tbuckley/cabot-search huggingface dataset:
Abstract 14743: BACE1-AS Long Noncoding RNA and beta-amyloid Increase In Ischemic Heart Failure
Authors: Simona Greco, Germana Zaccagnini, Paola Fuschi, Christine Voellenkle, Serenella C astelvecchio, Lorenzo Menicanti, Fabio Martelli
Journal: Circulation (2016)

Introduction:  The long noncoding RNA BACE1-AS is transcribed from the opposite strand of the β-secretase (BACE1) gene, coding for a protease generating beta-amyloid peptides from the Amyloid Precursor Protein. Unlike many antisense RNAs that display a negative effect on the sense counterpart, BACE1-AS positively modulates BACE1 expression. Intriguingly, heart failure and Alzheimer’s disease share several effectors and risk factors. Moreover, amyloids originating from a variety of amyloidogenic proteins, can accumulate in the heart and blood vessels and are associated with cardiovascular disorders   Hypothesis:  Evaluating if the BACE1-AS/BACE1/beta-amyloid pathway is dysregulated in ischemic heart failure.   Methods and results:  BACE1-AS and BACE1 transcripts were both up-regulated in left ventricle biopsies derived from 18 patients affected by non-end stage dilated ischemic cardiomyopathy compared with 17 matched controls. Increased BACE1-AS and BACE1 RNA levels were also observed in mice 1 month after myocardial infarction was induced by coronary artery ligation.  In situ  hybridization assay in human heart biopsies showed that BACE1-AS RNA displayed an ubiquitous distribution, being expressed in the nucleus of cardiomyocytes, endothelial and fibroblast heart cells. Up- or down-modulation of BACE1-AS levels induced the concordant regulation of BACE1 RNA and protein levels, as well as of beta-amyloid, in cell cultures of both endothelial cells and cardiomyocytes. Accordingly, beta-amyloid protein expression levels were significantly increased in both plasma and left ventricle tissue of heart failure patients. Transcriptomic analysis of cultured endothelial cells where BACE1-AS expression was blocked indicated changes of pathways and functions relevant for cardiovascular ischemic diseases. Accordingly, administration of both beta-amyloid 1-40 and 1-42 peptides induced the cell death of cultured cardiomyocytes and endothelial cells.   Conclusions:  Given the toxic role of beta-amyloid, the dysregulation of the BACE1/BACE1-AS axis might be a relevant component of heart failure pathogenesis, further involving noncoding RNAs in the complex scenario of proteotoxicity in cardiac dysfunction.
Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review
Authors: Emanuele Pontali, Giovanni Sotgiu, Simon Tiberi, Marina Tadolini, Dina Visca, Lia D'Ambrosio, Rosella Centis, Antonio Spanevello, Giovanni Battista Migliori
Journal: European Respiratory Journal (2018)

The World Health Organization (WHO) estimated that 490 000 cases of multidrug-resistant (MDR) tuberculosis (TB) (defined as TB caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin) occurred in 2016. Among them, ∼6.2% had extensively drug-resistant (XDR) TB ( i.e. TB caused by MDR strains with additional resistance to fluoroquinolones and at least one second-line injectable drug) [1]. Efficacy and safety of co-administered bedaquiline and delamanid in MDR-TB patients <http://ow.ly/Ctvj30kreEP> This paper is part of the European Respiratory Society (ERS)/Latin American Society of Respiratory Medicine (ALAT) and ERS/Brazilian Society of Pulmonology (SBPT) collaborative projects, and of the operational research plan of the WHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate, ITA-80, 2017-2020- GBM/RC/LDA.
Age-Related Impaired Efficacy of Bone Marrow Cell Therapy for Myocardial Infarction Reflects a Decrease in B Lymphocytes
Authors: Songtao An, Xiaoyin Wang, Melissa A. Ruck, Hilda J. Rodriguez, Dmitry S. Kostyushev, Monika Varga, Emmy Luu, Ronak Derakhshandeh, Sergey V. Suchkov, Scott C. Kogan, Michelle L. Hermiston, Matthew L. Springer
Journal: Molecular Therapy (2018)

Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments.
Major microbiota dysbiosis in severe obesity: fate after bariatric surgery
Authors: Judith Aron-Wisnewsky, Edi Prifti, Eugeni Belda, Farid Ichou, Brandon D Kayser, Maria Carlota Dao, Eric O Verger, Lyamine Hedjazi, Jean-Luc Bouillot, Jean-Marc Chevallier, Nicolas Pons, Emmanuelle Le Chatelier, Florence Levenez, Stanislav Dusko Ehrlich, Joel Dore, Jean-Daniel Zucker, Karine Clément
Journal: Gut (2018)

Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes.Sixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included.Low gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including glutarate, 3-methoxyphenylacetic acid and L-histidine) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients.We identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome-host interactions in severe obesity.NCT01454232.
Generalization and fine mapping of red blood cell trait genetic associations to multi‐ethnic populations: The PAGE study
Authors: Chani J. Hodonsky, Claudia Schurmann, Ursula M. Schick, Jonathan Kocarnik, Ran Tao, Frank J. A. van Rooij, Christina Wassel, Steve Buyske, Myriam Fornage, Lucia A. Hindorff, James S. Floyd, Santhi K. Ganesh, Dan‐Yu Lin, Kari E. North, Alex P. Reiner, Ruth J. F. Loos, Charles Kooperberg, Christy L. Avery
Journal: American Journal of Hematology (2018)

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10
FRI0519 Work productivity is impaired in patients with behÇet’s syndrome
Authors: N. Serin, Y. Ozguler, S.N. Esatoglu, V. Hamuryudan, G. Hatemi
Journal: Annals of the Rheumatic Diseases (2018)

Methods: This retrospective cohort study used the EGB (Echantillon Généraliste des Bénéficiaires) database which is a 1% random and representative sample of the French national Health insurance system.EGB contains anonymous demographic and comprehensive medical data on conditions with long-term disease (LTD) status, hospitalizations and reimbursement claims for medications dispensed in the community.The study used the data collected between January 1, 2007 and December 31, 2015.Inclusion criteria were: 1) age !50 years; 2) hospitalisation for GCA or LTD status for GCA (ICD-10 codes: M31.5/6); and 3) at least 4 drug dispensing of oral GCs within 6 months around the index date.The index date was defined as the date of 1 st occurrence of GCA code and cases were considered as incident if the GCA code first occurred after !2 years of follow-up.Demographics, co-morbidities, diagnostic tests and therapies were analysed.A treatment sequence was defined as the start of a new drug or the resumption of the same drug after a stop !3 months.Annual incidence was calculated by using the people recorded in the EGB as denominator.Results: Among the 7 52 717 pts recorded in the EGB, 241 pts fulfilled our criteria.Around 24 pts were newly diagnosed/year with an annual incidence of 7 to 10/ 100,000 people!50 years-old.72% of the 241 pts were females, mean age was 77.5 (±8.9) years, mean follow-up 3.7 (±2.6) years.In the 12 months before index date, 74.3% of the pts had at least 1 proxy for hypertension, 39.4% for depression/ insomnia and 33.6% for osteoporosis.After index date, temporal artery biopsy (TAB) was performed in 43.2%, high-resolution Doppler ultrasound in 35.3% and positron emission tomography (PET) in 11.6%.Among the 235 pts (97.5%) who had at least 1 drug dispensing of oral GCs, 198 pts (84.3%) used only GCs while 37 (16.7%) also received 1 to 3 adjunctive agents.Mean 1 st GCs sequence duration was 17.2 months (±16.5) in 96.6%.95 pts (40.4%) had a 2nd sequence, i.e. resume GCs and or start a new drug for a duration of 6.7 months (±8.1) for GCS alone or 12.2 months (±8.8) for GCs+adjunctive drug.The most prescribed GCssparing agent was methotrexate (12.0%).Others were marginal: hydroxychloroquine 7 pts, azathioprine 4, cyclophosphamide 1, infliximab 1, adalimumab 2 and etanercept 1 pt.Conclusions: These real-world data indicate an incidence of GCA in France of 7 to 10 cases/100,000 people!50 years-old and underline that most patients with GCA are treated with GCs alone whereas adjunctive agents, mainly methotrexate, are given to 17% of patients.The utilisation of TAB in only half of the patients might reflect a shift towards increasing use of imaging techniques to diagnosed GCA.
AB0974 The efficacy and safety of intra-articular botulinum toxin injection in knee osteoarthritis
Authors: S.M. Rayegani, S.A. Raeissadat, E. Enayati, S. Rahimi Dehgolan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Osteoarthritis (OA) is a common disease that has a great burden through pain and decreased functional capacity. Botulinum toxin-A (BTA) injection has been recently proposed for knee OA patients to reduce pain and disability. <h3>Objectives</h3> In this study we evaluate BTA injection efficacy and safety among non-advance knee OA participants in a before-after trial. <h3>Methods</h3> This trial was conducted on knee OA patients presented to our PM and R clinic. Thirty participants aged 40–75 years who had radiographic OA grades of II and III KLS were included. Single intra articular injection of half of a <i>500</i><sup>IU</sup>vial BTA was applied for all participants. Patients were prospectively evaluated at baseline and then at 8 and 24 weeks after injection using the visual analogue scale (VAS) for pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in three subscales: pain, stiffness and function. <h3>Results</h3> Both main outcome measures of this trial (VAS and WOMAC) significantly improved after 24 weeks follow up. About two third of final VAS improvement was achieved in the first week after injection (from 7.2 to 4.5, MD%=36%, p value=0.008); then at 8 and 24 weeks post injection VAS reached 3.8 and 3.3, respectively. Almost 81%–77% of patients had more than 30% decline in their baseline VAS at 8th and 24th week visits, respectively. Also a similar pattern was observed for WOMAC index of sixth month (from 56.7 to 31.0, Mean Difference=−25.7 [MD%=45%], p value=0.005), with more remarkable changes in function subscale (MD%=46%). In this study no major adverse events were noted. <h3>Conclusions</h3> BTA showed promising effects in improving knee pain, ROM and functional status. Therefore this single session method could be considered as an alternative to other intra articular injections in knee OA patients who did not response to preliminary conservative treatments. Further data is necessary to assess long-term effects and cost-benefit analysis of BTA against other similar choices. <h3>Disclosure of Interest</h3> None declared
AB0417 Biological drugs in the treatment of rheumatoid arthritis: real life data in a brazilian multicentric study
Authors: A. Gomides, G. Pinheiro, A. Santos, C. Albuquerque, R. Giorgi, S. Radominski, I. Pereira, M. Guimarães, M. Bértolo, P.L. Júnior, K. Bonfiglioli, C. Brenol, M. Cunha, L. Mota
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic disease, characterised by inflammatory involvement of the synovial joints. The "treat to target" concept is well established in the rheumatologic community, however, in many patients, especially in developing countries, its implementation is not feasible. Considering the high costs of treatment com of RA and the limited national epidemiological data available on this disease, we sought to describe the profile of use of biological drugs in Brazilian patients with RA to help the decision-making process by public health managers. <h3>Objectives</h3> To describe the frequency and time of use of biological drugs in Brazilian patients with rheumatoid arthritis. <h3>Methods</h3> The REAL – RA in real life in Brazil – is a multicenter prospective cohort study, with twelve-month follow-up period. To be included in this study, consecutive patients from 11 tertiary rheumatology centres had to meet the 1987 ACR or the 2010 ACR/European League Against Rheumatism (EULAR) criteria. Data were collected during routine clinical care and previous medical records were used as secondary sources. The present study present data taken from the participants' initial assessment. This research was approved by the Ethics Committees of each centre. <h3>Results</h3> A total of 1125 patients were analysed. 89% were women with a mean age of 56.6 years. The main clinic data were: DAS 28 (median)=3.52, HAQ (median)=0.87 and CDAI (median)=9. 1022 (90.84%) used synthetic DMARDs and 406 (36.09%) biologic therapy. The frequency of use of the biologic therapy was: abatacept (73 patients/6.49%), etanercept (66/5.87%), tocilizumab (60/5.33%), adalimumab (54/4.8%), infliximab (50/4.44%), rituximab (49/4.36%), golimumab (37/3.29%), certolizumab (17, 1.51%). The time of use of the biological drugs is presented in table 1. <h3>Conclusions</h3> The therapeutic profile of this cohort of Brazilian RA patients shows some interesting results. The relatively high number of patients on biologics, compared to other studies, may be related to fact that the centres involved were reference centres, probably dealing with more difficult cases. <h3>References</h3> [1] Azevedo AB, Ferraz MB, Ciconelli RM. Indirect Costs of Rheumatoid Arthritis in Brazil. Value in Health2008;11(5):869–877. [2] Boonen A, Severens JL. The burden of illness of rheumatoid arthritis. Clin Rheumatol2011;30(Suppl 1):S3–S8. <h3>Disclosure of Interest</h3> None declared
AB0770 18 fdg pet/ct predicts decline in functional respiratory tests in systemic sclerosis patients but not in rheumatoid arthritis patients
Authors: J. Ivorra, M. Martinez, J.L. Loaiza, M. Garijo, J.J. Alegre, S. Herrera, I. Chalmeta, L. Gonzalez, R. Negueroles, C. Alcañiz, K.R. Arevalo, I. Canovas, C. Feced, J.J. Fragio, R. Gonzalez, E. Grau, E. Labrador, I. Martinez, C. Najera, J.E. Oller, F.M. Ortiz, E. Vicens, M. De la Rubia, D. Hervas, J.A. Roman
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Interstitial lung diseases (ILD) it's a frequent complication in connective tissue diseases (CTD) such as rheumatoid arthritis (RA) or systemic sclerosis (SS), but the lung is the only affected organ in the idiopathic pulmonary fibrosis (IPF). Nonspecific interstitial pneumonia (NSIP) is the more frequent form in SS while usual interstitial pneumonia (UIP) predominates in RA patients and in the IPF form. Some studies suggested that 18-FDG-PET/CT could help to detect zones of activity in lung tissue in IPF and this in turn could predict the disease progress, but results are inconclusive. Moreover, little is known about the value of 18-FDG PET uptake in ILD associated to RA or SS. <h3>Objectives</h3> The purpose of this study is to evaluate the predictive value of 18 FDG-PET/CT scan images in functional pulmonary progression of ILD associated to RA or SS. <h3>Methods</h3> We conducted a 12 month prospective observational study on patients diagnosed with ILD associated to <sup>SS or RA between January 2015</sup> and May 2017. ILD diagnosis was based on clinical assessment, pulmonary function tests (PFTs) and expert HRCT evaluation. We performed three visits: basal, 6 month and 12 month. On all visits a general exploration, forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were carried out. On basal and 6 month visit a 18-FDG-PET/TC was performed within a period of three months from the PFTs. Patients continued with their treatment (corticosteroids, DMARDs or immunosuppressants). The nuclear medicine physician identified the maximum and mean standardised uptake value (SUVmax and SUVmean) in the three areas with the most FDG uptake, and adenopathies uptake. PET/CT images were reviewed by 2 combined radiologist/nuclear medicine physicians in consensus. <h3>Results</h3> We included 17 patients, 10 had UIP associated with RA and 7 NSIP related to SS. It appeared that RA patients had longer lung illness evolution and worse FVC than SS patients (table 1), in spite of not having found statistical differences. We detected significant statistical relation between the highest SUVmax and FVC (p=0.009) or DLCO progression (p=0.006) in SS patients, independently of the basal FVC and DLCO, and duration of lung illness in a multivariable linear mixed model. We didn't find any relation between SUVmax and FVC or DLCO progression in RA patients. <h3>Conclusions</h3> In our cohort of patients with SS, 18 FDG PET/TAC can aid in predicting the progression of ILD associated disease, which does not occur in RA patients. <h3>Disclosure of Interest</h3> None declared
Galactose protects against cell damage in mouse models of acute pancreatitis
Authors: Shuang Peng, Julia V. Gerasimenko, Tetyana M. Tsugorka, Oleksiy Gryshchenko, Sujith Samarasinghe, Ole H. Petersen, Oleg V. Gerasimenko
Journal: Journal of Clinical Investigation (2018)

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP.