tbuckley/cabot-search huggingface dataset:
AB0135 Four-day continuous blood exposure leads to prolonged joint damage in a canine in vivo model, not the cumulative blood load of intermittent exposures
Authors: M.E. van Meegeren, G. Roosendaal, S.C. Mastbergen, F.P. Lafeber
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In a canine model, intra-articular blood injections twice a week during 4 weeks resulted in transient damage only (1). Human in vitro studies have shown that there is a threshold for the blood load (duration and concentration) to which cartilage has to be exposed to blood, before cartilage damage becomes irreversible (2). This blood load was probably not reached in vivo in the canine model. <h3>Objectives</h3> In this study it was evaluated whether continuous blood exposure is more harmful than intermittent blood exposure in a canine model of knee arthropathy. <h3>Methods</h3> Seven dogs received 2 series of 4 daily blood injections (continuous exposure) with 2 weeks in between. Seven other dogs received a total number of 8 intra-articular blood injections intermittently over a 4 week period with at least 1 day in between. Contralateral knees served as controls. Ten weeks after the last injection cartilage matrix turnover and synovial inflammation were evaluated. <h3>Results</h3> In the blood-exposed joints of both groups proteoglycan synthesis rate was increased (both p≤0.02), as an attempt to repair cartilage. This mimics early features of joint degeneration. Only in the continuous blood-exposed knees the release of newly formed and total (resident) cartilage matrix glycosaminoglycans (GAGs) was increased (p=0.04 and p=0.01, respectively). Furthermore, in the animals with continuous exposure cartilage GAG content was decreased (p=0.01), and not in the animals with intermittent exposure. Mild synovial inflammation was observed in both groups (both p&lt;0.0001), not different between groups. <h3>Conclusions</h3> In contrast to intermittent exposure, a 4-day continuous blood exposure twice in 4 weeks leads to prolonged cartilage damage independent of the level of synovial inflammation. This model is of use to study treatment modalities preventing blood-induced arthropathy. <h3>References</h3> Hooiveld, M., et al., Blood-induced joint damage: longterm effects in vitro and in vivo. J Rheumatol, 2003. 30(2): p. 339-44. Jansen, N.W., et al., Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study. Arthritis Rheum, 2007. 56(1): p. 199-207. <h3>Disclosure of Interest</h3> None Declared
Labour calls for freeze on NHS contracts with the private sector until after general election
Authors: I. Torjesen
Journal: BMJ (2014)

The Labour Party has called for a moratorium on new contracts between the NHS and the private sector until after the 2015 general election, to halt what it has described as the “forced privatisation of the NHS.”

During a speech in Manchester on 29 July Andy Burnham, the shadow health secretary, urged NHS England to delay signing new NHS contracts for clinical services with the private sector until after the election. Last month it was confirmed that annual NHS spending on private sector and other providers had exceeded £10bn (€12.6bn; $17bn) for the first time.

Burnham said that voters had never given consent for the far reaching and forced privatisation of clinical services, and he highlighted three commissioning exercises that he said raised particular concerns. These were: two contracts with a combined value of £1.2bn to provide cancer care in Staffordshire for 10 years1; a five year contract worth £800m for the care of elderly …
OP0175 Systemic Lupus Erythematosous and Primary Sjogren’s Syndrome May Display Joint Erosions on MRI as Well as Healthy Control, but Cannot be Considered as Erosive Disease Such as Rheumatoid Arthritis: An MRI Observational Study of 90 Subjects
Authors: F. Gandjbakhch, V. Foltz, J. Renoux, N. Costedoat, D. SENE, G. Mercy, Z. Amoura, J. C. Piette, N. Morel, N. Cozic, P. Bourgeois, B. Fautrel
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Recent studies tend to demonstrate presence of MRI erosion in Systemic Lupus Erythematosous (SLE) and primary Sjogren's syndrome (pSS). Better knowledge of erosions' characteristics of these different diseases may improve MRI interpretation. <h3>Objectives</h3> To describe MRI characteristics (erosion and osteitis) of patients with SLE and pSS compared to "positive control", i.e. RA and "negative control" (sex/age- matched healthy controls ). <h3>Methods</h3> pSS, SLE, RA patients and HC were prospectively included from 2 departments (rheumatology and internal medicine) between 2009 and 2011. Inclusion criteria were: 1- for SLE and pSS : disease duration &gt;2 years, no association with RA, i.e. no arthritis, no ACPA, normal X rays of hand and feet. 2-for Healthy controls (HC): no history of tender/swollen joint or rheumatic disease. 3- for RA: established RA, i.e. duration&gt;2 years. MRI of MCP2 to 5 and wrist of the dominant hand was performed using a dedicated MRI (ESAOTE Cscan 0.2 Tesla) in coronal and axial plans using T1 and STIR sequences, without gadolinium injection, to evaluate erosion and osteitis according to the OMERACT definitions. Erosion was defined as an intra-articular cortical break visible in two planes (OMERACT definition), not related to vascular foramen or ligament insertion.2 independent readers evaluated MRI, blindly to clinical and radiographic data, using RAMRIS scores for erosion and osteitis. Statistics were performed using SAS 9.3 software. <h3>Results</h3> 90 subjects were included prospectively: 19 pSS, 21 SLE, 30 RA and 20 HC.Mean age was respectively 38.8±9.8, 54.4 ±14.2, 53.9±13.1, 42.7±11 years for SLE, pSS, RA patients and HC. 83% of RA patients were erosive on Xrays, 86% and 72% were RF and ACPA positive. All SLE and pSS patients had normal Xrays (inclusion criteria). Cortical break were seen in all groups without statistical difference. Frequencies and scores for erosion and osteitis were statistically different between RA and SLE/pSS while no statistical difference was seen between SLE/pSS and HC (Table). Sensitivity and specificity were respectively for erosion: 0.93 and 0.38, for erosion with grade ≥2: 0.4 and 0.88 and for osteitis: 0.77 and 0.78. <h3>Conclusions</h3> MRI Cortical break are frequent in SLE and pSS as well as in HC. Erosion may occur in SLE and pSS but erosion of grade≥2 and osteitis are highly specific of RA. Distinction of physiological cortical break and pathological erosion may lead to better interpretation of MRI. <h3>Disclosure of Interest</h3> None Declared
Nitric oxide and synaptic plasticity: NO news from the cerebellum
Authors: Steven R. Vincent
Journal: Behavioral and Brain Sciences (1996)

Interest in the role of nitric oxide (NO) in the nervous system began with the demonstration that glutamate receptor activation in cerebellar slices causes the formation of a diffusible messenger with properties similar to those of the endothelium-derived relaxing factor. It is now clear that this is due to the Ca2+/calmodulin-dependent activation of the enzyme NO synthase, which forms NO and citrulline from the amino acid L-arginine. The cerebellum has very high levels of NO synthase, and although it has low levels of guanylyl cyclase, cerebellar cyclic guanosine monophosphate (cGMP) levels are an order of magnitude higher than in other brain regions. A transcellular metabolic pathway is also present in the cerebellar cortex to recycle citrulline back to arginine. The NO formed binds to and activates soluble guanylyl cyclase to elevate cGMP levels in target cells. Studies employing NADPH-diaphorase, a selective histochemical marker for NO synthase, together with immunohistochemistry, in situ hybridization and biochemical studies have indicated that NO production occurs in granule and basket cells in the cerebellar cortex, whereas cGMP formation appears to occur largely in other cells, including Purkinje cells. Given that a long-term depression of AMPA currents can be seen in isolated Purkinje cells, this anatomical localization suggests that NO cannot play an essential role in the induction of this form of synaptic plasticity.In vitro studies using cerebellar slices or cultures, as well as in vivo studies, have demonstrated that NO formation and release occur in the cerebellar cortex in response to NMDA receptor activation. Using intracerebellar microdialysis in awake-behaving animals, we have found that this is associated with a large increase in extracellular cGMP levels in the cerebellar cortex. A similar increase in cGMP efflux is seen in response to activation of AMPA or metabotropic glutamate receptors, or to activation of the climbing fiber input. The increase in extracellular cGMP required the Ca2+-dependent activation of NO synthase, and was potentiated by inhibition of phosphodiesterases or organic anion transport. These results suggest a possible role for cGMP as an intercellular messenger in the cerebellar cortex.In summary, stimuli that elevate Ca2+ levels in granule or in basket cells will activate NO synthase, which by binding to its receptor-soluble guanylyl cyclase – causes an increase in cGMP. cGMP may then act through protein kinases, phosphodiesterases, and ion channels or receptors to affect cerebellar function.
FRI0137 Risk factors for major adverse cardiovascular (CV) events (MACE) in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ):
Authors: V.U. Rao, A. Pavlov, M. Klearman, D. Musselman, J.T. Giles, J.M. Bathon, N. Sattar, J.S. Lee
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The increased incidence of MACE in RA cannot be explained by traditional CV risk factors alone.<sup>1</sup> <h3>Objectives</h3> To examine associations of lipids, inflammation and RA disease activity with risk for MACE in TCZ-treated RA pts. <h3>Methods</h3> Pooled data of TCZ-exposed pts from phase 3 trials and long-term extensions were included in post hoc analyses. 50 pts with MACE (non-fatal myocardial infarction, non-fatal stroke or CV death) and 3,936 pts without MACE were identified via blinded, independent adjudicator. Cox proportional hazards models were used to evaluate the associations of various demographic, laboratory and disease measures (at baseline, wk 24 and change from baseline to wk 24) with time to future MACE. Simple univariate and multivariate models were estimated, and resulting hazard ratios with 95% CIs were used to assess predictors. <h3>Results</h3> For MACE during TCZ exposure, univariate analysis showed baseline age, history of cardiac disorders, statin use, TJC, SJC, DAS28, total cholesterol (TC)/HDL ratio, ApoB and ApoB/ApoA1 ratio as predictive (all p&lt;0.05). Age, history of cardiac disorders, DAS28 and TC/HDL ratio were joint predictors in multivariate models. Neither reduction in inflammation (CRP, ESR) nor lipid increase at wk 24 was statistically significantly associated with future MACE. Cox models using single predictors and adjusting for age and baseline values showed change in DAS28, area under the curve (AUC) of DAS28, EULAR response, TJC and SJC at wk 24 were statistically significant predictors of future MACE (Table). Greater reductions in DAS28, SJC and TJC from baseline to wk 24 were inversely associated with MACE (Table). <h3>Conclusions</h3> Among traditional CV risk factors and disease activity measures, age, DAS28, TC/HDL and history of cardiac disorders were independently associated with MACE in RA pts subsequently treated with TCZ. Risk for MACE was broadly linked to elevated baseline disease activity and less robust therapeutic response at wk 24, whereas no statistically significant association between lipid change and MACE risk was observed. These findings suggest that mitigating CV risk in RA pts may require a multifaceted approach, including effective disease activity control. <h3>References</h3> Gonzalez A et al. Ann Rheum Dis 2008;67:64-9. <h3>Disclosure of Interest</h3> V. Rao Employee of: Roche/Genentech, A. Pavlov Consultant for: Everest Clinical Research Services, Inc., M. Klearman Employee of: Roche/Genentech, D. Musselman Employee of: Roche/Genentech, J. Giles Consultant for: Roche, UCB, Regeneron, J. Bathon: None Declared, N. Sattar Grant/Research support from: Roche, Consultant for: Roche, Pfizer, Speakers Bureau: Roche, J. Lee Employee of: Roche
Case 44-1967
Authors: Lord Brock, Benjamin Castleman
Journal: New England Journal of Medicine (1967)

Presentation of CaseA thirty-nine-year-old woman was admitted to the hospital because of fever, cough and pain in the chest.She had been well until three years previously, when she first experienced intermittent epigastric pain between meals and at night, with relief after the ingestion of food. The pain gradually increased despite medical treatment, and four months later, after severe hematemesis, she entered another hospital, where an emergency gastrectomy was performed; pathological examination revealed a benign gastric ulcer. The epigastric distress subsided but recurred one year before entry, when a gastrointestinal series was interpreted as showing another ulcer. The symptoms . . .
SP0056 Raynaud's Phenomenon and Systemic Sclerosis
Authors: C.P. Denton
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Systemic sclerosis has high mortality and morbidity and is diverse in clinical manifestations. In approaching management it is important to consider baseline assessment that must include confirmation of diagnosis, ascertainment of any features of overlap connective tissue disease and determining the subset of disease (limited or diffuse) based upon the extent of skin sclerosis. Initial assessment should also include definition of the presence of any hallmark ANA reactivity that may predict the development or presence of internal organ disease. Baseline assessment of cardiac, pulmonary and renal function together with general evaluation and determination of modified Rodnan skin score is undertaken. Treatment depends on the stage and subset and pattern of disease and generally follows the EULAR-EUSTAR recommendations that suggest options for skin, lung and other internal organ disease. All patients will need treatment of secondary Raynaud9s phenomenon and gastro-oesophageal reflux symptoms. Raynaud9s phenomenon can be treated by oral vasodilators or in severe cases with parenteral prostacyclin and other strategies. Skin disease is generally treated with immunosuppression such as MMF or MTX and lung fibrosis is assessed depending on a well validated staging system, This is more than 20% lung parenchyma is judged affected then immunosuppression is used, often with intravenous cyclophosphamide. Other agents may be considered, especially for overlap disease with myositis and arthritis. High does corticosteroids may increase risk of renal crisis and are avoided if possible although low doses less than 10mg prednisolone per day may give symptomatic benefit for inflammatory symptoms and skin itching. If pulmonary hypertension (PH) is suspected then this must be investigated, often including right heart catheterisation and management is in line with other types of PH, including targeted therapies for pre-capillary pulmonary arterial hypertension (PAH). Outcomes have improved over the past two decades but vigilant follow up and attention to non-lethal complications that impact on quality of life is essential. These topics will be reviewed. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6249
ROLE OF SYSTEMIC OCTREOTIDE IN DECREASING RECURRENT LOWER GASTROINTESTINAL BLEEDS RELATED TO ARTERIOVENOUS MALFORMATION IN PATIENTS ON SYSTEMIC ORAL ANTICOAGULATION
Authors: Dhanunjaya R. Lakkireddy, Olyaee Mojtaba, Donita Atkins, Sandia Iskandar, Muhammad Afzal, Courtney Jeffery, Rakesh Gopinathannair, Luigi Di Biase, Andrea Natale, Jie Cheng, Vijay Swarup
Journal: Journal of the American College of Cardiology (2016)
VARIABLES PREDICTIVAS DE MAYOR DOSIS DE IRRADIACIÓN EN CPRE: ESTUDIO PROSPECTIVO EN 197 PACIENTES
Authors: V Lorenzo Zúñiga, J Boix, B Oller, JE Naves, C Leal, F Añaños, V Moreno de Vega
Journal: Endoscopy (2010)

Introducción: La colangiopancreatografía retrógrada endoscópica (CPRE) es una técnica que requiere de la fluoroscopia para la obtención de imágenes, y aunque comparado con otras exploraciones radiológicas el grado de irradiación es menor; conlleva un riesgo tanto para el personal sanitario como para los pacientes.
Tolerability of lapatinib given concurrently with paclitaxel and trastuzumab as part of adjuvant therapy in patients with resected HER2+ breast cancer: initial safety data from the Mayo Clinic cancer research consortium trial RC0639.
Authors: BS Johnson, AC Dueck, SR Dakhil, PJ Stella, DA Nikcevich, SX Franco, DB Wender, PL Schaefer, G Colon-Otero, BB Diekmann, EA Perez
Journal: Cancer Research (2009)

Abstract Abstract #2109 Background: Despite the impressive results of the recently released trastuzumab adjuvant therapy trials, 15% of patients with HER2 overexpressing or amplified breast cancer developed tumor relapse at 4 years. Lapatinib is a small molecule reversible TKI that inhibits both ErbB1 and ErbB2. The current study was developed to assess the cardiac safety and feasibility of adding lapatinib to paclitaxel and trastuzumab following as part of adjuvant therapy.&amp;#x2028; Methods: A single-arm phase II study of doxorubicin (A, 60 mg/m2 day 1) and cyclophosphamide (C, 600 mg/m2 day 1) [q2w or q3w for 4 cycles]; followed by paclitaxel (P, 80 mg/m2 days 1, 8, 15), trastuzumab (T, 4 mg/kg loading dose then 2 mg/kg days 1, 8, 15), and lapatinib (L, 1000 mg days 1-21) [12 weeks]; followed by T (6 mg/kg day 1) and L (1000 mg days 1-21) [40 weeks] was conducted. The primary endpoint was the incidence of congestive heart failure. The current unplanned safety analysis was undertaken due to the observance of a high rate of G3/4 diarrhea.&amp;#x2028; Results: From April 2007 to June 2008, 98 pts were enrolled and initiated study treatment. Median age was 51 (range 32-72). Among 83 pts with adverse event (AE) data available, 50 (60%) pts have experienced a G3/4 non-hematologic AE. During post-AC treatment, among 53 pts with AE data available, 31 (58.5%) patients have experienced a G3/4 non-hematologic AE with 24 (45%) patients reporting G3/4 diarrhea. Median cycle of onset of G3/4 diarrhea was cycle 5 (first cycle of PTL) with 16 (64%) cases first reported during cycle 5 and 5 (20%) cases first reported during cycle 6. Among 57, 46, 38, and 32 pts receiving treatment with PTL during cycles 5-8, 65%, 57%, 61%, and 72% of patients received the full L dose, respectively. 31 patients have ended active treatment with 10 due to patient refusal and 8 due to adverse events.&amp;#x2028; Conclusions: Preliminary data suggest that L given concurrently with P and T at a dose of 1000 mg per day induces an unacceptable rate of moderate to severe diarrhea. Careful monitoring of diarrhea as well as L dose reduction and initiation of loperamide at first occurrence of diarrhea are recommended. The dose of L when given concurrently with P and T has been amended to 750 mg per day in the current study and safety data for the 1000 mg and 750 mg per day cohorts will be presented. Implications for the ongoing ALTTO study will also be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2109.
Abstract 1004: Investigating the role of Cdc42 in the developing mouse mammary gland
Authors: Kristi M. Bray, Tracy Vargo-Gogola
Journal: Cancer Research (2010)

Abstract Rho GTPases coordinate and transmit extracellular signals to control downstream effectors. The Rho GTPase cell division cycle 42 (Cdc42) is overexpressed and hyperactivated in human breast cancers. Cdc42 regulates cell polarity, mitosis, adhesion, migration, and stem cell function. These same cellular processes also function in normal mammary gland development. Exactly which functions of Cdc42 are crucial for normal mammary gland (MG) development and its precise role in mammary tumor formation and progression remain unknown. We hypothesize that Cdc42 plays critical and pleiotropic roles in normal MG development and tumorigenesis through regulation of the signal transduction pathways that are involved in cell cycle progression, cell polarity determination, cell motility, and cell adhesion. To investigate the molecular mechanisms by which Cdc42 regulates MG development, we studied the effects of Cdc42 deletion on morphogenesis of primary mammary epithelial cells (MECs). Adeno-cre viral transduction was used to introduce cre recombinase into Cdc42fl/fl primary MECs, and effects on morphogenesis were assessed using a three-dimensional mammary morphogenesis assay. Transduction efficiency ranged from 50-80% and ∼70% percent knockdown of Cdc42 expression was achieved. Control Adeno-GFP transduced MECs developed into polarized mammary acini whereas morphogenesis was markedly perturbed in the Cdc42 deficient MECs. Cdc42 knockout MECs formed small (30 µm in diameter compared to 45 µm in the control structures, p &amp;lt; .001, n = 28), disorganized structures lacking polarity and lumens (99% vs. 8% in the controls, n &amp;gt; 30). Markers of normal development including polarity markers, pERM and α6; adhesion, ZO-1; and downstream signaling, pkc-ζ, displayed aberrant expression patterns in the knockout structures. Interestingly, Cdc42 deficient structures contained invasive cells, which were rarely seen in control acini (41% vs 7%, n=80), suggesting that loss of Cdc42 induces aberrant migration. Cdk4 levels were also reduced in Cdc42 deficient cells and cell cycle analysis by flow cytometry demonstrated an increase in the percentage of cells in G1, suggesting that loss of Cdc42 inhibits MEC proliferation by blocking the transition from G1 to S phase. In addition, analysis of an S phase marker, phospho-histone H3, was performed at an early time point (3 days) in morphogenesis. Only 35% of the transduced knockout structures expressed phospho-histone H3, compared to 100% in the controls (n&amp;gt;20). These studies demonstrate a vital role for Cdc42 in the processes of growth, adherence, and polarity establishment during mammary gland development. 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 1004.