tbuckley/cabot-search huggingface dataset:
Are there specific genetic risk factors for the different forms of ANCA-associated vasculitis?
Authors: Larissa Arning, Julia Ulrike Holle, Lorraine Harper, David S Millar, Wolfgang Ludwig Gross, Jörg Thomas Epplen, Stefan Wieczorek
Journal: Annals of the Rheumatic Diseases (2010)

There is continuous debate about whether Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS) represent one disease entity—‘antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV)’ (eg, as presented by Hogan et al 1) or whether they constitute separate diseases which share common features but are otherwise heterogeneous—a view held, for example, by Hoffman and Langford.2 ANCA are a common finding in AAV, yet the majority of patients with CSS are ANCA negative. Several clinical and histopathological features unique to one disease (eg, asthma for CSS) support Hoffman's opinion. Analysis of the genetic background of the three disorders may help to differentiate between both concepts. The strongest genetic association for WG pertains to the HLA-DPB1 region,3 4 an association not seen in CSS.5 For MPA HLA-DPB1 association …
PWE-094 Understanding non-participation in bowel cancer screening: a qualitative study
Authors: N J Hall, G P Rubin, D Weller, J Wardle, C Dobson, M Ritchie, C Rees
Journal: Gut (2012)

<h3>Introduction</h3> Uptake of the national bowel cancer screening programme (BCSP), at 52%, needs to be improved or at least maintained if the screening programme is to achieve projected reductions in mortality and morbidity. Understanding the origins of non-participation is therefore important. This study used qualitative methods to explore the beliefs and experiences of individuals who had not responded either to their screening invitation or reminder. <h3>Methods</h3> In-depth qualitative interviews with volunteers were used to enable maximum opportunity for exploration and inductive hypothesis generation. Non-participation was defined as having refused all of the invitations and reminders for FOB test screening received from the North East Hub of the BCSP at the time of contact. Interviewees were purposefully sampled to allow for diversity in terms of gender, geographical location and socio-economic status. Data collection and analysis were carried out using strategies consistent with the principles of grounded theory with an emphasis on the constant comparison method. Data collection and analysis took place concurrently and continued until saturation (27 interviews). <h3>Results</h3> The interviews provided an in-depth understanding of a range of reasons and circumstances surrounding non-participation, including contextual and environmental influences as well as factors specific to the screening test. The nature of the data also allowed an appreciation of the potential for changes in beliefs, awareness and intention over time. Most of the interviewees had positive attitudes towards the BCSP, even those who did not feel screening was appropriate for them or who did not wish to take part. Many had intended to take part or intended to take part in the future. The main emergent categories included: practicalities of screening, value of screening, knowledge and awareness, risk perceptions, intention, embarrassment, good “citizenship”, guilt, control, and the influence of others. <h3>Conclusion</h3> A range of different approaches may be required to improve uptake, depending on the experiences, circumstances, beliefs and existing levels of intention of non-participants. Many of the interviewees in this study reported an intention to take part in future screening rounds. This group might be responsive to repeat invitations, reminders, and aids to making the test practical. Individuals who are opposed to screening (or BCS in particular) may have been less willing to be interviewed. Research is needed to ascertain whether different groups of non-responders require different approaches to intervention. <h3>Competing interests</h3> None declared.
STUDIES ON COPPER METABOLISM. XIX
Authors: J. A. Bush, W. N. Jensen, J. W. Athens, Helen Ashenbrucker, G. E. Cartwright, M. M. Wintrobe
Journal: The Journal of Experimental Medicine (1956)

Ferrokinetic studies were performed in three copper-deficient swine and the results have been compared with similar studies in 18 normal pigs. The mean value for the plasma iron turnover rate in the deficient swine was 1.76 mg./kg. day; for the red cell iron incorporation rate, 1.24 mg./kg. day; for the red cell iron turnover rate, 1.18 mg./kg. day; for the red cell life span, 13 days. Corresponding figures in the normal swine were 1.11 mg./kg. day, 1.01 mg./kg. day, 0.59 mg./kg. day and 63 days, respectively. The red cell life span was measured by the use of radioactive chromium in a total of 26 pigs. The mean erythrocyte half-life of normal cells transfused into normal pigs was 17 days. The mean half-life of erythrocytes from copperdeficient swine transfused into copper-deficient swine was 9 days. The mean half-life of red cells from control animals transfused into copper-deficient swine was 16 days while that of erythrocytes from copper-deficient swine transfused into normal pigs, was 13 days. The mean half-life of cells from iron-deficient pigs transfused into iron-deficient pigs was 19 days. It is concluded that copper deficiency anemia results from both a shortened erythrocyte survival time and limited capacity of the bone marrow to produce red cells. It is suggested that copper is an essential component of erythrocytes in swine.
Distribution and partial characterisation of IgG Fc binding protein in various mucin producing cells and body fluids
Authors: K Kobayashi, H Ogata, M Morikawa, S Iijima, N Harada, T Yoshida, W R Brown, N Inoue, Y Hamada, H Ishii, M Watanabe, T Hibi
Journal: Gut (2002)

<b>Background and aims:</b> Mucus released from goblet cells is important in intestinal mucosal defence, and mucin glycoproteins are thought to be major components of mucus. Recently, we identified and cloned another component of human colonic mucus, IgG Fc binding protein (FcγBP). FcγBP is immunologically distinct from known Fcγ receptors and its structure contains repeated cysteine rich unit sequences resembling those present in mucins. In this work, we assessed the tissue distribution of FcγBP, its binding activity in various body fluids, and its ability to inhibit complement mediated haemolysis. <b>Methods:</b> Immunohistochemical localisation of FcγBP, using monoclonal antibodies against FcγBP (K9 or K17) and labelled IgG, was conducted in various mucin producing tissues: colon, small intestine, stomach, gall bladder, cystic duct, choledochus, bronchus, submandibular gland, conjunctiva, and cervix uteri. The binding activity of FcγBP in mucus extracted from colon, gastric juice, bile, nasal discharges, saliva, sputum, and tears was also examined by immunodotblot and immunoprecipitation using these monoclonal antibodies. Inhibition of complement mediated haemolysis by FcγBP was investigated using sheep red blood cells (SRBC) and anti-SRBC IgG. <b>Results:</b> The immunohistochemical study revealed that mucin secreting cells in the colon, small intestine, gall bladder, cystic duct, choledochus, bronchus, submandibular gland, and cervix uteri contained FcγBP, and immunodotblot and immunoprecipitation analysis using IgG and monoclonal antibodies demonstrated that the fluids secreted by these cells were capable of binding IgG. Mucin producing cells of the conjunctiva did not express FcγBP molecules or bind to IgG. The surface mucus cells in the stomach were variably positive for FcγBP. Perhaps because of proteolytic degradation, FcγBP in gut lavage fluid did not have IgG binding activity, although this activity was present in the mucus covering the colon. FcγBP suppressed complement mediated haemolysis of SRBC. <b>Conclusions:</b> FcγBP is widely expressed on mucosal surfaces and in external secretions. It is functionally intact in several fluids. These findings lend support to the concept that FcγBP is an important component of mucosal immunological defences.
OC-129 Metastatic pancreatic neuroendocrine tumours: does aggressive surgical intervention improve outcome?
Authors: M J White, L M Edwards, S O Cawich, C Frola, M Abu Hilial, N W Pearce
Journal: Gut (2012)

<h3>Introduction</h3> Pancreatic neuroendocrine tumours (PNETS) often present late. At diagnosis 65% of patients have metastases, with median survival of 24 months.<sup>1 2</sup> The conventional approach is conservative management. Recent evidence has suggested that aggressive treatment leads to better outcomes.<sup>3</sup> We aim to show that in a cohort of patients with advanced PNETs aggressive resection prolongs survival. <h3>Methods</h3> All patients with intra-abdominal neuro-endocrine tumours (NETs) were assessed by the Hepato-pancreatobiliary and NET MDTs from April 2005 to January 2012 were prospectively registered on a database. All patients with PNETs were identified. Demographic, treatment, peri-operative and survival data were analysed using SPSS. Peri-operative morbidity was graded using the Clavien system. Predicted survival was calculated using the Kaplan–Meier method. <h3>Results</h3> 239 patients were assessed. 61 patients had PNETs (36 female: 25 males) Median age of 65. 55 patients underwent 71 resections. 52 had primary tumours resected and three patients had the primary tumour left in situ. Procedures included: 29 conventional pancreatic resections; 17 extended (including vascular or multi-visceral resections); nine had pancreatic and liver (four synchronous, five sequential) resections; 16 were liver resections alone. 27 patients had 48 additional medical and radiological interventions. Peri-operative mortality was 0%. Overall morbidity 42%. Median blood loss was 700 ml. Three operated patients died from progressive disease. Five non-surgical patients died. Overall survival for PNETs was 92% at median follow-up of 3 years. Predicted 5 year survival rate was 72% in operated patients. <h3>Conclusion</h3> An aggressive multi-modal approach with resection of advanced PNETs leads to excellent long term survival with acceptable morbidity in patients. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Yao JC</b>, <i>et al.</i> Everolimus for advanced pancreatic neuroendocrine tumours. <i>N Engl J Med</i> 2011;<b>364</b>:514–23. 2. <b>Yao JC</b>, <i>et al.</i> One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumours in 35,825 cases in the United States. <i>J Clin Oncol</i> 2008;<b>26</b>:3063–72. 3. <b>Ong SL</b>, <i>et al.</i> A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive managemment improves outcome. <i>Pancreatology</i> 2009;<b>9</b>:583–600.
Phase I Study of Panobinostat plus Everolimus in Patients with Relapsed or Refractory Lymphoma
Authors: Yasuhiro Oki, Daniela Buglio, Michelle Fanale, Luis Fayad, Amanda Copeland, Jorge Romaguera, Larry W. Kwak, Barbara Pro, Silvana de Castro Faria, Sattva Neelapu, Nathan Fowler, Fredrick Hagemeister, Jiexin Zhang, Shouhao Zhou, Lei Feng, Anas Younes
Journal: Clinical Cancer Research (2013)

To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity.This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed.Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021).Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.
Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome
Authors: W.D. Foulkes, P.O. Chappuis, N. Wong, J.-S. Brunet, D. Vesprini, F. Rozen, Z.Q. Yuan, M.N. Pollak, G. Kuperstein, S.A. Narod, L.R. B´gin
Journal: Annals of Oncology (2000)
GABA<sub>A</sub> Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism
Authors: Uwe Rudolph, Hanns Möhler
Journal: The Annual Review of Pharmacology and Toxicology (2013)

The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.
‘Football for Health’—a football-based health-promotion programme for children in South Africa: a parallel cohort study
Authors: Colin W Fuller, Astrid Junge, Jeff DeCelles, James Donald, Ryan Jankelowitz, Jiri Dvorak
Journal: British Journal of Sports Medicine (2010)

Objectives To develop, implement and assess an interactive, football-based health education programme for children in South Africa. Design Prospective cohort study with control group. Setting Two schools in Khayelitsha township, South Africa. Participants 370 children making up two intervention groups (Grade 6: 125; Grade 7: 131) and one control group (Grade 7: 114). Intervention Eleven 90 min sessions, each divided into two 45 min halves of Play Football (football skills) and Play Fair (health issues), each session focused on one specific health risk factor. Main outcome measures Health knowledge using a 20-item questionnaire; coaches' attitudes towards their training programme using a 10-item questionnaire and children's attitudes towards the health education programme using a six-item questionnaire. Results Children in the Grade 7 intervention group showed significant (p&lt;0.05) increases in the proportion of correct responses for nine of the 20 health knowledge questions postintervention, and these increases were maintained at 3 months postintervention. The Grade 6 intervention group showed significant increases in the proportion of correct responses for 15 of the 20 health knowledge questions postintervention. The Grade 7 control group showed a significant increase in the proportion of correct responses to one of the 20 health knowledge questions post-Play Football sessions and nine of 20 questions post-Play Fair sessions. Over 90% of the children provided positive attitude responses to the health-education programme. Conclusions The programme demonstrated that it was possible to implement a football-based health-education programme for children in Africa that achieved significant increases in health knowledge and that was also well received by participants.
Characterization of paclitaxel (Taxol®) sensitivity in human glioma- and medulloblastoma-derived cell lines
Authors: Sheng Hong Tseng, Michael S. Bobola, Mitchel S. Berger, John R. Silber
Journal: Neuro-Oncology (1999)

Paclitaxel (Taxol®), a cytotoxic natural product that disrupts microtubule integrity, is being clinically evaluated for use against gliomas. We examined paclitaxel-induced killing in seven cell lines derived from human malignant astrocytic gliomas and medulloblastomas with the goal of characterizing range of sensitivity, contribution of P-glycoprotein 170–mediated drug efflux to resistance, and cross-resistance with alkylating agents. Exposure to paclitaxel for 8 h or less produced biphasic survival curves for all lines, with 40–75% of cells comprising a subpopulation that was 9–26 times more resistant to paclitaxel than the more sensitive fraction. Increasing exposure to 24 h eliminated the resistant subpopulation, increasing sensitivity 50- to 400-fold. The dose producing one log of kill (LD10) after a 24-h exposure ranged from 4 to 18 nM, comparable to concentrations in the cerebrospinal fluid of brain tumor patients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxel and either nimodipine or verapamil, inhibitors of P-glycoprotein activity, did not increase sensitivity, demonstrating that thefivefold range in sensitivity was not due to P-glycoprotein–mediated drug efflux. Importantly, there was no correlation between LD10 for paclitaxel and LD10 for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide, indicating no expression of cross-resistance to these different classes of tumoricidal agents. Our results suggest that greater clinical efficacy of paclitaxel against malignant brain tumors may be obtained by infusion for 24 h or longer and support the use of paclitaxel in combination with alkylating agents.
Quantitative assessment of passenger flows in Europe and its implications for tracing contacts of infectious passengers
Authors: M Askar, O Mohr, T Eckmanns, G Krause, G Poggensee
Journal: Eurosurveillance (2012)

In contrast to air travel, there are no recommendations on tracing ground transport passengers exposed to infectious pathogens. We analysed European statistics on passenger transport in different conveyances and conducted expert workshops to discuss environmental conditions in ground transport, indications and minimal datasets required for contact tracing. Transport performance in the 27 countries of the European Union increased from 5.3x10 12 passenger kilometres (pkm) in 1995 to 6.5x10 12 pkm in 2007. Each resident generated on average 13,092 pkm in 2007, of which 2,062 pkm were public ground transport and 1,155 pkm in air transport. In the same year in Germany the total passenger volume in all different conveyances was 67,937 million. Public ground transport accounted for a passenger volume of 11,387 million (16.8%) and air transport for 129 million (0.2%). High efficiency particulate air (HEPA) filtration is frequently used in airplanes but not in ground transport vehicles. Therefore opportunities for disease transmission in public ground transport are not necessarily lower than in air travel. However, contact tracing is rarely conducted in these settings because of immense logistic challenges. Indication for contact tracing should be revisited, including all kinds of passenger transport.
Dephosphorylation Targets Bcl-2 for Ubiquitin-dependent Degradation: A Link between the Apoptosome and the Proteasome Pathway
Authors: Stefanie Dimmeler, Kristin Breitschopf, Judith Haendeler, Andreas M. Zeiher
Journal: The Journal of Experimental Medicine (1999)

Injury of the endothelial cells by the induction of apoptotic cell death may play an important role in the pathophysiology of atherosclerosis and the progression of inflammatory diseases. Here, we demonstrate an essential role for the ubiquitin-dependent proteasome complex in stimulus-induced degradation of the antiapoptotic protein Bcl-2. Bcl-2 is specifically degraded after stimulation of human endothelial cells with tumor necrosis factor (TNF)-α in a process that is inhibited by specific proteasome inhibitors. In addition, the mutation of the potential ubiquitin-acceptor amino acids of Bcl-2 provides protection against TNF-α– and staurosporine-induced degradation in vitro and in vivo. Moreover, mimicking phosphorylation of the putative mitogen-activated protein (MAP) kinase sites of the Bcl-2 protein (Thr 56, Thr 74, and Ser 87) abolishes its degradation, suggesting a link between the MAP kinase pathway to the proteasome pathway. Finally, inhibition of Bcl-2 degradation either by suppressing ubiquitin-dependent proteasomal degradation or by mimicking continuous phosphorylation of the putative MAP kinase sites in the Bcl-2 protein confers resistance against induction of apoptosis. Thus, the degradation of Bcl-2 may unleash the inhibitory function of Bcl-2 over the apoptosome and may thereby amplify the activation of the caspase cascade.
Apelin Attenuates Hyperoxic Lung and Heart Injury in Neonatal Rats
Authors: Yvonne P. de Visser, Frans J. Walther, El Houari Laghmani, Arnoud van der Laarse, Gerry T. M. Wagenaar
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Apelin, a potent vasodilator and angiogenic factor, may be a novel therapeutic agent in neonatal chronic lung disease, including bronchopulmonary dysplasia.To determine the beneficial effect of apelin in neonatal rats with hyperoxia-induced lung injury, a model for premature infants with bronchopulmonary dysplasia.The cardiopulmonary effects of apelin treatment (62 μg/kg/d) were studied in neonatal rats by exposure to 100% oxygen, using two treatment strategies: early concurrent treatment during continuous exposure to hyperoxia for 10 days and late treatment and recovery in which treatment was started on Day 6 after hyperoxic injury for 9 days and continued during the 9-day recovery period. We investigated in both models the role of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in apelin treatment by specific inhibition of the nitric oxide synthase activity with N(ω)-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/d).Parameters investigated include survival, lung and heart histopathology, pulmonary fibrin deposition and inflammation, alveolar vascular leakage, lung cGMP levels, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Prophylactic treatment with apelin improved alveolarization and angiogenesis, increased lung cGMP levels, and reduced pulmonary fibrin deposition, inflammation, septum thickness, arteriolar wall thickness, and right ventricular hypertrophy. These beneficial effects were completely absent in the presence of L-NAME. In the injury-recovery model apelin also improved alveolarization and angiogenesis, reduced arteriolar wall thickness, and attenuated right ventricular hypertrophy.Apelin reduces pulmonary inflammation, fibrin deposition, and right ventricular hypertrophy, and partially restores alveolarization in rat pups with neonatal hyperoxic lung injury via a nitric oxide synthase-dependent mechanism.