tbuckley/cabot-search huggingface dataset:
P639Amiodarone and dronedarone inhibit inwardly rectifying Kir2.1 channels, but not Kir2.2 and Kir2.3 channels
Authors: C Seyler, P Xynogalos, D Scherer, C Koepple, EP Scholz, D Thomas, HA Katus, E Zitron
Journal: Cardiovascular Research (2014)

Background: Cardiac inwardly rectifying IK1 current drives terminal repolarisation. Inhibition of IK1 current can suppress re-entry based arrhythmias and has been demonstrated to exert anti-fibrillatory effects. Human IK1 current is mainly formed by heterotetrameric assembly of three subunits: Kir2.1, Kir2.2 and Kir2.3 channels. Amiodarone and dronedarone have been shown to inhibit cardiac IK1 current, but the molecular basis of these effects has not been elucidated to date. Methods: Human Kir2.1 - Kir2.3 channels were expressed in Xenopus oocytes and current recordings were performed using the double-electrode voltage-clamp technique. Results: Amiodarone and dronedarone exerted differential inhibitory effects on Kir2.1, Kir2.2 and Kir2.3 channels, respectively. Both drugs inhibited only Kir2.1 channels without an effect on Kir2.2 and Kir2.3 channels. We analyzed effects of dronedarone in detail. Onset of inhibition was slow, but the effect was completely reversible upon washout. Biophysical current characteristics such as inwardly-rectifying properties and reversal potential of Kir2.1 currents were not modified. The inhibitory effect did not exhibit frequency dependence. Interestingly, dronedarone inhibited Kir2.1 currents mainly at negative potentials. Conclusions: Amiodarone and dronedarone both inhibit only Kir2.1 channels without affecting Kir2.2 and Kir2.3 channels. In view of the functional significance of Kir2.1 channels, this effect probably underlies the observed inhibition of IK1 current by both compounds and may contribute to their anti-fibrillatory efficacy.
SAFETY AND EFFICACY OF THE ABSORB EVEROLIMUS-ELUTING BIORESORBABLE VASCULAR SCAFFOLD VERSUS NEW-GENERATION DURABLE POLYMER EVEROLIMUS-ELUTING STENTS: A META-ANALYSIS BASED ON CLINICAL OUTCOME DATA FROM RANDOMIZED COMPARISONS
Authors: Bertrand Njume Mukete, Kapil Yadav, Hassan Baydoun, Liefke C. van der Heijden, Kenneth Tandjung, Alvaro Alonso, Asif Anwar, Thierry Le Jemtel, Nidal Abi Rafeh, Clemens von Birgelen
Journal: Journal of the American College of Cardiology (2016)
S65 Raised CK Levels in Severe Asthmatics Admitted to the Critical Care Unit- A Retrospective Cohort Analysis
Authors: A Dushianthan, L Hawkins, K Golder, R Cusack
Journal: Thorax (2012)

<h3>Introduction and Aims</h3> Acute severe asthma is a life threatening condition. Mechanical ventilation may be indicated in about third of asthmatics admitted to the intensive care unit and has a mortality rate of 8%.<sup>1</sup> Several reports have identified elevated CK levels during an episode of acute severe asthma. Intense muscular workload during an acute episode and drugs such as steroids, anaesthetic induction agents, aminophylline and salbutamol are all implicated in raising plasma CK levels. Our aim was to retrospectively evaluate the CK levels and clinical implications in patients with acute severe asthma, who were admitted to our intensive care unit. <h3>Methods</h3> This was a retrospective survey of all asthmatics admitted to intensive care unit between October 2009 and July 2011. Patient’s case notes were screened to identify demographics and clinical details. <h3>Results</h3> Thirty asthmatics with 37 admissions were identified. Three patients had multiple admissions. Mean age was 37 and two third were female. Twelve patients had CK levels performed as part of clinical management. Seven patients (58%) had CK levels ≤320 IU/ml and 5 patients (42%) had CK levels ≥320 IU/ml. Patients with raised CK levels had more intubations, ICU days and hospital days. IV aminophyline and IV salbutamol infusions were more frequent in patients with raised CK levels. The elevated CK was noted on average 1.8 days after the admission (Table 1). Three patients with raised CK levels had severe renal failure with evidence of myoglobinuria. Statistical analysis is not performed due to small number of patients. <h3>Discussions</h3> Acute severe asthmatics may develop raised CK levels with evidence of myoglobinuria and subsequent renal failure. The exact mechanisms are not fully explored. Intravenous beta<sub>2</sub>-agonists with combination of IV aminophylline may be a contributory factor. Prospective studies are needed to evaluate the path ophysiological mechanisms and clinical implications. <h3>References</h3> McFadden ER Am J Respir Crit Care Med 2003. Pathologyharmony.co.uk (for reference range).
Prednisone and Cyclosporine in the Treatment of Severe Graves' Ophthalmopathy
Authors: Mark F. Prummel, Maarten Ph. Mourits, Arie Berghout, Eric P. Krenning, Ruth van der Gaag, Leo Koornneef, Wilmar M. Wiersinga
Journal: New England Journal of Medicine (1989)

It is uncertain what is the most appropriate medical therapy for patients with severe Graves' ophthalmopathy. Therefore, we carried out a single-blind, randomized clinical trial to compare the efficacy of prednisone with that of cyclosporine in 36 patients who had been euthyroid for at least two months. The two groups, each consisting of 18 patients, were similar in age, sex, and the duration and severity of ophthalmopathy. The initial dose of cyclosporine was 7.5 mg per kilogram of body weight per day, and that of prednisone was 60 mg per day, which was subsequently tapered to 20 mg per day. During the 12-week treatment period, 11 prednisone-treated and 4 cyclosporine-treated patients responded to therapy (61 percent vs. 22 percent; P = 0.018); response was manifested by decreases in eye-muscle enlargement and proptosis and improved visual acuity and total and subjective eye scores. There were no differences at base line between the patients who later responded and those who did not. Prednisone was tolerated less well than cyclosporine. After 12 weeks, patients who did not respond were treated for another 12 weeks with a combination of cyclosporine and a low dose of prednisone. Among the 9 patients who initially received prednisone, the addition of cyclosporine resulted in improvement in 5 (56 percent); among the 13 patients who received cyclosporine initially, 8 (62 percent) improved after the addition of prednisone. Combination therapy was better tolerated than prednisone treatment alone. We conclude that single-drug therapy with prednisone is more effective than cyclosporine in patients with severe Graves' ophthalmopathy. The combination can be effective in patients who do not respond to either drug alone. (N Engl J Med 1989; 321:1353–9.)
AB0653 Retention Rate and Predictive Factors of Tnf-α Inhibitor Discontinuation in Patients with Ankylosing Spondylitis - Results from the Rheumatic Diseases Portuguese Register Reuma.Pt
Authors: A.R. Sepriano, F. Araujo, R. Aguiar, R. Vieira, E. Sousa, F. Pimentel-Santos, G. Sequeira, H. Canhão, H. Santos, J. Garcia, J.A. Pereira Silva, J. Canas Silva, L. Miranda, M. Oliveira, M.J. Salvador, M. Bernardes, P. Monteiro, T. Nόvoa, J. Branco
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Tumor necrosis factor-alpha inhibitors (TNFi) are currently the only therapeutic option when conventional treatment fails in ankylosing spondylitis (AS) patients. <h3>Objectives</h3> To assess the retention rate and investigate predictive factors and reasons for drug discontinuation in patients with AS starting their first TNFi. <h3>Methods</h3> We included all new biological starters AS patients fulfilling the 1984 modified New York classification criteria, registered at the Rheumatic Diseases Portuguese Register, Reuma.pt from June 2008 until October 2011. Retention rate at 2 years was evaluated using survival-data analysis methods with discontinuation of the drug, regardless the reason, as the primary outcome. Potential predictive factors of drug discontinuation (demographic, clinical and laboratorial) were assessed using log-rank tests and a Cox proportional-hazards regression model. <h3>Results</h3> Of the 334 AS patients starting a TNFi, 265 (79.34%) maintain treatment after 2 years of follow-up. Median drug survival among patients who discontinued treatment was 10.9 months (95% CI: 7.7 – 13.0 months) with a discontinuation rate of 11.6% per year. The main reason for treatment cessation was adverse events (34.4%) followed by lack of response at 12 weeks (23.2%). Drug survivals were similar regardless of the reason for discontinuation or TNFi used. Compared with patients who retain their first TNFi those who discontinue treatment, were more frequently women (p=0.04), were older at disease beginning (p=0.01) and at TNFi beginning (p=0.03), had higher BMI (p=0.01) and higher Bath Ankylosing Spondylitis Functional Index (BASFI, p=0.02) at baseline. In multivariable Cox regression, older age at TNFi beginning was the only baseline predictor of drug discontinuation (HR 1.06, 95% CI 1.02 – 1.10, p=0.006). <h3>Conclusions</h3> Retention rate was high among AS patients starting their first TNFi. Adverse events were the main reason for drug discontinuation and older age at treatment onset was a predictor of shorter drug survival. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3916
A6.5 Versatile polyion complex micelles for peptide and sirna vectorization to engineer tolerogenic dendritic cells
Authors: R Vicente, N Mebarek, A Aubert-Pouëssel, J Quentin, AL Mausset-Bonnefont, JA Devoisselle, C Jorgensen, S Bégu, P Louis-Plence
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in maintaining the balance between immunity and tolerance and, as such are a promising immunotherapy tool to induce immunity or to restore tolerance. The main challenge to harness the tolerogenic properties of DCs is to preserve their immature phenotype. We recently developed polyion complex micelles, formulated with double hydrophilic block copolymers of poly (methacrylic acid) and poly (ethylene oxide) blocks and able to entrap therapeutic molecules, that did not induce DC maturation. In the current study, the intrinsic destabilising membrane properties of the polymers were used to optimise endosomal escape property of the micelles in order to propose various strategies to restore tolerance. <h3>Material and method</h3> PMAA- <i>b</i>-PEO copolymers with low (PMAA2100- <i>b</i>-PEO5000, PMAA3500- <i>b</i>-PEO5000) and high Mw (PMAA2500- <i>b</i>-PEO12000, PMAA16200- <i>b</i>-PEO30000) were used to formulate either OVA peptide-entrapped or siRNA-entrapped micelles. siRNA- and peptide-entrapment efficiency was monitored using fluorescent molecules. Peptide presentation was monitored using transgenic T cells and si-RNA silencing of target gene was followed by FACS. <h3>Results</h3> On the first hand, we showed that high molecular weight (Mw) copolymer-based micelles were efficient to favour the release of the micelle-entrapped peptide into the endosomes, and thus to improve peptide presentation by immature (i) DCs. On the second hand, we put in evidence that low Mw copolymer-based micelles were able to favour the cytosolic release of micelle-entrapped small interferent RNAs, dampening the DCs immunogenicity. <h3>Conclusion</h3> Therefore, we demonstrate the versatile use of polyionic complex micelles to preserve tolerogenic properties of DCs. Altogether, our results underscored the potential of such micelle-loaded iDCs as a therapeutic tool to restore tolerance in autoimmune diseases.
Transmission of<i>Mycobacterium tuberculosis</i>from a Cadaver to an Embalmer
Authors: Timothy R. Sterling, Diana S. Pope, William R. Bishai, Susan Harrington, Robyn R. Gershon, Richard E. Chaisson
Journal: New England Journal of Medicine (2000)

The risk of acquiring tuberculosis varies according to occupation and is high among funeral-home workers.1 Embalmers are at particularly high risk for reactivity on tuberculin skin testing.2 The increased risk may be due to exposure to Mycobacterium tuberculosis during the embalming process, which involves the aspiration of blood and other body fluids from the cadaver, resulting in the generation of potentially infectious aerosols. To our knowledge, however, the transmission of M. tuberculosis from a cadaver to an embalmer, with the subsequent development of active tuberculosis, has not been described. DNA fingerprinting by restriction-fragment–length polymorphism (RFLP) analysis can be useful in . . .
SPECT Imaging of Apical Hypertrophic Cardiomyopathy
Authors: William W Chu, Thomas R Wallhaus, Jesus A Bianco
Journal: Clinical Nuclear Medicine (2002)

Apical hypertrophic cardiomyopathy, common in Japan, is characterized by a spade-like configuration of the left ventricle on contrast angiography. The condition is identified by giant negative T waves in the precordial echocardiographic leads, no intraventricular pressure gradient, and mild symptoms. A case showing the typical scintigraphic and cardiac echocardiographic findings of apical hypertrophic cardiomyopathy is presented.
<i>The Emperor of All Maladies</i> — The Beginning of the Beginning
Authors: Robert Schwartz
Journal: New England Journal of Medicine (2011)

Interview with Dr. Robert Schwartz on the history of cancer research. (12:51)Download In his Pulitzer Prize–winning book, Siddhartha Mukherjee explores the great ideas of oncology, up to the development of imatinib. But the research direction set by imatinib has yielded few useful drugs; its model seems to be the wrong roadmap for finding magic bullets.
Usefulness of the rendezvous technique for deep scope insertion during endoscopic retrograde cholangiography in a patient with a Roux-en-Y hepaticojejunostomy
Authors: Koichiro Tsutsumi, Hironari Kato, Hiroyuki Okada, Kazuhide Yamamoto
Journal: Endoscopy (2014)

Difficulty with deep scope insertion can cause failure of endoscopic retrograde cholangiopancreatography (ERCP), which is an effective, safe treatment of biliary complications in patients with a Roux-en-Y hepaticojejunostomy, even when a balloon enteroscope is used [1]. Herein, we describe the recipient of a liver transplant, in whom the well-established rendezvous technique was demonstrated to be useful for scope insertion into the bilioenteric anastomosis during therapeutic ERCP ([Video 1]).
FRI0161 Raid is highly sensitive to change and is associated to DAS28 in follow-up of patients with ra starting treatment with anti-TNF alpha therapy
Authors: H.B. Hammer, T.K. Kvien
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The Rheumatoid Arthritis (RA) Impact of Disease (RAID) score includes questions regarding pain, functional capacity, fatigue, physical and emotional wellbeing, quality of sleep and coping, and by use of an equation the answers are converted to a score 0-10, with 10 being the worst score. <h3>Objectives</h3> The present objectives were to follow the changes in RAID scores in RA patients during their first months of treatment with anti-TNF alpha therapy, and to explore the associations between RAID and established measures of disease activity. <h3>Methods</h3> A total of 30 RA patients (mean (SD) age 50 (13) years, disease duration 8 (7) years, 26 women, 72% anti-CCP positive) were consecutively included as they started treatment with anti-TNF alpha therapy (Remicade (n=11), Enbrel (n=10), Humira (n=6), Simponi (n=3)) and they were followed monthly for three months. All patients answered the RAID questionnaire, and they were assessed for number of tender and swollen joints (of 28), the assessors global VAS and ESR/CRP with DAS28 (ESR) being calculated. Correlations were analyzed by use of Spearman's rank, Wilcoxon test was used to explore significant changes from baseline, one way ANOVA was used to explore differences between groups and sensitivity to change was calculated by use of Standardized Response Mean (SRM). <h3>Results</h3> RAID scores fell significantly (p&lt;0.001) after start of treatment with median (range) scores 4.4 (0.5-8.7) at baseline, 2.2 (0.1-8.4) after 1 month, 2.6 (0.0-9.1) after 2 months and 2.4 (0.2-9.1) after 3 months, and significant improvement was also found for DAS28 (4.5 (2.1-7.1), 3.7 (0.6-6.3), 2.9 (1.7-7.2) and 3.7 (1.0-6.8), at baseline and after 1, 2 and 3 months, respectively (p≤0.005)). There were significant correlations between RAID and DAS28 at all examinations (r=0.52-0.66, p&lt;0.01). At three of the four examinations, RAID had significant correlations with assessors global VAS (r=0.39-0.49, p&lt;0.05), number of tender joints (r=0.49-0.64, p&lt;0.01), ESR (r=0.54-0.60, p&lt;0.01) and CRP (r=0.50-0.52, p&lt;0.01), while there were no significant correlation between RAID and number of swollen joints. The RAID scores differentiated significantly between different levels of DAS28 (with cut-offs at 2.6, 3.2 and 5.1) at all examinations (p=0.038 - &lt;0.001). The SRMs for RAID was 0.84, 1.06 and 0.77 after 1, 2 or 3 months compared to 1.06, 0.97 and 0.60 for DAS28. <h3>Conclusions</h3> The present study found the RAID scores to fall extensively already 1 month after starting biologic medication and that the scores were highly associated to DAS28. Being rapid to answer, the RAID questionnaire may give the clinicians immediate information about important aspects of the patients life, and thus contribute to treatment decisions. <h3>Disclosure of Interest</h3> None Declared
BLOOD PRESSURE AND RISK FOR STROKE OR BLEEDING EVENTS IN PATIENTS WITH ATRIAL FIBRILLATION: RESULTS FROM THE ORBIT AF STUDY
Authors: Sreekanth Vemulapalli, Sunghee Kim, Laine Thomas, Gregg Fonarow, Michael Ezekowitz, Peter Kowey, Paul Chang, Manesh Patel, Jonathan Piccini, Kenneth Mahaffey, Alan Go, Bernard Gersh, Eric Peterson
Journal: Journal of the American College of Cardiology (2015)
House Passes 1994 NCI Appropriation
Authors: D. A. Tisevich
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article House Passes 1994 NCI Appropriation Get access Dorothy A. Tisevich Dorothy A. Tisevich Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 15, 4 August 1993, Page 1195, https://doi.org/10.1093/jnci/85.15.1195 Published: 04 August 1993
GE-09 * COMBINED HEREDITARY AND SOMATIC MUTATIONS OF REPLICATION ERROR REPAIR GENES RESULT IN RAPID ONSET OF ULTRA-HYPERMUTATED MALIGNANT BRAIN TUMORS IN CHILDREN
Authors: A. Shlien, B. B. Campbell, R. de Borja, L. B. Alexandrov, D. M. Merino, M. Remke, D. Bakry, P. Dirks, A. Huang, R. G. Grundy, C. Durno, M. Aronson, M. D. Taylor, Z. F. Pursell, C. E. Pearson, D. Malkin, E. Bouffet, C. Hawkins, P. J. Campbell, U. Tabori
Journal: Neuro-Oncology (2015)

BACKGROUND: Biallelic Mismatch Repair Deficiency (bMMRD) Syndrome is a childhood cancer predisposition syndrome with a wide tumor spectrum where malignant brain tumors predominate. Mismatch repair and DNA polymerase proofreading are two components necessary to repair DNA replication − associated mutations. The consequences of disruption to both repair components in humans are not well studied. Furthermore, it is unknown how defects in DNA repair processes cause and perpetuate childhood CNS tumorigenesis. METHODS: We analyzed17 bMMRD cancers using genome, exome sequencing and microarrays. Additionally, we sequenced non-neoplastic tissues from patients and compared the mutational landscape of bMMRD tumors to a reference data set of all childhood and adult cancers. RESULTS: BMMRD malignant brain tumors harbored massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most adult cancers (>7,000 analyzed). These cancers lacked copy number alterations (p < 0.01) and microsatellite instability as seen in sporadic glioblastoma and adult deficient MMR cancers respectively. These mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10−13). Strikingly, all ultra-hypermutated bMMRD cancers acquired early and conserved somatic mutations in DNA polymerases ɛ or δ. Polymerase driver mutations resulted in a unique mutation signature reflective of the repair processes and unique to MMRD/polymerase mutant cancers. Sequential tumor biopsy analysis revealed that MMR mutations and combined MMRD/polymerase mutations add a log-scale increment to cancer mutation load. BMMRD/polymerase mutant cancers rapidly amass mutations (∼600 mutations/cell division), reaching a threshold of ∼20,000 exonic mutations in <6 months. CONCLUSIONS/SIGNIFICANCE: Early-onset brain tumors from bMMRD patients offer an unobstructed view of mutation types and secondary pathways that drive carcinogenesis. We suggest a new mechanism of cancer progression where mutations develop in a rapid burst after ablation of replication repair. The high mutation load and threshold may be this cancer's Achilles' heel, exploitable for diagnosis and therapeutic intervention.
PTH-146 Optimising the Screening Strategy to Reduce Interval Cancers – Initial Experience in the Welsh Bowel Screening Programme
Authors: H Beer, H Heard
Journal: Gut (2013)

<h3>Introduction</h3> Analysis of interval bowel cancer rates within two years of a negative screening test kit result demonstrates rates twice as high following an equivocal FOB (Faecal Occult Blood test) with a negative FIT (Faecal Immunochemical Test), compared to a negative FOB. This analysis looks at the time to bowel cancer diagnosis following a negative FIT result to see whether participants may benefit from being recalled earlier for bowel screening than the current two year strategy. <h3>Methods</h3> In Wales, the routine recall interval is two years. A cohort of participants with negative results validated between Oct 2008 and August 2010 were reviewed, with two years follow up data. These records were compared with all screen detected and symptomatic bowel cancers diagnosed in the two year follow up time period. The time interval from the negative screening result to their diagnosis of bowel cancer was recorded. <h3>Results</h3> In the analysis time period, 9000 participants were issued with a negative FIT screening test result, 22 went on to develop bowel cancer within the next 2 years (0.24%). This compared to 0.14% of participants who had a negative FOB and were returned to routine recall (almost significantly different). Of the 22 participants with cancer diagnosed following a negative FIT screening test result, the mean time to diagnosis was 366 days (median 316 days). However this varied depending on gender and five year age group. 29% women had a bowel cancer diagnosed within 3 months of their negative test result, compared to 7% men. At 6 months 20% men had been diagnosed with cancer. Similarly with the younger age group, 18% of participants aged 60–64 years had a bowel cancer diagnosed within 3 months, compared to 9% of those aged 65 years and older. Analysing the potential costs of a tailored approach towards these equivocal test results, the cost to the bowel screening programme in Wales per year would be around 5,000 invitation letters with test kits to be posted out earlier (rather than at the two year routine recall interval). These potentially have the ability to diagnose the expected 10 cancers that would occur in the following twelve months. <h3>Conclusion</h3> Women and the younger age group (60–64 years) may benefit from an early repeat test either at three months or immediately following their negative FIT test result. Men and the older age group (65 years and above) may benefit from an early repeat test at six months. It is unclear whether these are false negatives or true interval cancers but these preliminary results would suggest that if validated in a larger cohort, a tailored approach to equivocal FOB tests may optimise yield and potentially reduce the incidence of interval cancers. <h3>Disclosure of Interest</h3> None Declared.