tbuckley/cabot-search huggingface dataset:
SP0126 How to Treat (HOT) Spondyloarthritis?
Authors: J. Sieper
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Spondyloarthritis (SpA) can be split into axial (ax) and peripheral SpA, according to the predominant clinical presentation. Major progresses have been made over the last decade defining optimal treatment for axial SpA while there are still only limted data how to treat peripheral SpA optimally, with the exception of psoriatic arthritis (PsA). The term axSpA covers both patients with non-radiographic axial SpA (nr-axSpA) and patients with radiographic axSpA (=ankylosing spondylitis, AS). A correct diagnosis is an important first step for developing a treatment strategy because non-inflammatory causes of chronic back pain, such as degenerative spine disease, will not respond to anti-inflammatory therapies. There are only two types of drugs which are highly effective in the treatment of axSpA: NSAIDs and TNF-blockers, glucocorticoids might work if given in a high dosis. Most treatment data are available for AS, but more recent studies indicate that the response to these drugs is similar in patients with nr-axSpA. NSAIDs are, together with physical therapy, the first line of treatment and a full dosis of an NSAID should be given if demanded by the symptoms. If patients are treated in the first three years of their disease remission rates up to 35% can be expected if treated with an NSAID. If NSAIDs fail TNF-blocker therapy would be the next step. Currently there are five TNF-blockers approved for the treatment of AS and two for the treatment of nr-axSpA. Elevated CRP, active inflammation on MRI and/or short disease duration are the best predictors for a good response to TNF-blocker therapy. Even if treated early with a TNF-blocker a TNF-blocker free remission can only be reached in up to 20%. However a dose reduction (or prolongation of the injection interval) is probably possible in a substantial proportion of patients. If TNF-blocker therapy fails a switch to another one would be the first option, especially in case of a secondary failure. There are currently no other approved (biologic) therapies for axSpA. However, therapies targeting the cytokines IL-23 (ustekinumab) or IL-17 (secukinumab) are currently the most promising. How to prevent best new bone formation and, in this context, with lonterm disability is currently still under debate. This can probably be achieved by early and/or longterm therapy with a TNF-blocker or by treatment with NSAIDs. Whether and how a combination of these two treatments should be used and which subgroup of patients benfits most from stopping progression of structural damage is a major focus of ongoing research. Only a few studies addressed so far the treatment of peripheral SpA, indicating that TNF-blockers but also some of the conventional DMARDs might work here. Studies performed so far in PsA investigated nearly exclusively patients with polyarthritic PsA, a manifestation not typically for peripheral SpA. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6346
P632Beat-to-beat variability in preload unmasks reduced repolarization reserve in anesthetized dogs with chronic atrio-ventricular block: a role for mechano-electrical feedback
Authors: P Oosterhoff, TRG Stams, A Heijdel, A Dunnink, HDM Beekman, R Van Der Nagel, HVM Van Rijen, MAG Van Der Heyden, MA Vos
Journal: Cardiovascular Research (2014)

Pronounced beat-to-beat variability in cardiac repolarization duration (BVR) is associated with increased arrhythmic risk in patients, animal models and isolated cardiomyocytes. However, the mechanisms linking an enhanced BVR to arrhythmogenicity is unknown and may differ between single cells and the intact heart, since cellular coupling is known to attenuate repolarization variability and suppress early afterdepolarizations. We hypothesized that in dogs with chronic AV-block (CAVB) and reduced repolarization strength, beat-to-beat variability in preload, only present in the intact heart, is required to increase BVR. Methods: Endocardial left ventricular monophasic action potential duration (LVMAPD80) was recorded in acute (AAVB, n=6) and CAVB dogs (n=7), before and after a challenge with the IKr blocker dofetilide. We used atrial and ventricular stimulation to provide either a constant or an alternating preload pattern, which was verified by PV-loop determined mechanical parameters. The effect of the stretch activated channel blocker streptomycin on baseline BVR and arrhythmic response to dofetilide was evaluated in a second CAVB group (n=9). Short-term variability of LVMAPD was used to quantify BVR. Arrhythmic outcome was quantified by combining the number of ectopic beats, episodes of TdP and defibrillations into a single arrhythmia score (AS). Results: Pro-arrhythmic remodeling (>3weeks AV-block) increased BVR during alternating preload, (0.45±0.14 AAVB vs 2.2±1.1 ms CAVB, p<0.01), while no change in BVR was seen at constant preload (0.35±0.12 AAVB vs 0.32±0.14 ms CAVB, NS). At AAVB, reduction of repolarization reserve by dofetilide did not induce TdP (AS 1[1-2], median[IQR]), but was pro-arrhythmic in CAVB (AS 27[9-62], p<0.05 vs AAVB). Variation of preload did not alter arrhythmic outcome at CAVB (AS 16[7-37] constant vs 47[2-57] alternating, NS), but was present in BVR determined prior to arrhythmias (2.5±1.4 constant vs 5.9±4.5 ms alternating, p=0.08). In the second group, the increase in BVR at baseline by alternating preload (0.3±0.03 vs 1.0±0.8 ms , p<0.01) was almost abolished by streptomycin (0.5±0.2 ms alternating, p<0.05 vs baseline alternating, NS vs baseline constant). Furthermore, arrhythmia score after dofetilide was reduced after streptomycin pre-treatment (AS 4[2-13], p=0.05). Conclusions: In the anesthetized CAVB dog BVR is a marker of pro-arrhythmic remodeling and critically reduced repolarization reserve, and originates from altered response to changes in preload. There is involvement of stretch activated channels both in the mechanisms of BVR and of drug-induced arrhythmia.
Abstract 4736: Pleiotropic effect of 5p and 8q chromosome regions: Analyses on the TURIN EPIC cohort
Authors: Fulvio Ricceri, Simonetta Guarrera, Carlotta Sacerdote, Silvia Polidoro, Alessandra Allione, Fabio Rosa, Karin Van Veldhoven, Paolo Vineis, Giuseppe Matullo
Journal: Cancer Research (2010)

Abstract BACKGROUND Common sequence variants in 8q24 and 5p15 chromosomal regions have recently been associated with several cancer types and other pathologies. Notably, for most of them a strong environmental risk component has been described. The aim of this study is to investigate for the first time in a cohort study the association among SNPs in those regions and several diseases. METHODS We conducted the study on Turin EPIC (European Perspective Investigation in Cancer and Nutrition) cohort: 10,604 volunteers recruited from 1993 to 1998, aged 35 to 64 years old. Each subject compiled a detailed questionnaire on life style and diet, provided a blood sample and was followed-up for life status, cancer, cardiovascular and diabetes incidence. We selected from literature two SNPs in 5p15 region (rs401681, rs2736098) and five SNPs in 8q24 region (rs672888, rs1447295, rs9642880, rs16901979, rs6983267) which proved to be associated with several diseases in previous studies. We calculated Hazard Ratios for each cancer site and cause of mortality under different genetic models, and incident diabetes Odd Ratios. RESULTS We observed 830 incident cancers (737 excluding skin carcinomas) and 342 overall death in the cohort since 1993. Considering all cancers together, we observed a statistically significant increase in risk when the variant allele in SNP rs6983267 was present (HR 1.19, p&amp;lt;0.01, per allele model); this increase is higher in men (HR 1.35, p&amp;lt;0.001, per allele model). We also found statistically significant associations among SNPs in 8q24 region and cancers of head and neck, colon-rectum, liver, lung, prostate, bladder, brain, thyroid, lymphomas, all cancers together and diabetes. We also observed statistically significant results for 5p15 region and melanoma. CONCLUSIONS Our analyses confirm for the first time in a cohort study the hypothesis of a pleiotropic effect on several disease susceptibility of 8q24 and 5p15 regions. We are also investigating if those associations are mediated by individual risk factors (diet, body mass index, smoking and blood pressure). Further functional analyses are needed to better elucidate the mechanisms underlying the risk increase conferred by genetic variation in 8q24 and 5p15 regions. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4736.
A HIGHLY SELECTIVE PPARα AGONIST K-877 SUPPRESSES NEOINTIMA FORMATION FOLLOWING CORONARY STENTING IN SWINE
Authors: Hiroshi Iwata, Eric Osborn, Giovanni Ughi, Kentaro Murakami, Claudia Goettsch, Joshua Hutcheson, Adam Mauskapf, Peter Mattson, Peter Libby, Elena Aikawa, Guillermo Tearney, Masanori Aikawa, Farouc Jaffer
Journal: Journal of the American College of Cardiology (2016)
Abstract 592: Novel IAP antagonist (822B) induces apoptosis through degradation of IAP proteins which have a BIR3 domain in human pancreatic cancer cells
Authors: Jae Sik Shin, Seung-Woo Hong, Dong-Hoon Jin, In-Hwan Bae, Maeng-Sup Kim, Young-Soon Na, Jae-Lyun Lee, Yong Sang Hong, Tae-Won Kim
Journal: Cancer Research (2011)

Abstract Several companies recently began to develop inhibitor of apoptosis (IAP) antagonist ‘Smac/Diablo mimetic’ compounds for the treatment of cancer. IAP antagonist compounds (IACs) was, therefore, designated as being able to induce apoptosis through the inhibition of IAP proteins in cancer cells. In our study we demonstrated that the novel-in what sense is it synthetic IAP antagonist, 822B, induces apoptotic cell death through proteasomal-dependent degradation of the inhibitor of apoptosis proteins (IAPs) with a BIR3 domain. We first found that apoptotic cell death is induced by exposure of pancreatic cancer cells to 822B. This apoptotic effect increased after the knockdown of endogenous IAPs using RNA interference. Moreover, 822B-induced apoptosis results from degradation of the inhibitor of apoptosis proteins (IAPs). 822B was preferable to Samc/Diablo for binding to IAPs and it induced ubiquitination. However, we also found that degradation of XIAP is not induced in several pancreatic cancer cell types in response to 822B. Interestingly, resistance to 822B was related to phosphorylation at the ser-87 site of XIAP. This resistant effect was eliminated using the (or “an” if there's more than one . . .) XIAP mutant that was replaced with alanine at 87 amino acid site. AKT CA (constitutive active) mutant and wild type-AKT that can induce phosphorylation at the ser-87 site of XIAP also suppressed the resistant effect to 822B. In addition, mutation in the RING domain of XIAP was not observed. Mutation in the RING domain of XIAP cannot induce XIAP ubiquitination, thus suggesting that the level of phospho-XIAP and phospho-AKT may be used as an indicator for cancer therapy using 822B. These results suggest that a novel synthetic inhibitor of the apoptosis (IAP) antagonist induces apoptosis through ubiquitination of IAPs with a BIR3 domain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2011-592
Case 50-1965
Authors: Martin J. Wohl, Benjamin Castleman
Journal: New England Journal of Medicine (1965)

Presentation of CaseA seventy-six-year-old man was admitted to the hospital because of inability to walk.One month previously, while on a Caribbean cruise, he and a number of other travelers had a respiratory infection with fever resembling grippe. A low-grade fever persisted, with anorexia and a loss of 20 pounds in weight, and a burning pain in both ankles developed. Tetracycline given for three days caused no improvement. Six days before admission his physician found a palpable liver and peripheral edema; a stool specimen gave a positive guaiac test, and the hemoglobin was 10.8 gm. per 100 ml. A . . .
O66 SOFOSBUVIR-BASED REGIMENS ARE ASSOCIATED WITH HIGH SVR RATES ACROSS GENOTYPES AND AMONG PATIENTS WITH MULTIPLE NEGATIVE PREDICTIVE FACTORS
Authors: G.R. Foster, S. Strasser, C. Christensen, J. Ma, B.N. Bekele, D.M. Brainard, W.T. Symonds, J.G. McHutchison, B. Conway, I. Crespo, S. Zeuzem
Journal: Journal of Hepatology (2014)
AB1003 Is the Ultrasound Score Based on 7 Joints (US-7 SCORE) A Valid Screening Tool for Inflammatory Joint-Diseases in A Population of Volunteers? Results from the “Rheuma-Truck” Cohort
Authors: P. Sewerin, S. Vordenbäumen, R. Brinks, A. Liedmann, S. Ohrndorf, M. Backhaus, O. Sander, M. Kümmel, M. Schneider, B. Ostendorf
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To investigate the value of ultrasound (US) and the US-7 score as a screening tool in a population of volunteers visiting the “Rheuma-Truck” <h3>Methods</h3> “Rheuma-Truck” was a mobile rheumatology office located in different city center of North Rhine Westphalia offering a screening for rheumatic diseases including Rheuma-Check questionnaire, lab-tests (MCV capillary test), imaging (US, capillaroscopy), and if positive a consultation with a rheumatologist to everybody free of charge. Ultrasound according to US-7 criteria, which is so far only evaluated as a parameter for therapy monitoring, with addition of the MCP-5 joint of the dominant hand of 605 volunteers was performed (MyLab 25 Gold, Esaote linear scanner, 15, Typ LA435). Moreover, in 236 of these volunteers the foot was assessed. Thus a total of 4102 joints were examined by ultrasound. Descriptive statistics for the patients were obtained and are reported as means ± standard deviation, ranges, frequencies or proportions as appropriate. Correlation coefficients are Pearson-correlations. <h3>Results</h3> The mean age of the investigated cohort was 52.72 years (min. 10, max. 89 years). Sex distribution shows 72.2% females and 27.8% males. 181 (29.9%) volunteer showed inflammatory signs in ultrasound. Overall MTP-2 was using the US-7 criteria the most frequently involved joint (11.4% B-mode and/or powerdoppler) followed by the dorsal wrist (8.9%), the MCP-2 (6.6%), PIP-3 (6.0%), PIP-2 (4.3%), the ulnar wrist (3.0%), MCP-3 (2.6%), the palmar wrist (0.5%) and MTP-5 (0.4%). The additionally evaluation of the MCP-5 joint showed with 7.6% the third most pathological findings anyway. Overall 378 volunteers referred a rheumatologist because of pathological findings in Rheuma-Check, lab-tests or ultrasound. 82 of these volunteers were diagnosed as rheumatoid arthritis (13.5%). First evaluations showed high correlations between ultrasound, MCV capillary test and the Rheuma-Check questionnaire. <h3>Conclusions</h3> Musculoskeletal ultrasound and US-7 scoring system are sufficient screening- and scoring tools for the detection of inflammatory joint alterations in a volunteer cohort. MCP-5 is a frequently involved joint in musculoskeletal ultrasound, which is not included in the US-7 scoring system yet. This study highlights the value of ultrasound in early detection of inflammatory joint diseases in a population of volunteers. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4228
What is the narrow content of <i>fence</i> (and other definitionally and interpretationally primitive concepts)?
Authors: Eric Mandelbaum
Journal: Behavioral and Brain Sciences (2011)

Abstract It's unclear what narrow content is interpersonally shared for concepts that don't originate from core cognition yet are still definitionally and interpretationally primitive. A primary concern is that for these concepts, one cannot draw a principled distinction between inferences that are content determining and those that aren't. The lack of a principled distinction imperils an account of interpersonally shared concepts.
Boxed Warning Added to Promethazine Labeling for Pediatric Use
Authors: Peter R. Starke, Joyce Weaver, Badrul A. Chowdhury
Journal: New England Journal of Medicine (2005)

subgroup of persons involved in mass-casualty situations who have been spared fragment injuries but might have sustained a blast injury.We agree that patients who incur pulmonary injuries from a blast, particularly in a confined space, will have immediate symptoms.
The traumas of casualty departments
Authors: C. Bulstrode
Journal: BMJ (1997)

Trauma care in Britain came in for a battering last week when the BBC's science programme QED screened a drama purporting to show a real life case of medical negligence. Christopher Bulstrode examines the controversy surrounding Cause of Death 

Mark was just a nice, ordinary lad on a big motorbike that crashed. He was fine when he got to the hospital, apart from a few broken bones, but then things started to go wrong. Within a few days he was in the intensive treatment unit after a cardiac arrest. His brain never recovered, and when they switched off the ventilator the family was left devastated. …
SAT0366 Absence of Impact of Febuxostat Treatment in Patients with Gout with and Without Altered Fiver Function Tests
Authors: F. Perez-Ruiz, A. M. Herrero-Beites
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patients with altered liver function test (LFTs) do not qualify to enter into clinical trials for registration purposes. Therefore, scarce data are available for patients with altered liver function test entering into treatments with new medications. <h3>Objectives</h3> To assess whether febuxostat has an impact in LFTs in patients with gout, and altered LFTs at baseline compared with patients with normal analysis. <h3>Methods</h3> Data from a prospective cohort of patients initiating febuxostat for gout were analyzed. ASAT, ALAT, and GGT were measured at baseline and at 3-6-12 months during follow-up. General characteristics of patients were obtained at entrance in the cohort, including parameters of gout severity, previous urate-lowering therapy, ethanol intake, hyperlipidemia, renal function impairment, and diabetes. Altered LFTs were defined as &gt; 1.5 upper normal limit (UNL). <h3>Results</h3> From a cohort of 79 patients (including 1 Child –A liver cirrhosis, 1 liver transplant, and 1 liver adenomatosis) there were 73, 60, and 50 patients with data at 3, 6, and 12 months of follow-up, respectively. There were 89% men, 49% polyarticular, 59% tophaceous, and 96% with previous failure to at least one urate-lowering drug. Comorbidities were very frequent: 47% renal function impairment (11% CKD 4-5), 30% high ethanol intake, 69% hypertension, 52% hyperlipidemia, 22% diabetes, 40% on diuretics, 12% ischemic heart disease, and 22% previous heart failure. ASAT, ALAT, and GGT were altered in 4, 9, and 15 % respectively, 30% of patients showing any LFTs altered at baseline. No patient withdrew due to altered liver function test. There was no significant change in paired means in any LFTs but a descent in GGT at 6 and 12 months (Table). The distribution of altered vs. non altered any of the LFTs showed a transient increase in altered ASAT and ALAT only detected at 3 months, and a significant decrease in patients with altered GGT at 3 and 6 months. <h3>Conclusions</h3> In this cohort of patients with severe gout and with frequent and severe comorbid conditions, patients with altered LFTs, including patients including chronic liver disease, showed no signal of worsening of LFTs compared to patients with normal LFTs at baseline and even there was an improvement in GGT in patients with previously altered LFTs. <h3>Acknowledgements</h3> Thanks to Mrs. Rosario Lopez Santamaría for adminsitrative support and coordination <h3>Disclosure of Interest</h3> F. Perez-Ruiz Consultant for: Ardea, Savient, Menarini, Astra, Metabolex, Pfizer, Novartis, SOBI, Speakers bureau: Menarini, A. Herrero-Beites: None Declared
Clinical Appraisal of Hexamethonium (C6) in Peripheral Vascular Diseases
Authors: Frank A. Finnerty, Edward D. Freis
Journal: New England Journal of Medicine (1951)

SINCE Paton and Zaimis1 suggested the clinical potentialities and demonstrated the ganglion-blocking properties of pentamethonium (C5) and hexamethonium (C6), much interest has centered on these compounds. Studies by Arnold and his co-workers,2 using C5, and by Burt and Graham, using C5 and C6,3 demonstrated that these agents are 5 times as potent as tetraethylammonium (TEA). Pentamethonium iodide in doses of 50 mg. given intravenously produced a rise of digital skin temperature with a simultaneous increase in digital blood flow and pulse volume lasting for one to two hours. Studies in this laboratory4 confirmed the observations of these British investigators and . . .
Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline
Authors: Andreas H. Diacon, Alexander Pym, Martin P. Grobusch, Jorge M. de los Rios, Eduardo Gotuzzo, Irina Vasilyeva, Vaira Leimane, Koen Andries, Nyasha Bakare, Tine De Marez, Myriam Haxaire-Theeuwes, Nacer Lounis, Paul Meyvisch, Els De Paepe, Rolf P.G. van Heeswijk, Brian Dannemann
Journal: New England Journal of Medicine (2014)

Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks.In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline.Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).