required. Furthermore, the conservation of transcriptomes extends to cell-type specific expression. Conclusions These findings suggest that developmental programs are remarkably conserved at the transcriptome level, considering the great evolutionary distance between the genomes. Moreover, this transcriptional conservation may be responsible for the similar developmental anatomies of Dictyostelium discoideum and Dictyostelium purpureum .
Responding to unexpected events: Maybe skills for this case were missing
Authors: W N. Brown
Journal: BMJ (2003)

Editor—Saunders et al describe a difficult and sad case, something of which they were very aware.1 As a non-medical healthcare professional I was acutely aware of the absence of certain aspects of care in the case history.

No description is provided of the technically difficult task of sitting with this man at midnight to help him decide what he wanted in this situation, to help him in making a choice about the course of action that would be consistent with his values and wishes. In the United States clinically trained chaplains and social workers provide this kind of technical care. It entails skills that are not taught in every medical school curriculum.

If patients are to retain control of their environment and destiny they need the skills of others who have been trained to help people do that. It is not always doctors who have best been prepared to do this. Benefits are to be gained by having a non-doctor function in that role.
Percutaneous gastrostomy (PEG) insertion under general anaesthesia (GA) in ventilator-dependent patients with neuromuscular disease (NMD)
Authors: Alanna Hare, Michelle Chatwin, Matthew Hind, Michael Polkey, Simon Jordan, Anita Simonds
Journal: European Respiratory Journal (2013)

Introduction: NMD patients often develop dysphagia and/or aspirate, becoming malnourished, exacerbating weakness. PEG tubes offer nutritional support. Previous studies report poor outcomes for PEG insertion under GA, particularly in patients with severe ventilatory failure.

Aim: We examined outcomes of protocolised PEG insertion under GA for ventilator-dependent NMD patients.

Methods: Retrospective case review of adult NMD patients with PEGs inserted in our hospital.

Results: 27 patients identified:

View this table:



Protocol: PEG insertion under GA via gastroscope using “pull through” method. All patients (unless using T-IPPV) extubated onto NIV post-operatively and monitored for ≥1 night on ICU. All received dietetic input and physiotherapy, including use of cough-assist device. Outcomes: 8 complications: 3 local PEG site infections; 1 recurrent PEG blockage; 2 episodes transient abdominal distension on feeding; 2 pneumonias resolving with standard care. No NIV patients re-intubated; no deaths. All patients discharged from hospital. Median length of ICU stay: 1 (range 1-29) days; hospital stay 7 (range 2-121) days.

Conclusion: In this group of ventilator-dependent NMD patients, PEG insertion under GA, early extubation to usual ventilatory support, and careful monitoring and multidisciplinary care in the post-operative period, proved safe and effective.
Stimulated Emission Depletion Live-Cell Super-Resolution Imaging Shows Proliferative Remodeling of T-Tubule Membrane Structures After Myocardial Infarction
Authors: Eva Wagner, Marcel A. Lauterbach, Tobias Kohl, Volker Westphal, George S.B. Williams, Julia H. Steinbrecher, Jan-Hendrik Streich, Brigitte Korff, Hoang-Trong M. Tuan, Brian Hagen, Stefan Luther, Gerd Hasenfuss, Ulrich Parlitz, M. Saleet Jafri, Stefan W. Hell, W. Jonathan Lederer, Stephan E. Lehnart
Journal: Circulation Research (2012)

Rationale: Transverse tubules (TTs) couple electric surface signals to remote intracellular Ca 2+ release units (CRUs). Diffraction-limited imaging studies have proposed loss of TT components as disease mechanism in heart failure (HF). Objectives: Objectives were to develop quantitative super-resolution strategies for live-cell imaging of TT membranes in intact cardiomyocytes and to show that TT structures are progressively remodeled during HF development, causing early CRU dysfunction. Methods and Results: Using stimulated emission depletion (STED) microscopy, we characterized individual TTs with nanometric resolution as direct readout of local membrane morphology 4 and 8 weeks after myocardial infarction (4pMI and 8pMI). Both individual and network TT properties were investigated by quantitative image analysis. The mean area of TT cross sections increased progressively from 4pMI to 8pMI. Unexpectedly, intact TT networks showed differential changes. Longitudinal and oblique TTs were significantly increased at 4pMI, whereas transversal components appeared decreased. Expression of TT-associated proteins junctophilin-2 and caveolin-3 was significantly changed, correlating with network component remodeling. Computational modeling of spatial changes in HF through heterogeneous TT reorganization and RyR2 orphaning (5000 of 20 000 CRUs) uncovered a local mechanism of delayed subcellular Ca 2+ release and action potential prolongation. Conclusions: This study introduces STED nanoscopy for live mapping of TT membrane structures. During early HF development, the local TT morphology and associated proteins were significantly altered, leading to differential network remodeling and Ca 2+ release dyssynchrony. Our data suggest that TT remodeling during HF development involves proliferative membrane changes, early excitation-contraction uncoupling, and network fracturing.
Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk
Authors: H G Raterman, V P van Halm, A E Voskuyl, S Simsek, B A C Dijkmans, M T Nurmohamed
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> Rheumatoid arthritis (RA) patients have an increased risk of developing cardiovascular diseases (CVD). Other autoimmune diseases such as hypothyroidism are also associated with an enhanced risk for CVD. Our objective was to determine first, the prevalence of hypothyroid disorders in RA patients, and second, the risk of CVD in RA patients with hypothyroid abnormalities. <h3>Methods:</h3> Subjects were RA patients who participated in an ongoing prospective cohort study of cardiovascular mortality and morbidity (n = 358) in which hypothyroid abnormalities were assessed. CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease. <h3>Results:</h3> Clinical hypothyroidism was observed in 16 of 236 female RA patients (6.8%), which is significantly higher than in the general population of The Netherlands. Subclinical hypothyroidism was detected in 6 out of 236 RA women (2.5%). In female RA patients, CVD was present in 6 out of 16 (37.5%) of all hypothyroid women. The odds ratio for CVD comparing female hypothyroid RA patients with female euthyroid RA patients was 4.1 (95% CI 1.2–14.3) after adjustment for sex, age, diabetes, smoking (ever), hypertension and statin use. <h3>Conclusions:</h3> Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.
Dachshund Binds p53 to Block the Growth of Lung Adenocarcinoma Cells
Authors: Ke Chen, Kongming Wu, Shaoxin Cai, Wei Zhang, Jie Zhou, Jing Wang, Adam Ertel, Zhiping Li, Hallgeir Rui, Andrew Quong, Michael P. Lisanti, Aydin Tozeren, Ceylan Tanes, Sankar Addya, Michael Gormley, Chenguang Wang, Steven B. McMahon, Richard G. Pestell
Journal: Cancer Research (2013)

Abstract Hyperactive EGF receptor (EGFR) and mutant p53 are common genetic abnormalities driving the progression of non–small cell lung cancer (NSCLC), the leading cause of cancer deaths in the world. The Drosophila gene Dachshund (Dac) was originally cloned as an inhibitor of hyperactive EGFR alleles. Given the importance of EGFR signaling in lung cancer etiology, we examined the role of DACH1 expression in lung cancer development. DACH1 protein and mRNA expression was reduced in human NSCLC. Reexpression of DACH1 reduced NSCLC colony formation and tumor growth in vivo via p53. Endogenous DACH1 colocalized with p53 in a nuclear, extranucleolar location, and shared occupancy of −15% of p53-bound genes in ChIP sequencing. The C-terminus of DACH1 was necessary for direct p53 binding, contributing to the inhibition of colony formation and cell-cycle arrest. Expression of the stem cell factor SOX2 was repressed by DACH1, and SOX2 expression was inversely correlated with DACH1 in NSCLC. We conclude that DACH1 binds p53 to inhibit NSCLC cellular growth. Cancer Res; 73(11); 3262–74. ©2013 AACR.
Induced sputum cytokines and chemokines and mechanistic pathways in adult asthma phenotypes
Authors: Ioana Agache, Cristina Ciobanu, Costel Agache, Beate Rückert, Cezmi Akdis
Journal: European Respiratory Journal (2013)

Background:  Evaluation of induced sputum can be used to predict asthma severity or exacerbation    Research hypothesis:  Relate asthma visible properties to sputum cytokines to define new mechanisms for asthma.    Methods:   The Local Ethics Committee approved the study. Asthma phenotypes evaluated: early and late onset, premenstrual, atopic, exercise-induced, aspirin-sensitive, remitting/relapsing, near-fatal, brittle asthma, frequent exacerbator, smokers, comorbidities (obesity, chronic rhinosinusitis-CRS, nasal polyps, food allergy), corticosteroids (CS) responsiveness and lung function (fixed airway obstruction and fast FEV1 decline). Both sputum and serum were sampled outside an asthma exacerbation. Sputum induction and processing was performed according to the ERS recommendations. Sputum and serum cytokines were measured with the 27 Plex Human Cytokine Group I Bioplex (Biorad). Correlations were analyzed with SPSS 21 (One Way Anova).    Results:  24 adult asthma patients, mean age 47.75±15.57 years old, 79% of them are females were enrolled. Many of the sputum and serum cytokine levels correlated, except for IL-9, IL-10 and IL-12. Correlations for sputum cytokines were IL-17, eotaxin and RANTES and smokers with asthma; IL-13 and MCP-1 and atopic asthma; IL-5 and IL-10 and asthma associated with CRS, IL-6 and fast FEV1 decline, IL-10 and CS responsive asthma, IL-2 and brittle asthma, VEGF and near-fatal asthma and IP-10 and frequent exacerbators.    Conclusion:  Several new pathogenetic mechanisms in asthma can be pinpointed by correlating the expression of cytokines in sputum and serum with asthma phenotypes.
Extracellular Calcium Sensitivity and Voltage-Dependent Calcium Channels in C Cells*
Authors: FRIEDHELM RAUE, HANS SCHERÜBL
Journal: Endocrine Reviews (1995)

EXTRACELLULAR Ca2+ ([Ca2+]e) as well as intracellular calcium ([Ca2+]i) play an essential role in stimulussecretion coupling in endocrine cells, stimulus-contraction coupling in muscle tissue, the transmission of neuronal signals, cell growth, and cell differentiation (1). Thus, the maintenance of tightly regulated [Ca2+]e levels in mammals is an absolute necessity for survival. The three major Ca2+-regulating hormones, PTH, calcitonin (CT), and 1,25-dihydroxyvitamin D3 (1,25–(OH)2D3), are directly involved in maintaining Ca2− homeostasis (2). Low [Ca2+]e is a major stimulus for secretion of PTH from the parathyroid glands and synthesis of 1,25-(OH)2D3 from the kidneys. High [Ca2+]e is the stimulus for CT secretion from the parafollicular cells (C cells) of the thyroid gland. In a feedback loop PTH increases [Ca2+]e, while CT decreases it very rapidly via the effects on its target tissues, bone, and kidney. 1,25-(OH)2D3 increases [Ca2+]e more slowly by activating Ca2+ absorption from the gut.
Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies
Authors: G. Caramori, S. Lim, K. Ito, K. Tomita, T. Oates, E. Jazrawi, K.F. Chung, P.J. Barnes, I.M. Adcock
Journal: European Respiratory Journal (2001)

GATA-binding proteins are a subfamily of zinc finger transcription factors with six members (GATA-1-6) that interact with the GATA deoxyribonucleic acid (DNA) sequence. This sequence is found in the regulatory regions of many genes including those encoding T-helper 2 (Th2)-like cytokines, receptors, adhesion molecules and enzymes, which may be important in the pathogenesis of bronchial asthma. The expression of GATA-3, -4 and -6 was investigated in peripheral blood T-lymphocytes and monocytes and bronchial biopsies from 11 normal subjects and 10 steroid-naïve asthmatic patients. Using Western blot analysis, T-cells from asthmatic subjects expressed 5 times the level of GATA-3 compared to that in normals. Confocal microscopy indicated that GATA-3 expression was both nuclear and cytoplasmic. GATA DNA binding complex containing GATA-3 was elevated in Th2 cells as determined by electrophorectic mobility shift assay. In contrast, monocytes from normal and asthmatic subjects expressed GATA-4 and -6 in equal amounts, but no GATA-3 was found. Using immunohistochemistry in bronchial biopsies, epithelial cells expressed high levels of GATA-3, GATA-4 and GATA-6 proteins. Comparison of Western blots of bronchial biopsies showed no significant differences between normal and asthmatic subjects. In conclusion, the increased expression of GATA-3 in asthmatic T-cells may underlie augmented T-helper 2-like cytokines in this disease. However, the unaltered GATA-3 expression in epithelial cells suggests a distinct role for GATA-3 in these cells unrelated to T-helper 2-like cytokine release. Finally, no evidence was found for an increased expression of GATA-4 and GATA-6 in asthma.
Patient Beliefs and Tamoxifen Discontinuance in Older Women With Estrogen Receptor—Positive Breast Cancer
Authors: Aliza K. Fink, Jerry Gurwitz, William Rakowski, Edward Guadagnoli, Rebecca A. Silliman
Journal: Journal of Clinical Oncology (2004)

Purpose To investigate the patterns and predictors of tamoxifen discontinuance throughout a 2-year period in a cohort of women 65 years or older with newly diagnosed, estrogen receptor (ER)–positive breast cancer, focusing on the role of patients’ beliefs about the risks and benefits of tamoxifen therapy. Subjects and Methods We enrolled a convenience sample of women cared for in four geographic regions of the United States with stage 1 (≥ 1 cm), stage II, or stage IIIA disease; no prior history of breast cancer; and no simultaneously diagnosed second primary breast cancer. Data sources included medical records and telephone interviews with patients at 3, 6, 15, and 27 months following definitive surgery. Results Of the 597 women with ER-positive tumors, 516 women (86%) were prescribed tamoxifen, and of these, 88 (17%) stopped taking tamoxifen during the 2-year follow-up period. Of the women who stopped taking tamoxifen, the majority (68%) took it for less than 1 year. Women with neutral or negative beliefs about the value of tamoxifen (3.0; 95% CI, 1.6 to 5.6) and those with positive nodes (odds ratio = 2.5; 95% CI, 1.0 to 6.3) were more likely to discontinue tamoxifen therapy. Conclusion How women with early-stage breast cancer perceive the risks and benefits of tamoxifen therapy seems critical for sustaining adherence to adjuvant tamoxifen therapy. Interventions designed to educate women about the benefits and risks of tamoxifen therapy may help to reduce discontinuance.
Influence of body mass index on outcome of the mechanically ventilated patients
Authors: A. Anzueto, F. Frutos-Vivar, A. Esteban, N. Bensalami, D. Marks, K. Raymondos, C. Apezteguia, Y. Arabi, J. Hurtado, M. Gonzalez, V. Tomicic, F. Abroug, J. Elizalde, N. Cakar, P. Pelosi, N. D. Ferguson
Journal: Thorax (2010)

<h3>Background</h3> There are limited data on the impact of body mass index on outcomes in mechanically ventilated patients. <h3>Methods</h3> Secondary analysis of a cohort including 4698 patients mechanically ventilated. Patients were screened daily for management of mechanical ventilation, complications (acute respiratory distress syndrome, sepsis, ventilator associated pneumonia, barotrauma), organ failure (cardiovascular, respiratory, renal, hepatic, haematological) and mortality in the intensive care unit. To estimate the impact of body mass index on acute respiratory distress syndrome and mortality, the authors constructed models using generalised estimating equations (GEE). <h3>Results</h3> Patients were evaluated based on their body mass index: 184 patients (3.7%) were underweight, 1995 patients (40%) normal weight, 1781 patients (35.8%) overweight, 792 patients (15.9%) obese and 216 patients (4.3%) severely obese. Severely obese patients were more likely to receive low tidal volume based on actual body weight but high volumes based on predicted body weight. In obese patients, the authors observed a higher incidence of acute respiratory distress syndrome and acute renal failure. After adjustment, the body mass index was significantly associated with the development of acute respiratory distress syndrome: compared with normal weight; OR 1.69 (95% CI 1.07 to 2.69) for obese and OR 2.38 (95% CI 1.15 to 4.89) for severely obese. There were no differences in outcomes (duration of mechanical ventilation, length of stay and mortality in intensive care unit and hospital) based on body mass index categories. <h3>Conclusions</h3> In this cohort, obese patients were more likely to have significant complications but there were no associations with increased mortality.
Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity
Authors: Marion Espéli, Menna R. Clatworthy, Susanne Bökers, Kate E. Lawlor, Antony J. Cutler, Frank Köntgen, Paul A. Lyons, Kenneth G.C. Smith
Journal: The Journal of Experimental Medicine (2012)

Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1–binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation–induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.