tbuckley/cabot-search huggingface dataset:
Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort
Authors: Liesbet Van Praet, Lennart Jans, Philippe Carron, Peggy Jacques, Elien Glorieus, Roos Colman, Heleen Cypers, Herman Mielants, Martine De Vos, Claude Cuvelier, Filip Van den Bosch, Dirk Elewaut
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Introduction</h3> Bone marrow oedema (BMO) of the sacroiliac joints (SIJs) is a hallmark of axial spondyloarthritis (SpA). However, the relationship between the extent of BMO and disease phenotype is poorly understood. <h3>Objective</h3> To assess the link between BMO of the SIJs and gut inflammation. We have also evaluated the correlation between BMO and established disease activity parameters. <h3>Methods</h3> Sixty-eight patients with axial SpA from the Gent Inflammatory Arthritis and spoNdylitis cohorT underwent ileocolonoscopy and MRI of the SIJs. Histopathological analysis and SPondyloArthritis Research Consortium of Canada (SPARCC) scores were performed. <h3>Results</h3> A significant higher SPARCC score (median (range)) was observed in axial SpA patients showing chronic gut inflammation (16.9 (3.8–68.3)) compared with axial SpA patients showing normal gut histology (9.8 (0.0–45.0); p&lt;0.05). In a multiple linear regression model, we identified, besides chronic gut inflammation (effect size of 11.3, 95% CI (2.1 to 20.4)), male sex (effect size of 10.5, 95% CI (3.3 to 17.8)) to be independently associated to the extent of BMO. There was a low to moderate correlation between the degree of BMO and C-reactive protein(r=0.39, p=0.002) and Ankylosing Spondylitis Disease Activity Score (r=0.35, p=0.007). <h3>Conclusions</h3> Higher degrees of BMO were observed in patients showing chronic gut inflammation. These data solidify a link between mucosal inflammation and progressive disease in axial SpA.
Low Doses of Lipopolysaccharide and Minimally Oxidized Low-Density Lipoprotein Cooperatively Activate Macrophages via Nuclear Factor κB and Activator Protein-1
Authors: Philipp Wiesner, Soo-Ho Choi, Felicidad Almazan, Christopher Benner, Wendy Huang, Cody J. Diehl, Ayelet Gonen, Susan Butler, Joseph L. Witztum, Christopher K. Glass, Yury I. Miller
Journal: Circulation Research (2010)

Rationale : Oxidized low-density lipoprotein (LDL) is an important determinant of inflammation in atherosclerotic lesions. It has also been documented that certain chronic infectious diseases, such as periodontitis and chlamydial infection, exacerbate clinical manifestations of atherosclerosis. In addition, low-level but persistent metabolic endotoxemia is often found in diabetic and obese subjects and is induced in mice fed a high-fat diet. Objective : In this study, we examined cooperative macrophage activation by low levels of bacterial lipopolysaccharide (LPS) and by minimally oxidized LDL (mmLDL), as a model for subclinical endotoxemia-complicated atherosclerosis. Methods and Results : We found that both in vitro and in vivo, mmLDL and LPS (Kdo2-LipidA) cooperatively activated macrophages to express proinflammatory cytokines Cxcl2 (MIP-2), Ccl3 (MIP-1α), and Ccl4 (MIP-1β). Importantly, the mmLDL and LPS cooperative effects were evident at a threshold LPS concentration (1 ng/mL) at which LPS alone induced only a limited macrophage response. Analyzing microarray data with a de novo motif discovery algorithm, we found that genes transcribed by promoters containing an activator protein (AP)-1 binding site were significantly upregulated by costimulation with mmLDL and LPS. In a nuclear factor–DNA binding assay, the cooperative effect of mmLDL and LPS costimulation on c-Jun and c-Fos DNA binding, but not on p65 or p50, was dependent on mmLDL-induced activation of extracellular signal-regulated kinase (ERK) 1/2. In addition, mmLDL induced c-Jun N-terminal kinase (JNK)-dependent derepression of AP-1 by removing nuclear receptor corepressor (NCoR) from the chemokine promoters. Conclusions : The cooperative engagement of AP-1 and nuclear factor (NF)-κB by mmLDL and LPS may constitute a mechanism of increased transcription of inflammatory cytokines within atherosclerotic lesions.
Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain.
Authors: Christopher D Toscano, Vinaykumar V Prabhu, Robert Langenbach, Kevin G Becker, Francesca Bosetti
Journal: Genome biology (2007)

Abstract Background Cyclooxygenase (COX)-1 and COX-2 produce prostanoids from arachidonic acid and are thought to have important yet distinct roles in normal brain function. Deletion of COX-1 or COX-2 results in profound differences both in brain levels of prostaglandin E 2 and in activation of the transcription factor nuclear factor-κB, suggesting that COX-1 and COX-2 play distinct roles in brain arachidonic acid metabolism and regulation of gene expression. To further elucidate the role of COX isoforms in the regulation of the brain transcriptome, microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1 -/- ) or COX-2 (COX-2 -/- ) was performed. Results A majority (&gt;93%) of the differentially expressed genes in both the cortex and hippocampus were altered in one COX isoform knockout mouse but not the other. The major gene function affected in all genotype comparisons was 'transcriptional regulation'. Distinct biologic and metabolic pathways that were altered in COX -/- mice included β oxidation, methionine metabolism, janus kinase signaling, and GABAergic neurotransmission. Conclusion Our findings suggest that COX-1 and COX-2 differentially modulate brain gene expression. Because certain anti-inflammatory and analgesic treatments are based on inhibition of COX activity, the specific alterations observed in this study further our understanding of the relationship of COX-1 and COX-2 with signaling pathways in brain and of the therapeutic and toxicologic consequences of COX inhibition.
Endoscopic bronchial occlusion with Watanabe silicone prosthesis and biological glue for the treatment of alveolopleural fistulas
Authors: Cayo Garcia Polo, Mercedes Merino-Sanchez, Antonio León Jimenez, Mercedes Sanchez Benitez, Mercedes Sanchez Bommatty, Aurelio Arnedillo Muñoz
Journal: European Respiratory Journal (2012)

Introduction: Alveolopleural fistula (APF) is the communication of the distal bronchial tree and pleural space, and supposes a serious problem for its associated morbi-mortality. The objective is to evaluate a endoscopic bronchial occlusion with a silicone prosthesis (Watanabe spigots) and biological glue.

Patients and methods: Observational, retrospective, descriptive study, collecting bronchial occlusion cases in our hospital from 2004 to 2010. General data collected, including details of previous and current illnesses, pleural drainage, fiberbronchoscopy, location of dependent bronchus, spigots implanted, glue instilled, recurrences, pleurodesis and monitoring.

Results: 6 patients and 7 sessions of bronchial occlusion. Average age 60, 3F/3M. The predisposing diseases were neoplasia, pneumonia and lung abscess. Debuting as empyema or pneumothorax, with a drain placed 23 days on average prior to the occlusion. Performed under general anaesthesia, the responsible bronchus located with balloon catheter, ventilator volumes, dye or sight of bubbling. Two spigots placed per session on 3 occasions, and 1 in 4 others, in sizes M and S. N-butyl cyanoacrylate was instilled in 4 sessions. The leak stopped in the operating theatre in all cases, with late recurrence in 3. No complications except expectoration of 2 spigots. Definitive lung re-expansion in 4 patients, with subsequent pleurodesis and drain removal. Two patients died from the progression of their underlying disease.

Conclusions: Endoscopic bronchial occlusion with Watanabe spigots and N-butyl-cyanoacrylate is an effective, technically simple method without complications for the treatment of APF.
An Orthotopic Murine Model of Sinonasal Malignancy
Authors: Alexander Gelbard, Michael E. Kupferman, Samar A. Jasser, Wantao Chen, Adel K. El-Naggar, Jeffrey N. Myers, Ehab Y. Hanna
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Malignant sinonasal tumors are clinically challenging due to their proximity to vital structures and their diverse histogenesis and biological behavior. To date, no animal models accurately reflect the clinical behavior of these malignancies. We developed an orthotopic murine model of sinonasal malignancy that reproduces the intracranial extension, bony destruction, and spread along neural fascial planes seen in patients with aggressive sinonasal malignancies of various histologies. Experimental Design: Human squamous cell carcinoma line (DM14) and adenoid cystic carcinoma line (ACC-3) were implanted in the right maxillary sinus or soft palate in male nude mice. Animals were monitored for tumor growth and survival. Tumor specimens were removed for histopathologic evaluation to assess for intracranial extension, orbital invasion, bony invasion, perineural invasion, and distant metastasis. Statistical analysis was done to calculate P values with the Student's t test for individual tumor volumes. Differences in survival times were assessed using the log-rank test. Results: Mice with DM14 or ACC-3 implanted in either the maxillary sinus or the soft palate developed large primary tumors. A statistically significant inverse correlation between survival and the number of tumor cells implanted was found. Histopathologic evaluation revealed orbital invasion, intracranial extension, pulmonary metastasis, lymph node metastasis, and perineural invasion. Conclusions: We describe the first orthotopic model for sinonasal malignancy. Our model faithfully recapitulates the phenotype and malignant behavior of the aggressive tumor types seen in patients. This model offers an opportunity to identify and specifically target the aberrant molecular mechanisms underlying this heterogeneous group of malignancies.
Pharmacologic Modulation of Hand Pain in Osteoarthritis: A Double‐Blind Placebo‐Controlled Functional Magnetic Resonance Imaging Study Using Naproxen
Authors: Duncan Sanders, Kristina Krause, Jonathan O'Muircheartaigh, Michael A. Thacker, John P. Huggins, William Vennart, Nathalie J. Massat, Ernest Choy, Steven C. R. Williams, Matthew A. Howard
Journal: Arthritis & Rheumatology (2014)

Objective In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint. Methods A placebo‐controlled, double‐blind, 2‐period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between‐period differences in brain activity. Results Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity. Conclusion This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self‐report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain.
A Mouse Model System to Genetically Dissect the Molecular Mechanisms Regulating Tumorigenesis
Authors: Kurt Degenhardt, Eileen White
Journal: Clinical Cancer Research (2006)

The vast majority of human tumors are of epithelial origin and result from the accumulation of mutations that alter the function of pathways that control critical cellular processes, including proliferation, checkpoint regulation, and apoptosis. Authentically replicating these events in animal models is critical to understanding the biology of cancer and for testing the feasibility of novel therapies. We developed a mouse model that recapitulates the steps of epithelial tumor progression of multiple tissue types (kidney, breast, ovarian surface, and prostate epithelia), which takes advantage of the power of mouse genetics, and that allows for biochemical analysis, genetic selection, and screening. Moreover, this model enables functional interrogation of far more complex tumor genotypes, both of the tumor cells themselves, and of the cells in the tumor microenvironment. This is a crucial advantage, as human tumors result from multiple compound mutations, most of which are difficult to achieve through standard mutant mouse technology. We have applied this model to establish the role of apoptosis in epithelial solid tumor progression and in treatment response, which has provided novel opportunities for cancer therapies in humans.
Carboplatin in Clinical Stage I Seminoma: A Valuable Option for Patient Management
Authors: Sally Stenning, Tim Oliver, Ben Mead, Rhian Gabe
Journal: Journal of Clinical Oncology (2011)

TO THE EDITOR: In their editorial 1 accompanying our article, 2 Bosl and Patil make a number of incorrect assertions which require a response. The majority of these issues relate directly to  design and interpretation of  TE19/30982 trial, while their current preferred managementoptionissurveillance.Whileweagreedinourpaperthat surveillance is an entirely logical management approach, to dismiss theresultsofwhatisbyfarthelargestrandomizedtrialeverconducted in testicular cancer, and stage I seminoma in particular, shows an unfortunatedegreeofparochialism.Surveillancewillnotbeappropri- ate in all settings. Regarding  trial design, TE19 was not designed as an equiva- lence trial. If a suitably modest increase in relapse rates could be excluded, advantages to carboplatin were clear—a single day of treat- ment,quickerrecoverytime,lessimpactonemployment(allasshown intheoriginalarticle 2 );hencethenoninferioritydesignwasappropri- ate. The assumption of equivalence (ie, no underlying difference in relapse rates between  trial arms) is however an important part of thedesignthatmustbestated.Thisisbecauseassumingtheretrulywas asmalldifferenceinrelapseratesinfavorofonearmortheother,beyond which an unacceptable increase in relapse rates after carboplatin must be excluded, would lead to a substantially different sample size. Bosl and Patil 1 agree that noninferiority was shown in  origi- nal study report, but question if that is  case in these updated results, concluding that the difference in RFR (relapse-free rate) is widening in a direction favoring RT (radiotherapy). This conclusion is difficult to understand. Inspection of  relapse-free curves shows that  absolute difference is greatest at our quoted point of 5 years and actually slightly reduced later due to late events on  radiotherapy arm. Such small fluctua- tions at specific timepoints are inevitable however. More im- portantly,  hazard ratios (HRs) from  earlier analysis (1.28; 90% CI, 0.85 to 1.93) and  second—misquoted in  editorial as 1.28 again, but actually 1.25 (90% CI, 0.83 to 1.89)— show a small shift towards a HR of 1. This is in keeping with  fact that  only relapse to be reported since our original analysis has occurred in  radiotherapy arm. We therefore have no reason to retract a previous assertion of noninferiority.
Endoscopic treatment of post-surgical bile duct injuries: long term outcome and predictors of success
Authors: P. R de Reuver, E. A Rauws, M. Vermeulen, M. G W Dijkgraaf, D. J Gouma, M. J Bruno
Journal: Gut (2007)

To analyse the short and long term outcome of endoscopic stent treatment after bile duct injury (BDI), and to determine the effect of multiple stent treatment.A retrospective cohort study was performed in a tertiary referral centre to analyse the outcome of endoscopic stenting in 67 patients with cystic duct leakage, 26 patients with common bile duct leakage and 110 patients with a bile duct stricture.Long term outcome and independent predictors for successful stent treatment.Overall success in patients with cystic duct leakage was 97%. In patients with common bile duct leakage, stent related complications occurred in 3.8% (n = 1). The overall success rate was 89% (n = 23). In patients with a bile duct stricture, stent related complications occurred in 33% (n = 36) and the overall success rate was 74% (n = 81). After a mean follow up of 4.5 years, liver function tests did not identify "occult" bile duct strictures. Independent predictors for outcome were the number of stents inserted during the first procedure (OR 3.2 per stent; 95% CI 1.3 to 8.4), injuries classified as Bismuth III (OR 0.12; 95% CI 0.02 to 0.91) and IV (OR 0.04; CI 0.003 to 0.52) and endoscopic stenting before referral (OR 0.24; CI 0.06 to 0.88). Introduction of sequential insertion of multiple stents did not improve outcome (before 77% vs after 66%, p = 0.25), but more patients reported stent related pain (before 11% vs after 28%, p = 0.02).In patients with a postoperative bile duct leakage and/or strictures, endoscopic stent treatment should be regarded as the choice of primary treatment because of safety and favourable long term outcome. Apart from the early insertion of more than one stent, the benefit from sequential insertion of multiple stents did not become readily apparent from this series.
Evaluation of the Risk of Congenital Cardiovascular Defects Associated With Use of Paroxetine During Pregnancy
Authors: Adrienne Einarson, Alessandra Pistelli, Marco DeSantis, Heli Malm, Wolfgang D Paulus, Alice Panchaud, Debra Kennedy, Thomas R Einarson, Gideon Koren
Journal: American Journal of Psychiatry (2008)

In 2005-2006, several studies noted an increased risk of cardiovascular birth defects associated with maternal use of paroxetine compared with other antidepressants in the same class. In this study, the authors sought to determine whether paroxetine was associated with an increased risk of cardiovascular defects in infants of women exposed to the drug during the first trimester of pregnancy.From teratology information services around the world, the authors collected prospectively ascertained, unpublished cases of infants exposed to paroxetine early in the first trimester of pregnancy and compared them with an unexposed cohort. The authors also contacted the authors of published database studies on antidepressants as a class to determine how many of the women in those studies had been exposed to paroxetine and the rates of cardiovascular defects in their infants.The authors were able to ascertain the outcomes of 1,174 infants from eight services. The rates of cardiac defects in the paroxetine group and in the unexposed group were both 0.7%. The rate in the database studies (2,061 cases from four studies) was 1.5%.Paroxetine does not appear to be associated with an increased risk of cardiovascular defects following use in early pregnancy, as the incidence in more than 3,000 infants was well within the population incidence of approximately 1%.
Diabetic Retinopathy Predicts All-Cause Mortality and Cardiovascular Events in Both Type 1 and 2 Diabetes
Authors: Caroline K. Kramer, Ticiana C. Rodrigues, Luis H. Canani, Jorge L. Gross, Mirela J. Azevedo
Journal: Diabetes Care (2011)

The prognostic significance of diabetic retinopathy (DR) for death and cardiovascular (CV) outcomes is debated. We investigated the association of DR with all-cause mortality and CV events in patients with diabetes by a systematic review and meta-analysis.The electronic databases Medline and Embase were searched for cohort studies that evaluated DR in type 2 or type 1 diabetic patients and reported total mortality and/or fatal and nonfatal CV events, including myocardial infarction, angina pectoris, coronary artery bypass graft, ischemic changes on a conventional 12-lead electrocardiogram, transient ischemic attack, nonfatal stroke, or lower leg amputation. Data extraction was performed by two reviewers independently. Pooled effect estimates were obtained by using random-effects meta-analysis.The analysis included 20 studies that fulfilled the inclusion criteria, providing data from 19,234 patients. In patients with type 2 diabetes (n = 14,896), the presence of any degree of DR increased the chance for all-cause mortality and/or CV events by 2.34 (95% CI 1.96-2.80) compared with patients without DR. In patients with type 1 diabetes (n = 4,438), the corresponding odds ratio was 4.10 (1.50-11.18). These associations remained after adjusting for traditional CV risk factors. DR was also predictive of all-cause mortality in type 2 diabetes (odds ratio 2.41 [1.87-3.10]) and type 1 diabetes (3.65 [1.05-12.66]).The presence of DR was associated with an increased risk of all-cause mortality and CV events in both type 2 and type 1 diabetic patients.
Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells
Authors: Virgilio L. Lew, Nuala Daw, Zipora Etzion, Teresa Tiffert, Adaeze Muoma, Laura Vanagas, Robert M. Bookchin
Journal: Blood (2007)

Little is known about age-related changes in red blood cell (RBC) membrane transport and homeostasis. We investigated first whether the known large variation in plasma membrane Ca(2+) (PMCA) pump activity was correlated with RBC age. Glycated hemoglobin, Hb A1c, was used as a reliable age marker for normal RBCs. We found an inverse correlation between PMCA strength and Hb A1c content, indicating that PMCA activity declines monotonically with RBC age. The previously described subpopulation of high-Na(+), low-density RBCs had the highest Hb A1c levels, suggesting it represents a late homeostatic condition of senescent RBCs. Thus, the normal densification process of RBCs with age must undergo late reversal, requiring a membrane permeability increase with net NaCl gain exceeding KCl loss. Activation of a nonselective cation channel, Pcat, was considered the key link in this density reversal. Investigation of Pcat properties showed that its most powerful activator was increased intracellular Ca(2+). Pcat was comparably selective to Na(+), K(+), choline, and N-methyl-D-glucamine, indicating a fairly large, poorly selective cation permeability pathway. Based on these observations, a working hypothesis is proposed to explain the mechanism of progressive RBC densification with age and of the late reversal to a low-density condition with altered ionic gradients.