tbuckley/cabot-search huggingface dataset:
SAT0240 IL-22 Levels after Abatacept Treatment in Rheumatoid Arthritis
Authors: M. Scarsi, E. Colombo, S. Piantoni, R. Ottaviani, F. Allegri, A. Tincani, P. Airò
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Interleukin (IL)-17 plays a pivotal role in Rheumatoid Arthritis (RA) pathogenesis, driving the T-helper (Th) response to the auto-reactivity and pro-inflammatory status (Th1-Th17 branch). Among cytokines involved in IL-17 cascade, IL-22 is produced by T-cells producing IL-17 (Th17) and allows the proliferation and survival of themselves. It has been described that IL-22 levels in RA are related to the clinical disease activity and to the presence of bone erosions. In our previous evaluation, we showed that costimulation blockade performed by Abatacept (ABA) is able to reduce circulating T-cells able to produce IL-17 after in vitro stimulation; the reduction of this subpopulation was directly related to the improvement of clinical disease activity (1). <h3>Objectives</h3> The aim of this study is to investigate whether the reduction of Th17 cells after ABA treatment in RA may be influenced by variation of IL-22 serum levels. <h3>Methods</h3> 30 patients (4 male, 26 female; median age: 53, IQR:44-60 years) treated with ABA for at least 6 months were enrolled. Disease activity and clinical response to the treatment were evaluated with DAS-28(CRP) and EULAR Response Criteria respectively. IL-17 production by T cells was evaluated by flow-cytometry, with intracytoplasmatic staining of PBMC stimulated for 6 hours with PMA-ionomycin, as previously reported (1); IL-22 serum levels were evaluated by ELISA (R&amp;D System). <h3>Results</h3> After 6 months of treatment 16 patients achieved the clinical remission. At baseline, 10 patients showed raised serum levels of IL-22 than the range of normality, provided by the manufacturers (&gt;53.3 pg/ml), whereas 20 patients showed normal levels (≤53.3 pg/ml). At baseline, no significant difference was observed in IL-22 levels between patients that achieved clinical remission and the others (24.6 (7.5-106.4) vs 42.7 (11.7-52.7)pg/ml; p: 0.15). After 6 months of treatment, a not significant reduction of IL-22 levels was seen in the total cohort of patients (from 38.3 (7.7-93.0) to 33.8 (11.1-74.8) pg/ml; p: 0.56). Patients that achieved clinical remission showed a significant lower probability of serum-conversion after 6 months of ABA treatment (from normal to high titer), than non-responders (0 vs 55%; p:0.01). The variation of IL-22 levels correlated with the modification of the number of circulating T-cells able to produce IL-17 after in vitro stimulation (p:0.002; r: 0.75). No correlation was seen between the variation of IL-22 titer and of DAS-28. <h3>Conclusions</h3> IL-22 serum levels seem to be not modified by ABA treatment, whereas the reduction of IL-17 producing T-cells yet described is correlated to the modification of IL-22 titer. Further studies need to clarify the effects of ABA on IL-22. <h3>References</h3> Scarsi M, et al. Clin Exp Rheum 2014, in press. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5999
PTU-006 Using Digistories to Challenge Student Attittudes to Addiction
Authors: L Macdougall, A Teodorczuk, A Hearn
Journal: Gut (2013)

Introduction Addiction to both alcohol and other drugs creates a large health burden within the NHS. Undergraduate exposure to these patients tends to be opportunistic and sporadic; we wanted to create a learning experience for large groups of 30+ students using a real patient storey. Patients with drug and alcohol dependence can lead chaotic lives and may feel threatened by a large group teaching encounter, they may struggle to talk about their often highly personal experiences. Moreover patients with addictions may only volunteer for teaching once they are have been abstinent and consequently their storey whilst relevant is no longer current. Methods A transdisciplinary group of Gastrointestinal and Mental Health teachers elected to produce a digital storey (digistory) of a patient currently dependent on both alcohol and opiates. A digistory is a personal narrative normally set to still images which change in reference to the person’s storey. Typically it is recorded using a Dictaphone and embedded within a PowerPoint picture presentation. The advantage of a digistory over conventional video is that the patient’s anonymity is preserved whilst the patient retains their own voice; the addition of appropriate images makes the storey more powerful and creates a focus whilst listening to the audio. A patient known to a regional addictions service was approached, consented and recorded. The digistory was shown to the patient prior being shown to the students. In groups students discussed their previous experiences of addiction and then watched the digistory. To enhance knowledge transfer they were asked to consider a biopsychosocial problem list for the patient. They then reflected on their own preconceived ideas about addictions, reaction to the storey and developed a patient problem list. Students completed a written evaluation of the session. Results There was consensus that the digistory was a powerful learning tool and that the session was thought provoking. Furthermore they stated that the storey’s power arose from the fact the patient was a similar age to them and was local to the area. Students fed back in post-session evaluation that it had changed their perception of those with alcohol and drug problems. Conclusion Some students did state a desire to still see patients for themselves; seeing patients personally will always remain important but we describe the use of a digistory as a powerful teaching tool to generate dialogue amongst learners, enhance knowledge exchange and address possibly misplaced attitudes to a vulnerable patient group. We recommend the use of digistories as a novel and effective teaching method to enable patients to tell very personal storeys whilst still protecting their anonymity. Disclosure of Interest None Declared
Deposition of Terminal C5b–9 Complement Complexes on Erythrocytes and Leukocytes during Cardiopulmonary Bypass
Authors: A Salama, F Hugo, D Heinrich, R Höge, R Müller, V Kiefel, C Mueller-Eckhardt, S Bhakdi
Journal: New England Journal of Medicine (1988)

Hemolysis, leukopenia, a hemostatic deficit, and nonspecific systemic reactions collectively known as the postperfusion syndrome develop in patients who undergo cardiopulmonary bypass. We now report that terminal C5b-9 complement complexes are deposited on erythrocytes and polymorphonuclear neutrophilic leukocytes during cardiopulmonary bypass. Plasma samples taken from 48 unselected patients during and at the end of cardiopulmonary bypass contained raised levels of fluid-phase SC5b-9 complement complexes, indicating that the complement sequence had been activated to completion. Various degrees of overt intravascular hemolysis were observed in all the patients, and lysed erythrocyte membranes were recovered from the blood samples. Immunoassays performed with use of antibodies to C5b-9 neoantigens demonstrated the presence of C5b-9 on red-cell ghosts but not on intact erythrocytes. The appearance of ghosts carrying C5b-9 always coincided with hemolysis. Furthermore, granulocytes isolated from 20 patients during bypass were all found to carry C5b-9 complexes, whereas cells isolated before or 24 hours after surgery carried no C5b-9. The neoantigen-positive material present in detergent extracts of granulocytes sedimented in a broad peak (25 to 40 sedimentation coefficient [S]) in sucrose-density gradients, exactly as did pore-forming C5b-9 complexes. Deposition of C5b-9 on blood cells during cardiopulmonary bypass may be partly responsible for the hemolysis and may augment granulocyte activation by the stimulation of arachidonate metabolism in those cells.
Abstract 2080: miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma
Authors: Mayuko Furuta, Ken-ichi Kozaki, Shinji Tanaka, Shigeki Arii, Issei Imoto, Johji Inazawa
Journal: Cancer Research (2010)

Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs that, in general, negatively regulate gene expression. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. Some miRNA genes harboring CpG-islands undergo methylation-mediated silencing, a characteristic of many tumor-suppressor genes. To identify such miRNAs in hepatocellular carcinoma (HCC), we first examined the methylation status of 43 loci containing CpG-islands around 39 mature miRNA genes in a panel of HCC cell lines and non-cancerous liver tissues as controls. Among 11 miRNA genes frequently methylated in HCC cell lines but not in non-cancerous liver tissues, 3 miRNA genes, i.e. miR-124, miR-203, and miR-375, were selected as silenced miRNAs through CpG-island methylation by comparing methylation and expression status and evaluating restored expression after treatment with 5-aza-2′-deoxycytidine. In primary tumors of HCC with paired non-tumorous liver tissues, only miR-124 and miR-203 showed frequent tumor-specific methylation, and their expression status was inversely correlated with methylation status. Ectopic expression of miR-124 or miR-203 in HCC cells lacking their expression inhibited cell growth, with direct down-regulation of possible targets, cyclin-dependent kinase 6 (CDK6), vimentin (VIM), SET and MYND domain containing 3 (SMYD3), and IQ motif containing GTPase activating protein 1 (IQGAP1) or ATP-binding cassette, sub-family E, member 1 (ABCE1), respectively. Our results suggest that miR-124 and miR-203 are novel tumor-suppressive miRNAs for HCC epigenetically silenced and activating multiple targets during hepatocarcinogenesis. 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 2080.
Silas Weir Mitchell
Authors: Lawrence C. McHenry
Journal: New England Journal of Medicine (1959)

SILAS WEIR MITCHELL, physiologist, neurologist, psychiatrist, novelist and poet, has often been regarded as the most versatile American since Benjamin Franklin. Over a period of fifty years he wrote nineteen novels, seven books of poetry, a scholarly and controversial biography of Washington, a children's story (Kris-Kringle) that went through twelve editions, and a dissertation on William Harvey, and translated a fourteenth-century poem into modern verse, as well as making outstanding investigations on rattlesnake venom, peripheral nerve injuries, traumatic neuroses, erythromelalgia, posthemiplegic chorea, epilepsy, disorders of sleep and rest treatment for psychiatric patients. His novel, Hugh Wynne, has been compared . . .
Case 25-2005
Authors: Dennis L. Kasper, Dushyant Sahani, Joseph Misdraji
Journal: New England Journal of Medicine (2005)

A 40-year-old man was admitted to the hospital because of fever and weight loss of two months' duration. He had been well until an episode of gastroenteritis, after which daily fever, anorexia, and weight loss developed. A laparoscopic appendectomy was performed, but symptoms persisted. Repeated imaging showed occlusion of the portal vein.
Abstract LB-276: CLCA2 interactor EVA1 maintains epithelial differentiation of HMEC.
Authors: Randolph C. Elble, Grace Ramena, Vijay Walia
Journal: Cancer Research (2013)

Abstract CLCA2 is a p53-inducible transmembrane protein that is frequently downregulated in breast cancer. It is induced during MET in immortalized HMEC, and its knockdown causes EMT. To determine how CLCA2 promotes epithelial differentiation, we searched for interactors using membrane dihybrid screening. We discovered a strong interaction with the cell junctional protein EVA1 (Epithelial V-like Antigen 1), confirmed by co-immunoprecipitation and immunolocalization experiments. Like CLCA2, EVA1 is a type I transmembrane protein that is regulated by p53. It mediates homophilic cell-cell adhesion in diverse epithelial tissues. We found that EVA1 is frequently downregulated in breast tumors and breast cancer cell lines, especially those of mesenchymal phenotype. Like CLCA2, knockdown of EVA1 resulted in rapid EMT in immortalized HMEC and increased invasiveness. The interacting domains were delimited by deletion analysis, revealing that the CLCA2 transmembrane segment (TMS) alone was sufficient for the interaction with EVA1. Surprisingly, EVA1 bound to the TMS only in the context of full length CLCA2 precursor, but not in the context of the C-terminal cleavage product, suggesting that cleavage of CLCA2 causes a conformational shift and release of EVA1. The interaction was specific, as other transmembrane proteins did not interact with CLCA2 or EVA1. To determine whether CLCA2 regulates EVA1 localization to tight junctions or hemophilic ligation, we fused the CLCA2 or EVA1 TMS to a secreted heterologous protein to create competitive inhibitors. These results identify the CLCA2-EVA1 complex as pivotal in maintaining epithelial differentiation and explain the downregulation of both genes during tumor progression. Citation Format: Randolph C. Elble, Grace Ramena, Vijay Walia. CLCA2 interactor EVA1 maintains epithelial differentiation of HMEC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-276. doi:10.1158/1538-7445.AM2013-LB-276
Children's champion says more needs to be done for children whose parents misuse alcohol
Authors: I. Torjesen
Journal: BMJ (2012)

More help and support need to be given to the hundreds of thousands of children living with a parent who misuses alcohol regularly, a report from England’s Office of the Children’s Commissioner says.1

The report describes how more children are affected by parents who drink alcohol excessively than the number whose parents take illegal drugs. But parental alcohol misuse is not taken as seriously as parental drug misuse by children’s services, despite alcohol being a far easier to obtain addictive substance, as it is legal, advertised, and easy to buy, the report explains.

The researchers held focus groups with children who had at least one parent who drank alcohol to excess to …
Abstract 295: PKCε phosphorylates and modulates the cell membrane translocation of RhoA
Authors: Ti-Zhi Su, Samuel Straight, Li-Wei Bao, Greg Cavey, Quintin Pan
Journal: Cancer Research (2010)

Abstract Accumulating evidence has clearly defined the importance of PKCε and small Rho GTPases in tumor metastasis. Previous studies in our laboratory have demonstrated that PKCε signals through RhoA to modulate tumor cell invasion and motility in head and neck squamous cell carcinoma. In this study, we further delineated the link between PKCε and RhoA. Recombinant PKCε directly phosphorylated recombinant RhoA using an in vitro kinase assay. Phosphopeptide mapping with LC-MSE identified T127 and S188 as confident phosphorylation sites and T19 and S26 as tentative phosphorylation sites on RhoA. Interestingly, recombinant PKCε was able to bind to recombinant RhoA in the absence of PKC activators and ATP. This observation demonstrates that the binding interaction between PKCε and RhoA does not require an active PKCε conformation and thus, the interaction between these proteins may be more complex than a typical substrate-kinase event. N-terminus fluorophore-tagged PKCε (CherryFP or CFP) and RhoA (GFP or YFP) were co-expressed in HEK293 cells to examine the interaction between these two proteins in live-cells. Live-cell fluorescence microscopy followed by FRET stoichiometric analysis confirmed the interaction between PKCε and RhoA in the cytoplasm of non-stimulated cells. Stimulation of the cells with PMA to activate PKCε resulted in the translocation of PKCε and RhoA from the cytoplasm to the cell membrane and increased the binding of PKCε to RhoA at the cell membrane by three-fold as measured by FRET. Taken together, our results demonstrate, for the first time, that PKCε phosphorylates, co-localizes, and regulates the cell membrane translocation of RhoA. 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 295.
P692Metabolic control of vessel diameters: vasodilation with low or vasoconstriction with high PO2?
Authors: B Reglin, AR Pries
Journal: Cardiovascular Research (2014)

Purpose: Metabolic regulation of blood flow is needed to match tissue substrate supply to demand. In this process, metabolic signal substances are assumed to act as mediators: decreasing Po2 has been shown to evoke not only increasing release of vasodilators (e.g. NO, adenosine) but also declining release of vasoconstrictors (e.g. HETE). Here, a previously developed model simulation of vascular adaptation was used to compare the suitability for vessel diameter control of vasodilators released in response to declining Po2 with vasoconstrictors which are increasingly released at high Po2. Methods: In the simulation model, all vessels of a rat mesentery microvascular network (576 vessels) change diameter in response to wall shear stress, transmural pressure and local Po2. Local metabolic information is transferred downstream via convection of metabolic signal substances and upstream via conduction along the vessel wall. Information transfer is crucial to prevent shunting. Decreasing levels of local Po2 were assumed to evoke (A) increasing amounts of vasodilators or (B) decreasing amounts of vasoconstrictors. For all conditions tested, model parameters were optimized to achieve lowest deviation between predicted and measured flow velocities (velocity error, VErr). Results: (A) Of all conditions tested, lowest VErr was found for release of substances evoking vasodilation locally, downstream via convection and upstream via conduction assuming oxygen dependence over the full range or restricted to high Po2 levels. (B) Much higher VErr resulted from release of substances evoking vasoconstriction locally, up- and downstream. VErr could be reduced (but not to the VErr level reached by vasodilating effects) by assuming that metabolic signalling evokes vasoconstriction locally but vasodilation up- and downstream. Conclusion: Vasodilators are better suited than vasoconstrictors to metabolically control vessel diameters. The suitability of vasoconstrictors is restricted by the fact that the increase in diameter in response to low Po2 (evoked by low vasoconstrictor release) is partially counteracted by a concentration increase of the vasoconstricting substance in the vessel with decreasing flow (“dilution effect”). Also, for feeding and draining vessels the constrictive signal increases in proportion to the number of capillaries supplied, which is in contrast to the requirements for flow distribution within a vascular network.
FRI0064 Patients with rheumatoid arthritis have fall more often than healthy individuals: the tomorrow study
Authors: K. Mamoto, T. Koike, T. Okano, Y. Sugioka, M. Tada, K. Inui, H. Nakamura
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Patients with rheumatoid arthritis (RA) who have muscle weakness and stiff or painful joints might be at increased risk of falling and vertebral fractures. The present study prospectively determines the incidence of falls and associated risk factors in patients with RA in the TOMORROW study (UMIN000003876) that started in 2010. <h3>Methods</h3> We evaluated muscle volume, bone density, thoracolumbar spine X-rays and disease activity in 202 consecutive patients with RA (54% using biological agents) and 202 age- and sex-matched healthy individuals as controls and then assessed the incidence of falls for 2 years. <h3>Results</h3> The incidence of having at least one fall during the 2-year period did not significantly differ between the patients and controls (29.7% vs. 26.7%, NS). However, the patients fell significantly more often than controls (2.37 vs.1.56 falls; p = 0.03) and had a higher prevalence of vertebral fractures (45.5% vs. 30%) and semiquantitative (SQ) grade ≥2 (15% vs. 5%) than the controls. After adjusting for risk factors of falls such as age, gender, smoking and BMI, multiple logistic regression analysis identified that a history of falls was the most significant parameter associated with the incidence of falls (odds ratios: all, 2.44, p &lt; 0.001; patients, 2.40, p = 0.014; controls, 2.72, p = 0.015; Table 1). Existing vertebral fractures and SQ grade ≥2 did not correlate with the incidence of falls (Table 1). Multiple regression analysis revealed that the number of falls experienced by patients with RA was associated with doses of prednisolone (PSL; β = 0.188, P = 0.010,) and matrix metalloproteinase-3 (MMP-3; β = 0.156, P = 0.028). <h3>Conclusions</h3> A history of falls was an independent risk factor for any fall in all participants. Patients with RA receiving high doses of PLS or MMP-3 tended to fall more frequently than healthy individuals. <h3>Disclosure of Interest</h3> K. Mamoto: None Declared, T. Koike Speakers bureau: akeda Pharmaceutical, Mitsubishi, T. Okano: None Declared, Y. Sugioka: None Declared, M. Tada Grant/research support from: Japan Osteoporosis Foundation grant 2013, K. Inui: None Declared, H. Nakamura: None Declared
ECHOCARDIOGRAPHIC STUDY OF RIGHT VENTRICULAR REMODELING IN TOP-LEVEL GEORGIAN ATHLETES
Authors: L Maskhuliva, V Akhalkatsi, K Chelidze, Z Kakhabrishvili, M Matiashvili, N Chabashvili, T Chutkerashvili
Journal: British Journal of Sports Medicine (2014)

Background There are a large number of studies which have focused on left ventricular (LV) structural and functional characteristics, however insufficient data exist concerning right heart response to exercise in elite athletes of different sporting disciplines. Objective To investigate right ventricular (RV) dimensions and function in top-level athletes. Design Retrospective study. Setting Sports Medicine Clinical Centre. Participants 124 top-level male athletes (18 cyclists, 62 football and 21 basketball players, 23 wrestlers) and 57 age-matched healthy sedentary controls were studied . All subjects were evaluated with 2D, spectral conventional, and tissue Doppler echocardiography. According to the guidelines of American Society of Echocardiography (ASE), RV subcostal wall thickness, RV diameters (RVD1, RVD2, RVD3, RVOT-Prox, RVOT-Distal) indexed by BSA, and functional parameters (TAPSE, FAC, TD MPI, E/A, E/E') were evaluated. Main outcome measurements Athletes of various sport disciplines with respect to RV remodeling. Results Morphologic parameters in most of the athletes and in all controls were within normal limits. Increased RV dimensions were found in 43(35%) athletes. RV wall thickness (3,82±0,71 vs. 3,51±0,32 mm) and RV diameters were significantly greater in athletes than in controls (P&lt;.001). Most of the RV parameters in athletes were within the range of Mean and Upper Reference Values (URV), however RVD1 in 34 (27%) and RVD2 in 22 (18%) athletes exceeded URV by ASE criteria. By sporting disciplines RVD1 exceeded URV in 39% cyclists, 25% basketball players, 23% football players, 22% wrestlers. Interestingly, less than half of these athletes (47%) exhibited concomitant LV enlargement. RV functional parameters were in normal limits in athletes as in controls and did not differ (P&gt;.20). Conclusions In elite athletes long-term intensive training was associated with RV remodeling, particularly of RV base. RV function was not altered despite significant chamber dilatation. The extent of changes in RV morphology varied between sports: cyclists were more prone to exercise-induced RV structural remodeling.