tbuckley/cabot-search huggingface dataset:
Abstract 378: Endothelial Cell Hypoxia-inducible Factor (HIF) Activity is Necessary for Right Ventricular Remodeling in a Murine Model of Chronic-hypoxic Pulmonary Hypertension
Authors: Todd M Kolb, Ben Singer, Franco D’Alessio, Mahendra Damarla, Rachel L Damico, Paul M Hassoun, Gregg L Semenza, Larissa A Shimoda
Journal: Circulation Research (2015)

Introduction: Pulmonary hypertension induced myocardial remodeling is required to minimize RV wall stress as pulmonary arterial pressures increase. Myocardial angiogenesis is presumed to play an integral role in early RV remodeling, though molecular regulators remain undefined. Endothelial cell (EC) expression of HIF-1 is necessary for adaptive LV remodeling during chronic pressure overload, with loss of EC-specific HIF-1 activity associated with reduced LV capillary density. We hypothesized that EC HIF activity may also be necessary for adaptive RV remodeling and angiogenesis in a model of chronic RV pressure overload. Methods: We used a murine model of chronic hypoxic pulmonary hypertension (CH-PH) to induce RV remodeling. Conditional transgenic mice lacking expression of the obligate HIF-1α/HIF-2α co-factor ARNT (aryl hydrocarbon receptor nuclear translocator) in Tie2+ lineage cells ( ARNT fl/fl ; Tie2-Cre +/- ) and ARNT fl/fl ;Tie2-Cre -/- controls were exposed to normobaric hypoxia (10% FiO 2 ) for 1-5 weeks. We measured RV hypertrophy (RVH), RV systolic pressure (RVSP), and myocardial EC proliferation (flow cytometry) as a marker for sprouting angiogenesis. Results: After three weeks of CH-PH, RVH was observed in ARNT fl/fl ;Tie2-Cre -/- control mice, as anticipated (0.332±0.02 vs. 0.231±0.02; P &lt; 0.05). CH-PH induced RVH in ARNT fl/fl ;Tie2-Cre -/- mice was associated with an early (1 week) increase in RV EC proliferation (vs. LV, 4.5±1.3% vs.1.8±0.5%; P &lt; 0.05). Conversely, ARNT fl/fl ; Tie2 - Cre +/- mice did not develop RVH after 3 weeks of CH ( 0.222±0.01 vs. 0.241±0.02; P = NS), and early RV EC proliferation was attenuated (vs. LV, 2.9±1.2% vs. 1.5±0.3%; P = NS). Despite similar increases in CH-PH induced RVSP after 3 weeks, after 5 weeks RVSP normalized in ARNT fl/fl ; Tie2 - Cre +/- mice, but remained elevated in ARNT fl/fl ;Tie2-Cre -/- controls. Conclusions: These preliminary findings confirm that EC-specific HIF activity is necessary for CH-PH induced RVH, and suggest that reduced EC proliferation (and potentially angiogenesis) may contribute to abrogated RV remodeling in ARNT fl/fl ; Tie2 - Cre +/- mice. We hypothesize that late normalization of RVSP in these mice may be indicative of premature RV failure.
The effect of community-based support for caregivers on the risk of virological failure in children and adolescents with HIV in Harare, Zimbabwe (ZENITH): an open-label, randomised controlled trial
Authors: Rashida A Ferrand, Victoria Simms, Ethel Dauya, Tsitsi Bandason, Grace Mchugh, Hilda Mujuru, Prosper Chonzi, Joanna Busza, Katharina Kranzer, Shungu Munyati, Helen A Weiss, Richard J Hayes
Journal: The Lancet Child & Adolescent Health (2017)

<h2>Summary</h2><h3>Background</h3> Children and adolescents have poorer HIV treatment outcomes than adults. We aimed to assess the effect of community-based support for caregivers of HIV-infected children and adolescents, who are key mediators to children engaging with care, on treatment outcomes. <h3>Methods</h3> In this open-label, randomised contolled trial, we recruited children aged 6–15 years with newly-diagnosed HIV attending primary health-care clinics in Harare, Zimbabwe. Children were randomly assigned to receive decentralised primary health-care clinic-based HIV care (control group), according to national guidelines for 18 months, or decentralised care plus structured support visits by trained community health workers (intervention group) according to national guidelines for 18 months. Primary outcomes were the proportion of participants who died or had an HIV viral load of 400 copies per mL or higher at 12 months after antiretroviral therapy (ART) initiation (among those who started ART within 6 months of enrolment); and the proportion who missed two or more scheduled clinic visits by 18 months post-enrolment (among all participants). Analyses were complete-case, modified-intention-to-treat. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201212000442288. <h3>Findings</h3> Between January, 2013, and January, 2015, 470 participants tested HIV-positive at seven study primary health-care clinics and were screened for eligibility. Of the 334 eligible children and adolescents, 166 were randomly assigned to the intervention group and 168 to the control group. The median age of participants was 11 years (IQR 8–13) and 178 (53%) were girls. Among the 238 participants who started ART within 6 months of enrolment, the proportion who died or had a viral load of 400 copies/mL or higher at 12 months post-ART initiation was significantly lower in the intervention group than in the control group (31 [33%] of 94 participants <i>vs</i> 42 [49%] of 86 participants, respectively, adjusted odds ratio [aOR] 0·46, 95% CI 0·23–0·89; p=0·02). The proportion of children missing two or more scheduled visits was similar in the intervention group and control group (27 [17%] of 155 <i>vs</i> 30 [18%] of 165, aOR 0·92, 95% CI 0·49–1·74; p=0·79). One participant withdrew from the trial 240 days after enrolment and 12 died during follow-up (five in the intervention group; seven in the control group). <h3>Interpretation</h3> Community-based support for caregivers has high potential for scalability and could have a substantial effect on HIV virological suppression in children and adolescents, a group with disproportionately poor treatment outcomes. <h3>Funding</h3> Wellcome Trust.
Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients
Authors: Joseph D. Schonhoft, Cecilia Monteiro, Lars Plate, Yvonne S. Eisele, John M. Kelly, Daniel Boland, Christopher G. Parker, Benjamin F. Cravatt, Sergio Teruya, Stephen Helmke, Mathew Maurer, John Berk, Yoshiki Sekijima, Marta Novais, Teresa Coelho, Evan T. Powers, Jeffery W. Kelly
Journal: Science Translational Medicine (2017)

Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure-based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses.
AB0998 Diagnostic value of 14-3-3 (ETA) in rheumatoid arthritis
Authors: A Novikov, E Aleksandrova, M Cherkasova, T Popkova, E Luchihina, D Novikova, D Karateev
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Protein 14-3-3η (eta) involved in the upregulation of inflammatory and joint damage factors [1]. 14-3-3η is the candidate biomarker of rheumatoid arthritis (RA) [2]. <h3>Objectives</h3> To evaluate the clinical utility of 14-3-3η for diagnosis of RA. <h3>Methods</h3> We studied 44 patients (pts) with RA, 5 man and 39 women, median (25–75 percentile) of age 45 (33–59) years; disease duration is 10 (5–20) months, DAS28 5,2 (4,4–6,2); 5 pts with systemic lupus erythematosus, 4 – ankylosing spondylitis, 5 – OVERLAP, 4 with psoriatic arthritis and 20 healthy individuals. 14-3-3η, anti-cyclic citrullinated peptide autoantibody (anti-CCP) was measured in serum by commercial enzyme-linked immunosorbent assays, IgM rheumatoid factor (IgM RF) measured – by immunonephelometry. <h3>Results</h3> The diagnostic sensitivity of 14-3-3η for RA (cut off 0,19 ng/ml) is 70,5%, specificity – 83,7%; positive likelihood ratio – 4,33, negative likelihood ratio – 0,35; positive predictive value – 81,6%, negative predictive value – 73,5%; AUC – 0,78 (CI 0,68–0,88). Concomitant presence of 14-3-3η and IgM RF, anti-CCP was determined in 68%, 73% of the patients with RA respectively. 14-3-3η had correlation with IgM RF (r=0,7, p&lt;0,05). <h3>Conclusions</h3> Serum 14-3-3η are helpful for the diagnosis of RA. <h3>References</h3> van Beers-Tas MH, Marotta A, Boers M, Maksymowych WP, van Schaardenburg D. A prospective cohort study of 14-3-3η in ACPA and/or RF-positive patients with arthralgia. Arthritis Res Ther. 2016 Apr 1;18:76. doi: 10.1186/s13075–016–0975–4. Maksymowych WP, Boire G, van Schaardenburg D, Wichuk S, Turk S, Boers M, Siminovitch KA, Bykerk V, Keystone E, Tak PP, van Kuijk AW, Landewé R, van der Heijde D, Murphy M, Marotta A. 14-3-3η Autoantibodies: Diagnostic Use in Early Rheumatoid Arthritis. J Rheumatol. 2015 Sep;42(9):1587–94. doi: 10.3899/jrheum.141385. Epub 2015 Jul 15. <h3>Disclosure of Interest</h3> None declared
AB0842 Sarcopenia and osteoporosis in patients with rheumatoid arthritis
Authors: K Aminov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Musculoskeletal disorders in RA are characterized by lesions of the peripheral joints, the development of local and systemic osteoporosis (OP), as well as a decrease in muscle mass and strength, which are currently being considered within the framework associated with chronic diseases syndrome sarcopenia and cachexia. <h3>Objectives</h3> To determine the prevalence and the relationship between sarcopenia and OP in patients with RA. <h3>Methods</h3> 156 RA patients were examined, of whom 83 postmenopausal women (mean age-61.7 years) and 73 males (mean age, 59 years). The control group consisted of 35 healthy subjects matched for age and sex. Exclusion criteria were: other rheumatic and endocrine diseases, severe somatic diseases, cancers, etc. The states of bone mineral density (BMD) at the lumbar spine (L1-L4) and femoral bone were assessed by dual-energy X-ray absorptiometry (DXA). <h3>Results</h3> Most RA patients (83% women and 63% men) were observed to decrease in BMD of osteopenia/OP level. BMD were negatively correlated with radiographic stage of RA, the DAS 28 and HAQ. IPC also revealed significant correlations with laboratory parameters such as creatinine, total protein, albumin, rheumatoid factor, and 1,25 (OH) D. Investigation of body composition showed a statistically significant reduction ITM RA patients compared to the control group, with no differences between the groups for fat mass. Sarcopenia had 25% of women and 55% men with RA, whereas the control groups, 8.7% and 0%, respectively. The majority of patients of both sexes sarcopenia observed on the background of the normal range of body fat index. Status of TM in patients with RA was statistically significant (p&lt;0,05) associated with femoral BMD and lumbar spine (r=0,3), BMI (r=0,5), force brush compression (r=0,4) RA radiographic stage (r= -0,4), indicators of total protein (r=0,5). <h3>Conclusions</h3> Patients with RA, together with OP/osteopenia have a significant reduction in muscle (lean) mass. Sarcopenia in patients with RA was observed in the majority of men (55%) and 25% of women, significantly more than the control groups. Implementation of the DRA with the program "whole body" will allow time to identify not only bone, but also muscle loss in RA patients, which will help to intensify targeted therapy. <h3>Disclosure of Interest</h3> None declared
OP0116 Switch from non-radiographic to radiographic axial spondyloarthritis is highly dependent of baseline objective signs of inflammation: 5 year data of the desir cohort
Authors: M Dougados, A Sepriano, A Molto, S Ramiro, M De Hooge, R Van Den Berg, V Navarro Compan, C De Mattei, R LandewΈ, D Van Der Heijde
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The natural history (e.g. appearance of structural damage) of non-radiographic (nr) axial (ax) Spondyloarthritis (SpA) is not well known. <h3>Objectives</h3> To evaluate the switch from nr- to radiographic (r) status of recent onset axSpA after 5 years of follow-up and its predisposing factors. <h3>Methods</h3> <i>Patients:</i> Recent onset axial SpA (DESIR Cohort). <i>Outcome measure:</i> Radiographic SIJ status according to the mNY criteria after 5 years follow-up. <i>Reading of the SIJ-X-Rays:</i> 3 trained readers unaware of the chronology of the films. <i>Potential predisposing factors:</i> Demographics, smoking status, HLA-B27, Bone Marrow Edema (BME) at MRI of the SIJ, CRP, disease activity and treatment. <i>Statistical analysis:</i> The radiographic progression has been evaluated in both the completers and after Linear Extrapolation (LE) and Last Observation Carried Forward (LOCF) technique in case of missing data. The predictive factors of radiographic progression were evaluated on the completer population using multilevel binomial GEE analysis incorporating measurements from all readers at 5-years and taking into account the within-reader correlation.Moreover, the progression rate was assessed in subgroups of patients according to CRP status and MRI-SIJ status at baseline. <h3>Results</h3> At baseline, 62 out of the 416 patients (14.9%) were considered r-ax-SpA. Out of these 416 patients, 24 (5.8%) changed from mNY negative to mNY positive after 5-years. Conversely, 3 patients changed from mNY positive at baseline to negative at year 5 (e.g. 0.7%) resulting in a net progression of 5.1%. These results were similar when applying LOCF and LE (4.1% and 3.8% net progression). In the multivariate analysis, presence of BME at MRI-SIJ was highly predictive of radiographic progression (OR=4.85 [95% CI: 2.95–7.97]) together with a younger age (OR=0.97 [95% CI: 0.94–0.99]) and longer symptom duration (OR=1.40 [95% CI: 1.04–1.89]). Of the 383 patients with complete data, the net % patients who switched from nr-axSpA to r-axSpA after 5 years ranged from 2.0% to 13.5% according to the presence of objective signs of inflammation at baseline (see figure). <h3>Conclusions</h3> This is the first cohort in early axSpA with 5-year follow-up demonstrating the importance of presence of objective signs of inflammation as predisposing factors of development of radiographic sacroiliitis. <h3>Disclosure of Interest</h3> None declared
FRI0063 Resveratrol attenuates synovial hyperplasia in an acute antigen-induced arthritis model by augmenting autophagy and decreasing angiogenesis
Authors: M Almonte-Becerril, JA Fernandez-Rodriguez, JA Fernandez-Rodriguez, O Ramil-Gomez, RR Riveiro-Naveira, L Hermida-Carballo, A Concha, A Vela-Anero, S Viñas, FJ Blanco, MJ Lopez-Armada
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Previously, we have demonstrated that dietary supplementation with resveratrol lowers synovial hyperplasia, inflammatory markers and oxidative damage in an acute antigen-induced arthritis (AIA) model. <h3>Objectives</h3> In this work, we investigated whether resveratrol can also regulate this abnormal proliferation of synovial tissue in an acute AIA model by inducing cell death pathways and by modifying the angiogenesis in the synovial membrane. <h3>Methods</h3> Animals were randomly divided into 3 groups: control, AIA, and resveratrol-treated AIA group. Resveratrol (12,5 mg/kg/day) was given orally 8 weeks before AIA induction until sacrifice day (48 h after intra-articular injection). Control and AIA animals were administered 100 μl of water. Resveratrol effects on autophagy and apoptosis were evaluated by LC3 and active caspase-3 expression (confocal and immunohistochemistry, respectively). Angiopoietin 1 (Ang-1), vascular endothelial growth factor (VEGF), and the nuclear factor NF-<i>kappa</i>-B p65 subunit (p65) were also determined by immunohistochemistry and cartilage degradation with Safranin-O. <h3>Results</h3> Resveratrol significantly reduced the histological score of synovial tissue. Results showed a significant higher expression of LC3 signals in the AIA synovial membranes, compared with control samples, in which the presence of vesicles was easily observed. Interestingly, the synovial tissues from the resveratrol group showed a significantly (p≤0.001) higher signal for LC3, compared with the AIA samples. Active caspase-3 expression was up-regulated at the same level in the synovial membranes of AIA group than in resveratrol-treated AIA group; however, in resveratrol-treated AIA group active caspase-3 signal was mainly located in the inflammatory cells. Resveratrol consumption significantly attenuated Ang-1 signal, whereas expression of VEGF showed a non significant reduction. Resveratrol administration also mitigated, even not significantly, p65 expression that was significantly higher in the AIA animals than those from the control animals. In addition, resveratrol decreased articular cartilage degradation. <h3>Conclusions</h3> These data suggest that resveratrol is able to modulate synovial hyperplasia by increasing autophagic cell death and limiting angiogenic response in an acute AIA model, which could also modulate the inflammatory and destructive processes for rheumatoid arthritis. <h3>Acknowledgements</h3> Instituto de Salud Carlos III-Ministerio de Economía y Competitividad N° Expediente PI12/02771. Uniόn Europea-Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” <h3>Disclosure of Interest</h3> None declared
FRI0478 Subchondral bone sclerosis on computed tomography – does it have any value in the diagnosis of inflammatory sacroiliitis or is it a non-specific finding?
Authors: O Azmat, RG Lambert, Z Jibri, WP Maksymowych
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Sclerosis in the sacroiliac joints (SIJ) on radiography and computed tomography (CT) is common but widely considered a non-specific finding of sacroiliitis due to an association with degeneration and osteitis condensans ilii, despite little formal study. Availability of low dose radiation CT may lead to more widespread use for diagnostic evaluation. <h3>Objectives</h3> We standardized the definition of sclerosis on CT and then aimed to determine whether this lesion could be reliably detected and its diagnostic utility. <h3>Methods</h3> 215 CT scans were obtained from patients with a history of low back pain. 107 patients had a clinical diagnosis of spondyloarthritis (SpA) and 108 patients were clinically proven not to have SpA. Groups were age and gender matched (140 males, 75 females, mean age was 45 years). Three musculoskeletal radiologists, blinded to patient demographics and diagnosis, scored the CTs after standardization of lesion definitions and calibration. Erosions, sclerosis, and ankylosis were graded by size and number of articular surfaces/ joints involved. Sclerosis was considered definite if located along the cartilaginous compartment, measured &gt;5mm in all 3 planes, and present &gt;5mm from the joint surface. Discrepant scores were arbitrated and inter-reader reliability calculated by intra-class correlation coefficient (ICC). Diagnostic utility of CT lesions was determined by calculating sensitivity and specificity for the clinical diagnosis and by logistic regression. <h3>Results</h3> ICC for sclerosis and erosion for each articular surface ranged from 0.65–0.76 and 0.71–0.78, respectively. ICC for ankylosis was 0.87–0.89. Sclerosis occurred in 87 (81%) cases with SpA and 25 (23%) controls. For a single articular surface the specificity for sacroiliitis ranged between 88–94%, for any two articular surfaces 95–100%, for all 4 articular surfaces 100%. Sensitivity ranged from 14% (4 articular surfaces) to 55% (either ilium). Erosion and ankylosis had a similar specificity range of 91–100% and 92–93%. The odds ratio was 4.9 for presence of definite sclerosis, and 12.6 for bilateral joint involvement. The odds ratio increased to 84.2 for bilateral erosion and 22.8 for bilateral ankylosis. <h3>Conclusions</h3> When sclerosis measures &gt;5mm in three planes and is located &gt;5mm from a joint perimeter, it has high specificity for sacroiliitis, regardless of how many articular surfaces are involved, with similar specificity to erosion and ankylosis. <h3>Disclosure of Interest</h3> None declared
FRI0404 The effect of a home-based orofacial exercise program on oral aperture of systemic sclerosis patients
Authors: N Cuzdan Coskun, I Turk, V Ciftci, D Aslan Tas, MC Dogan, I Unal
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Microstomia is one of the major problems that causes multiple dysfunctions and affects quality of life in systemic sclerosis (SSc).<sup>1</sup> <h3>Objectives</h3> The purpose of this study is to evaluate the effect of a home-based orofacial exercise program on the oral aperture (OA) of SSc patients. <h3>Methods</h3> SSc patients who fulfilled the <i>American College of Rheumatology</i> (ACR) 2013 criteria with an OA of &lt;40mm were included in the study. Patients were randomly divided into two groups. Group 1 was given oral augmentation and mouth stretching exercises with combination of strengthening exercise to masseter muscle twice a day for one month in addition to oral hygiene care advices; followed by no activity but oral hygiene care for the next four weeks. Group 2 received oral hygiene care advices for the first one month followed by the same orofacial exercise program twice a day for the next four weeks. Patients9 OA was measured by a dentist at baseline, 1-month, and 2-months. <h3>Results</h3> A total of 52 patients were included in the study. Twenty-seven patients were assigned to group 1 (mean age 53.70±9.79 years; 96.3% female) and twenty-five patients to group 2 (mean age 50.68±11.93 years; 96.0% female). A total of 28 patients (group 1, n=18; group 2, n=10) completed the study. After four weeks period, OA increased in group 1 (<i>P</i>&lt;0.001), whereas no change was observed in group 2 (<i>P</i>=0.906). At the end of 2 months the intragroup analysis showed no additional increase in group 1 (<i>P</i>=0.283), but a statistically significant increase in group 2, regarding the measurement of OA (<i>P</i>=0.010). We didn9t find any statistically significant difference between OA measurements of the groups 1 and 2 at the end of the trial (<i>P</i>=0.830). <h3>Conclusions</h3> The results of this pilot study suggested that an intervention of combined home-based orofacial exercise program might improve oral aperture of SSc patients. Future studies with longer follow-up period and higher number of patients are needed to observe the long-term benefits of the presented home-based exercise program. <h3>References</h3> Frantz C, Avouac J, Distler O, Amrouche F, Godard D, Kennedy AT, Connolly K, Varga J, Matucci-Cerinic M, Allanore Y. Impaired quality of life in systemic sclerosis and patient perception of the disease: A large international survey. Semin Arthritis Rheum. 2016 Aug;46(1):115–23. <h3>Disclosure of Interest</h3> None declared