tbuckley/cabot-search huggingface dataset:
ELR+ CXC chemokine signalling in articular chondrocyte phenotypic stability
Authors: J Sherwood, G Nalesso, J Bertrand, T Pap, P Achan, C Pitzalis, F Dell'Accio
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> The production of ELR+ CXC chemokines is widely studied in arthritis and is postulated to contribute to the inflammatory phenomena that lead to cartilage breakdown. Healthy articular chondrocytes however, also express their own chemokine receptors and ligands. The function of CXC chemokine receptors in these cells is puzzling because chondrocytes are encased in a dense extracellular matrix and are not known to migrate in vitro. This study aims to identify the function of this signaling mechanism in articular cartilage. <h3>Materials and methods</h3> Adult human articular chondrocytes (AHAC) were expanded in monolayer culture under standard conditions. Receptor expression was confirmed using semiquantitative RT-PCR, western blot and immunohistochemistry. CXCR1/2 combined and individual functionality was tested using an in vitro calcium mobilisation assay. CXCR1/2 signalling was blocked at specific receptor level using validated blocking antibodies and siRNA, or at the downstream level using Pertussis toxin, PI3K inhibitors and intracellular calcium chelators. Chondrocyte phenotypic gene expression was assessed using real time RT-PCR. The content of highly sulphated proteoglycans in chondrocyte micromasses was analysed using Alcian blue staining followed by guanidine HCl extraction and spectrophotometric quantification. CXCL6 and CXCL8 were detected in heparitinase digested, chondroitinase ABC digested and un-digested paraffin sections from healthy and osteoarthitis full thickness human articular cartilage using immunohistochemistry. <h3>Results</h3> Receptors were expressed in normal human articular cartilage. Disruption of CXCR1/2 signalling at receptor level or by downstream blockade in chondrocytes resulted in reduced extracellular matrix sulphated glycosaminoglycan content, which was found to be PI3K-dependant, and reduced expression of the chondrocyte differentiation markers COL2A1, Aggrecan, and SOX9. CXCL6 and CXCL8 were found in cartilage extracellular matrix in healthy tissue in distinct localisation patterns, which were disrupted in osteoarthritic tissue. CXCL8 was lost from territorial matrix following heparitinase digestion, but not following digestion in chondroitinase ABC. <h3>Conclusions</h3> Our findings indicate that CXCR1/2 signalling is required for the maintenance of phenotypic stability in articular chondrocytes. Interactions with heparan sulphate proteoglycans and distribution patterns of ligands within the ECM, together with their disruption during pathology, indicate the presence of a homeostatic mechanism whereby CXCL8 is retained within the articular cartilage matrix via its interaction with heparan sulphate proteoglycans, contributing to chondrocyte phenotypic stability.
FRI0259 Ectopic lymphoid structures support epstein-barr virus persistence and autoreactive plasma cell infection in sjogren’s syndrome salivary glands
Authors: C. Croia, B. Serafini, A. Tappuni, F. Aloisi, N. Sutcliffe, C. Pitzalis, M. Bombardieri
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The ubiquitous □-herpesvirus Epstein-Barr virus (EBV) infects B cells and modifies their differentiation programme leading to B cell activation and immortalization. Due to these unique properties, EBV has been suggested to play a role in rescuing autoreactive B cells and promoting autoimmunity. Although different evidences support a link between EBV infection and Sjogren's syndrome (SS), the exact role of EBV in SS pathogenesis remains elusive. <h3>Objectives</h3> To investigate the potential role of EBV in SS pathogenesis by analysing EBV infection in the SS salivary glands and its relationship with ectopic lymphoid structures (ELS), in situ autoreactive plasma cell differentiation, autoantibody production and cytotoxic immune response in the salivary glands. <h3>Methods</h3> Latent and lytic EBV infection was investigated in SS and non-specific chronic sialoadenitis (NSCS) labial salivary glands characterised for presence/absence of ELS by RT-PCR, in situ hybridization and immunohistochemistry/immunofluorescence. Glandular production of anti-Ro52 antibodies and anti-EBV peptides antibodies was investigated in situ and/or in vivo in a novel SCID/SS chimeric model. <h3>Results</h3> EBV dysregulation was observed exclusively in ELS+ SS salivary glands as revealed by presence EBV-encoded small RNA (EBER) transcripts and EBER+ cells and immunoreactivity for EBV latent (LMP1, LMP2A) and lytic (BFRF1) antigens in ELS-associated B cells and plasma cells, respectively. Importantly, a subset of EBV+ peri-follicular plasma cells produced anti-Ro52 antibodies. Furthermore, ELS-containing SS salivary glands transplanted into SCID mice supported the production of anti-Ro52, anti-La and anti-EBV antibodies. Analysis of CD4+ and CD8+ T-cell localization and granzyme B expression suggested that EBV persistence in ELS-containing SS salivary glands is favoured by exclusion of CD8+ T cells from B-cell follicles and impaired CD8-mediated cytotoxicity. <h3>Conclusions</h3> We demonstrated latent and active EBV infection within ELS in the SS salivary glands that appears to contribute to local growth and differentiation of autoreactive B cells producing SS-associated autoantibodies. <b>Disclosure of Interest</b>: None Declared
Use of Benzodiazepines in Anxiety Disorders
Authors: R I Shader, D J Greenblatt
Journal: New England Journal of Medicine (1993)

Beginning with chlordiazepoxide in 1960, benzodiazepines have been used extensively for the treatment of anxiety and related disorders. Eight benzodiazepine derivatives have been approved by the Food and Drug Administration for this purpose (Table 1). Another benzodiazepine, clonazepam, is also prescribed for this purpose but is labeled as an anticonvulsant.The clinical, pharmacokinetic, and neurochemical properties of the benzodiazepine derivatives have been the focus of many articles in the scientific literature16. Much is known about their molecular mechanisms of action, properties of distribution and elimination, clinical activity, and side effects. Like many other classes of drugs that are . . .
Outcome and Toxicity Associated with Maximum Safe Dose Radioiodine Treatment of Metastatic Thyroid Cancer
Authors: WILLIAM R. ROBESON, JOANMARIE E. ELLWOOD, PAUL MARGULIES, DONALD MARGOULEFF
Journal: Clinical Nuclear Medicine (2002)

Purpose This study was designed to determine the outcomes of patients referred to the authors’ nuclear medicine service for dosimetric evaluation and treatment of metastatic thyroid cancer with radioiodine I-131. In addition, the incidence and severity of hematologic toxicity associated with treatment were determined. Methods A retrospective review of patients referred for dosimetric evaluation was undertaken for the years 1984 to 2000. Chart reviews were performed for 20 patients treated with at least 80% of the calculated maximum safe dose. Outcomes were evaluated for 15 patients for whom sufficient follow-up information was available. The incidence and severity of hematologic toxicity were determined for 12 of the 20 patients. Results Outcomes were defined as good, fair, or poor. One third of the patients had good, one third had fair, and one third had poor outcomes. Three patients experienced anemia, but no life-threatening hematologic toxicity was observed in any of the patients. Serum thyroglobulin measurements proved to be an efficacious way to predict outcome. The use of recombinant human thyrotropin appears to have increased the sensitivity of the thyroglobulin measurements. Conclusions Radioiodine I-131 treatments produce variable outcomes in patients with advanced disease. Hematologic toxicity is well controlled in patients if dosimetric guidelines are followed. I-131 treatment appeared to retard the progression of metastatic thyroid cancer in 50% of the patients who were not cured. Radioiodine doses may be increased to improve efficacy without associated irreversible toxicity.
EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response
Authors: N. L. Spector, K. Blackwell, J. Hurley, J. L. Harris, D. Lombardi, S. Bacus, S. B. Ahmed, H. Boussen, M. Frikha, F. B. Ayed
Journal: Journal of Clinical Oncology (2006)

502 Background: Data from preclinical studies and small numbers of IBC patients inPhase I clinical trials suggest that IBC may be particularly sensitive to the anti-tumor effects of lapatinib, an inhibitor of ErbB1/ErbB2 tyrosine kinases. EGF103009 was initiated to confirm and expand these initial observations and identify a tumor profile predicting for the sensitivity of IBC to lapatinib. Methods: Patients with relapsed/refractory IBC based on clinical criteria, were assigned to Cohort A (ErbB2 overexpressors: 2/3+ IHC/FISH+) or B (ErbB1 +/ErbB2 non-overexpressors) after analysis of a fresh tumor biopsy in a central reference lab. Patients received lapatinib daily (1500mg/d). Clinical response was documented at day 56 and in the case of CR/PR, confirmed on day 84 and every 8 weeks thereafter. Target lesions were assessed according to RECIST criteria and response in skin disease documented by digital photography. Tumor expression of ErbB2, p-ErbB2, ErbB1, p-ErbB3, IGF-IR, PTEN, ER/PR, E-cadherin, β-catenin, and Rho B/C was analyzed by quantitative IHC from a fresh, pre-treatment biopsy. Results: Of 34 patients enrolled, clinical response data is available from 22 patients of which 17 had biopsies analyzed at a reference lab and assigned to Cohorts A (N=11) and B (N=6). Eight of 11 patients (72%) in Cohort A had a clinical response (CR/PR) to lapatinib documented by RECIST, skin disease, or both. There were no responders in Cohort B. All responders (i) overexpressed ErbB2 (2/3+ IHC or FISH+), (ii) increased p-ErbB2 (2/3+), (iii) co-expressed IGF-IR, and (iv) expressed activated, p-ErbB3. PTEN status did not affect response to lapatinib. Toxicity was generally grade I/II skin and G.I. with one grade III cardiotoxicity necessitating withdrawal from study. Conclusions: ErbB2 overexpression but not ErbB1 expression alone, predicts for sensitivity to lapatinib in IBC. High ErbB2, p-ErbB2 and IGF-IR co-expression predict for clinical response to lapatinib monotherapy in patients with relapsed/refractory IBC, illustrating the importance of selecting patients based on biology rather than histology alone, to maximize the clinical efficacy of ErbB kinase inhibitors in breast carcinomas. [Table: see text]
Transmural right ventricular myocardial blood flow during systole in the awake dog.
Authors: D S Hess, R J Bache
Journal: Circulation Research (1979)

This study was designed to quantify and compare transmural myocardial blood flow in the right and left ventricles of awake dogs during systole and diastole, and during total coronary artery occlusion.Studies were performed in six awake dogs chronically prepared with electromagnetic flowmeters and pneumatic occluders on the left circumflex and right coronary arteries.Intermittent coronary perfusion, confined to the interval of cardiac systole or an equivalent period during diastole, was effected by an R wave-triggered pneumatic valve connected to the occluders.To measure regional myocardial blood flow, radionuclide-la'oeled microspheres, 7-10 jim in diameter, were injected into the left atrium.We found that when arterial inflow was confined to systole, blood flow was normal in the left ventricular subepicardium, whereas flow to deeper myocardial layers was decreased as a linear function of tissue depth.When coronary arterial inflow was limited to an equivalent period in diastole, left ventricular transmural flow was uniform.In contrast to this, right ventricular transmural myocardial blood flow was unchanged from control values when coronary inflow was confined to systole or to an equivalent interval in diastole.During total coronary artery occlusion, absolute blood flow decreased similarly in myocardial areas perfused by the left circumflex and right coronary arteries.However, the transmural distribution of collateral blood flow was markedly different in the two ventricles.Left ventricular collateral flow was preferentially directed to the subepicardial layers, but right ventricular collateral flow was distributed uniformly across the ventricular wall.The transmural gradients observed in the left ventricle during total coronary artery occlusion and when arterial inflow was confined to systole can be explained by the functioning of a vascular waterfall during left ventricular contraction.
Dynamic Alteration in Splenic Function during Acute falciparum Malaria
Authors: Sornchai Looareesuwan, May Ho, Yupaporn Wattanagoon, Nicholas J. White, David A. Warrell, Danai Bunnag, Tranakchit Harinasuta, David J. Wyler
Journal: New England Journal of Medicine (1987)

Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated 51Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes [mean +/- SD] vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.
FRI0375 Clinical characteristics and vitamin D insufficiency in a population of 54 adults with osteogenesis imperfecta
Authors: J. Payet, C. Cormier
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Osteogenesis imperfecta is a rare heritable disorder of connective tissue characterized by bone fragility and fractures occuring with trivial traumatism. It is caused in 90% of cases by mutations in genes encoding the type 1 collagen. Vitamin D insufficiency is defined by 25 OH vitamin D &lt;30 ng/ml and vitamin D deficiency by 25 OH vitamin D &lt;20 ng/ml. It is considered that 40 to 100% of the healthy adult population is insufficient in vitamin D. <h3>Objectives</h3> To describe clinical characteristics of a population of 54 adult patients with osteogenesis imperfecta, to establish prevalence of vitamin D deficiency and to analyze bone mineral densities (BMD). <h3>Methods</h3> <i>Study design:</i> retrospective, observational study. <i>Patients:</i> adults with osteogenesis imeprfecta coming in day hospital after a recent bone event. <i>Data collection:</i> clinical features (number of fractures, family history, received treatment), 25OH vitamin D level, BMD when feasible. <i>Statistical analyses:</i> descriptive analyses. <h3>Results</h3> In all, 54 patients were included in the study. Mean (±SD) age was 39.3 (±11.3) years at the time of inclusion in the study. Among the 54 patients, 16 (39.6%) were men and 26 (48.1%) had family history of osteogenesis imperfecta. Mean (±SD) number of fractures per patient was 30.7 (±30.9). Mean age at the time of last fracture was 33.8 (±14.8) years. Mean level of vitamin D was 21.9 (±11.3) ng/ml. In all, 39 patients (72.2%) had 25 OH vitamin D level &lt;30 ng/ml and 27 patients (50.0%) had a level &lt;20 ng/ml. The Z score was less than -2 DS at one or more site in 34/40 (85.0%) patients. There was no correlation between total number of fracture and BMD. Twenty seven patients (56.2%) had vitamin D supplementation. Twenty seven patients (61.4%) had a history of treatment with bisphosphonates. Patients with vitamin D supplementation were less often insufficient in 25 OH vitamin D (p=0.005). Patients with insufficiency in vitamin D were not different from the population with normal level of vitamin D concerning total number of fractures or recent fracture. <h3>Conclusions</h3> In a population of 54 adults with OI, 72.2% had vitamin D insufficiency and 50% had vitamin D deficiency. Juste over half of them had a vitamin D supplementation. Systematic supplementation at adequate doses seems necessary. <h3>Disclosure of Interest</h3> None Declared
Case 29-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, J.M. Richter, F. Graeme-Cook
Journal: New England Journal of Medicine (1992)

Presentation of CaseA 76-year-old woman was admitted to the hospital because of persistent diarrhea during treatment for possible tropical sprue.The patient was well until approximately eight months earlier, when diarrhea developed while she was visiting the Taj Mahal on the second day of a stop in India during an around-the-world cruise. Diarrhea occurred at about the same time in travelers who accompanied the patient, but their symptoms soon improved and hers did not. She continued to pass 5 to 15 watery stools daily, with minimal crampy abdominal pain and anorexia. On four occasions during the next three weeks . . .
P214 Gastro-Oesophageal Reflux Symptoms During COPD Exacerbations
Authors: ARC Patel, BS Kowlessar, GC Donaldson, AJ Mackay, R Singh, S Brill, JA Wedzicha, JR Hurst
Journal: Thorax (2012)

<h3>Introduction</h3> Gastro-oesophageal reflux disease (GORD) has been associated with increased COPD exacerbation frequency (Terada et al, Thorax 2008) and was independently associated with the frequent exacerbator phenotype in the ECLIPSE study (Hurst et al, NEJM 2010). We aimed to quantify any changes in GORD symptoms during COPD exacerbations. <h3>Methods</h3> Outpatients from the London COPD cohort completed the Frequency Scale for the Symptoms of Gastro-oesophageal reflux (FSSG) and Hull Airway Reflux Questionnaire (HARQ) during stable-state clinic visits and at exacerbation, within a week of symptom-onset, and prior to systemic therapy. FSSG and HARQ scores range from 0–48 and 0–70 respectively, with significant reflux thought to be associated with scores of ≥8 and ≥13 respectively. Exacerbations were defined using our usual symptomatic criteria from daily diary cards (Seemungal et al, AJRCCM 1998). <h3>Results</h3> 42 COPD patients had a mean±SD age of 72.7±8.7 years, 64% male, 17% current smokers, median(IQR) 46 (19.71) pack years, mean±SD stable FEV1 1.22±0.64L and 50.7±21.5%predicted, BMI 27.7±7.4kg/m2. 13 (31%) patients had a diagnosis of GORD, of whom 12 (92%) were taking regular acid suppression therapy. There was a median (IQR) interval of 141(80,233) days between the stable and exacerbation visits. Although median (IQR) FSSG and HARQ scores were higher at exacerbation compared to the stable state, this was not statistically significant due to high variability (6.5 (4.0,13.0) vs 5.0 (1.5,11.5), p=0.247 and 15.5 (9.0,23) vs 18.5 (11.5,24.5), p=0.096 respectively). 16/42 (38%) patients had a high FSSG score (≥8) in the stable state compared with 20/42 (48%) at exacerbation (p=0.378). 10/42 (24%) changed from a low stable FSSG to a high score at exacerbation. 27/42 (64%) patients had a high HARQ score (≥13) in the stable state compared with 30/42 (71%) at exacerbation (p=0.483). 7/42 (17%) changed from a low stable HARQ to a high score at exacerbation. <h3>Conclusions</h3> GORD symptom scores are not significantly higher during acute COPD exacerbations. Due to high variability, approximately one fifth of COPD patients had a low GORD symptom score when stable and high scores at exacerbation implicating worsening reflux in some exacerbations. Further work is required to understand the potential mechanisms.
The Latex-Fixation Reaction in Nonrheumatic Diseases
Authors: Ellis Dresner, Patricia Trombly
Journal: New England Journal of Medicine (1959)

THE serum agglutinating factor for amboceptor-sensitized or FII (fraction II)-coated erythrocytes and latex particles is still thought to be specific for rheumatoid arthritis and closely allied diseases,1 , 2 and the variable occurrence of positive reactions in control subjects has not been satisfactorily explained. The incidence of these so-called "false-positive" reactions in serums from normal subjects and patients with nonrheumatic diseases varies in different reports from less than 1 per cent to as high as 30 per cent and is not related to the agglutinating system used; claims for both increased sensitivity in, and specificity for, rheumatoid arthritis by any particular system . . .
Is timely endoscopy the answer for cost-effective management of acute upper gastrointestinal bleeding?
Authors: I. Pedroto, M. Dinis-Ribeiro, T. Ponchon
Journal: Endoscopy (2012)

Endoscopy plays a major role in the management of acute upper gastrointestinal bleeding (UGIB) as it is currently accepted to be an effective procedure for the reduction of the rate of rebleeding, the need for surgery, and mortality [1]. However, because the safety of a very early endoscopy has been questioned and due to the associated organizational needs and related costs, diverse attempts have been made over the years to determine the best combination of peri- and intra-endoscopy procedures ("how"?), "when" to provide endoscopy, and the patients "to whom" endoscopy must be offered to achieve a cost-effective model of healthcare. It seems, however, that there is still room for improvement. In fact, even the group involved in the most recent recommendations for the management of acute nonvariceal UGIB [2] were only able to include the statements "endoscopy should be recommended within 24 hours of presentation for most patients" and "prognostic scales to stratify patients according to their death and rebleeding risks" should be used.
Increase in gonorrhoea among very young adolescents, Catalonia, Spain, January 2012 to June 2013
Authors: N Vives, R Lugo, E López, P Garcia de Olalla, S Minguell, I Barrabeig, P Pons, E Lopez-Grado, I Ferré, R Escriche, P Armengol, M Vall, P Soler-Palacin, I Leon, I Gascon, A M Vicente, G Falguera, A Avecilla-Palau, C Martinez, M J Barberá, V González, J Caylà, J Casabona
Journal: Eurosurveillance (2013)

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