tbuckley/cabot-search huggingface dataset:
SP0125 Renal Handling of Urate and Gout
Authors: H.-J. Anders
Journal: Annals of the Rheumatic Diseases (2016)

Humans, birds, reptiles have (dinosaurs had) a tendency to develop gout because they lack sufficient uricase expression. Elimination of uric acid largely depends on excretion in the urine. A number of factors can limit this process such as genetic variants of uric acid transporters, drug-related inhibition of uric acid excretion, urine pH or loss of GFR. Visceral gout is a common phenomenon on birds, poultry, and reptiles with renal failure. Excreting large amounts of uric acid crystals is no problem for birds and reptiles (birds droppings are white for this reason), because urine concentration takes place in the cloacae close to the external orifice. In humans urine concentration takes place in the collecting ducts, which implies that hyperuricosuria imposes a risk for urolithiasis. By contrast, uric acid retention is a common cause for hyperuricemia together with increased purine load from metabolism and diet. Conceptually, a visit is a beer garden is dangerous for two reasons, the intake of purine rich food and drinks (beer) and the intake of fructose-rich soft drinks that blocks certain urate transporters that facilitate urate excretion. A number of well-known triggers for gout relate to renal function. For example, saturnine gout, the gout of the whine-drinking romans or of noblemen of the 17<sup>th</sup> century related to the cups made of lead or other nephrotoxic metals used at that time that caused chronic kidney disease (CKD)-related hyperuricemia. Also the prevalence of gout and CKD increase both with age. The lecture discusses the role of hyperuricemia and gout in CKD and the role of different therapeutic options in CKD patients. <h3>Disclosure of Interest</h3> None declared
Surgeons’ and Trauma Care Physicians’ Perception of the Impact of the Globalization of Medical Education on Quality of Care in Lima, Peru
Authors: Lacey N. LaGrone, Leah N. Isquith-Dicker, Eduardo Huaman Egoavil, Manuel J. A. Rodriguez Castro, Alfredo Allagual, Fernando Revoredo, Charles N. Mock
Journal: JAMA Surgery (2016)

The globalization of medical education-the process by which trainees in any region gain access to international training (electronic or in-person)-is a growing trend. More data are needed to inform next steps in the responsible stewardship of this process, from the perspective of trainees and institutions at all income levels, and for use by national and international policymakers.To describe the impact of the globalization of medical education on surgical care in Peru from the perspective of Peruvian surgeons who received international training.Observational study of qualitative interviews conducted from September 2015 to January 2016 using grounded theory qualitative research methods. The study was conducted at 10 large public institutions that provide most of the trauma care in Lima, Peru, and included urban resident and faculty surgery and trauma care physicians.Access to international surgical rotations and medical information.Outcome measures defining the impact of globalization on surgical care were developed as part of simultaneous data collection and analysis during qualitative research as part of a larger project on trauma quality improvement practices in Peru.Fifty qualitative interviews of surgeons and emergency medicine physicians were conducted at 10 hospitals, including multiple from the public and social security systems. A median of 4 interviews were conducted at each hospital, and fewer than 3 interviews were conducted at only 1 hospital. From the broader theme of globalization emerged subthemes of an eroded sense of agency and a perception of inadequate training on the adaptation of international standards as negative effects of globalization on surgical care in Peru. Access to research funds, provision of incentives for acquisition of advanced clinical training, increased expectations for patient outcomes, and education in quality improvement skills are ways in which globalization positively affected surgeons and their patients in Peru.Short-term overseas training of surgeons from low- and middle-income countries may improve care in the surgeons' country of origin through the acquisition of skills and altered expectations for excellence. Prioritization of evidence-based medical education is necessary given widespread internet access and thus clinician exposure to variable quality medical information. Finally, the establishment of centers of excellence in low- and middle-income countries may address the eroded sense of agency attributable to globalization and offer a local example of world-class surgical outcomes, diminishing surgeons' most frequently cited reason for emigration: access to better surgical training.
A question of evidence
Authors: Theodora Bloom
Journal: BMJ (2016)

A central tenet of evidence based medicine is that practice should change when new evidence comes to light. But how good does the evidence have to be?

Public Health England recently recommended that everyone over 4 years old should take a low dose of vitamin D, particularly to compensate for low sunlight in autumn and winter (doi:10.1136/i6183). But the evidence to support this recommendation is as yet weak (doi:10.1136/bmj.i6201 …
Thrombopoietin-Mimetic Romiplostim Confers the Complete Survival Rate to Mice Exposed to Lethal Ionizing Radiation
Authors: Masaru Yamaguchi, Tokuhisa Hirouchi, Mitsuru Chiba, Satoru Monzen, Hironori Yoshino, Junya Ishikawa, Takakiyo Tsujiguchi, Ayaka Nishiyama, Sho Murakami, Junichiro Komura, Ikuo Kashiwakura
Journal: Blood (2015)
T-Cell Depleted (TCD) Hematopoietic Stem Cell (HSC) Boosts From the Original Donor without Conditioning for Poor Graft Function (PGF) Following Allogeneic Hematopoietic Stem Cell Transplants (HSCT)
Authors: Michael A. Rosenzweig, Nancy A. Kernan, Trudy N Small, Molly Maloy, Ann A. Jakubowski, Esperanza B Papadopoulos, Miguel-Angel Perales, Farid Boulad, Sergio Giralt, James W Young, Richard J. O'Reilly, Hugo R Castro-Malaspina
Journal: Blood (2011)
Rapidly Growing, Bleeding Mass on a Golfer’s Back
Authors: SreyRam Kuy
Journal: JAMA Surgery (2016)

A professional golfer aged 69 years with a history of frequent outdoor sun exposure presented to the surgery clinic with a mass on his left upper back. Clinical examination revealed an 8 × 6 × 4-cm multilobulated, purplish lesion that was fungating and friable. What is your diagnosis?
THU0145 Pharmacokinetics and Safety of GP2015, A Proposed Etanercept Biosimilar, and Etanercept Originator Product in Healthy Male Subjects: A Randomised Two-Way Crossover Study
Authors: M. Afonso, S. Sanguino Heinrich, J. Poetzl, H. Woehling
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> GP2015 is a proposed etanercept (tumor necrosis factor inhibitor) biosimilar. <h3>Objectives</h3> To compare the pharmacokinetics (PK) and safety of GP2015 and etanercept originator product (EU-authorised) in healthy subjects. <h3>Methods</h3> Healthy subjects (N=54) were randomised to receive a single 50 mg subcutaneous (sc) injection of GP2015 or etanercept originator product, followed by a wash-out period of at least 35 days, and a single 50 mg sc injection of originator product or GP2015, respectively. Subsequent follow up was 28 days. The primary PK parameters were normalised by the protein content of the administered dose before fitting in the analysis of variance model (dose normalised PK analysis). Bioequivalence between GP2015/etanercept originator product for primary PK parameters [maximum observed serum concentration (C<sub>max</sub>), area under the serum concentration-time curve measured from the time of dosing to the last measurable concentration (AUC<sub>0-tlast</sub>) and AUC measured from the time of dosing and extrapolated to infinity (AUC<sub>0-inf</sub>)] was demonstrated if the 90% confidence intervals (CIs) for the ratio of geometric means were completely contained within the predefined bioequivalence limits of 0.80–1.25. <h3>Results</h3> The 90% CIs for the ratios of geometric means of dose normalised primary PK parameters (C<sub>max</sub>, AUC<sub>0-tlast</sub> and AUC<sub>0-inf</sub>) were within the interval of 0.80–1.25 (Table). For the respective nominal dose (not dose normalised) primary PK parameters, the 90% CIs of the ratios of geometric means were also within the interval of 0.80–1.25 (Table). The most common AEs regardless of relationship to study drug were neutropenia [GP2015, n=7 (13%); originator product, n=8 (14.8%)], headache [GP2015, n=5 (9.3%); originator product, n=5 (9.3%)] and nasopharyngitis [GP2015, n=4 (7.4%); originator product, n=4 (7.4%)]. All treatment-related AEs were of mild or moderate intensity. No serious AEs and deaths occurred during the study. Three subjects had low titer and non-neutralising anti-drug antibodies (ADAs) at the 28-day follow-up visit (treatment sequence GP2015/etanercept originator product). <h3>Conclusions</h3> This study demonstrated PK bioequivalence between GP2015, a proposed etanercept biosimilar and the etanercept originator product with no relevant differences in safety. The safety and immunogenicity profiles observed in this study are consistent with previous reports on etanercept originator product. <h3>Disclosure of Interest</h3> M. Afonso Employee of: Hexal AG, affiliate of Novartis, S. Sanguino Heinrich Employee of: Hexal AG, affiliate of Novartis, J. Poetzl Employee of: Hexal AG, affiliate of Novartis, H. Woehling Shareholder of: Hexal AG, affiliate of Novartis, Employee of: Hexal AG, affiliate of Novartis
Prospective Nationwide Observational Study of Hepatitis B Virus (HBV) DNA Monitoring and Preemptive Antiviral Therapy for HBV Reactivation in Patients with B-Cell Non-Hodgkin Lymphoma Following Rituximab Containing Chemotherapy: Results of Interim Analysis.
Authors: Shigeru Kusumoto, Yasuhito Tanaka, Ritsuro Suzuki, Takashi Watanabe, Masanobu Nakata, Hirotaka Takasaki, Noriyasu Fukushima, Takuya Fukushima, Yukiyoshi Moriuchi, Kuniaki Itoh, Kisato Nosaka, Ilseung Choi, Masashi Sawa, Rumiko Okamoto, Hideki Tsujimura, Toshiki Uchida, Sachiko Suzuki, Masataka Okamoto, Tsutomu Takahashi, Isamu Sugiura, Yasushi Onishi, Mika Kohri, Shinichiro Yoshida, Rika Sakai, Minoru Kojima, Hiroyuki Takahashi, Akihiro Tomita, Dai Maruyama, Yoshiko Atsuta, Eiji Tanaka, Takayo Suzuki, Tomohiro Kinoshita, Michinori Ogura, Masashi Mizokami, Ryuzo Ueda
Journal: Blood (2012)
Inherited Genetic Variation and the Risk of Developing Venous Thrombosis with Thalidomide Treatment in Myeloma Patients.
Authors: David C. Johnson, Suzanne Grindle, Faith Davies, David Gonzalez, Christine Ramos, Kim Hawkins, Suzanne Bell, Heather Kesby, S. Vincent Rajkumar, Erik Rassmusen, John Crowley, Emily Blood, J. Anthony Child, Brian G.M. Durie, Brian G. Van Ness, Gareth J. Morgan
Journal: Blood (2005)
High Frequencies of Compound BCR-ABL Mutations and Their Association with Imatinib Resistant, Disease Progression and Late Chronic Phase Disease in Pakistani Chronic Myeloid Leukemia Patients Necessitate the Inclusion of Molecular Testing in Routine Clinical Settings
Authors: Zafar Iqbal, Afia Muhammad Akram, Tanveer Akhtar, Muhammad Khalid, Zeba Aziz, Aamer Aleem, Ammara T Gill, Ahmad M Khalid, Abdullah Alanazi, Ijaz H Shah, Muhammad Khalid, Muhammad Farooq Sabar, Mudassar Iqbal
Journal: Blood (2015)
Aberrant Hematopoietic Stem Cell Function in Mice Haploinsufficient for a 2 Mb Deletion of Chromosome 5A3 Syntenic to a Region of Human 7q22 Frequently Deleted in Myelodysplastic Syndromes
Authors: Jasmine C. Wong, Kelley Weinfurtner, Pilar Alzamora, Scott C. Kogan, Michael R. Burgess, Yan Zhang, Joy Nakitandwe, Jing Ma, Jinjun Cheng, Shann-Ching Chen, Johanna Flach, Damien Reynaud, Emmanuelle Passegue, James R Downing, Kevin Shannon
Journal: Blood (2014)
Population Heterogeneity in Mutation Rate Increases the Frequency of Higher-Order Mutants and Reduces Long-Term Mutational Load
Authors: Helen K. Alexander, Stephanie I. Mayer, Sebastian Bonhoeffer
Journal: Molecular Biology and Evolution (2016)

Mutation rate is a crucial evolutionary parameter that has typically been treated as a constant in population genetic analyses. However, the propensity to mutate is likely to vary among co-existing individuals within a population, due to genetic polymorphisms, heterogeneous environmental influences, and random physiological fluctuations. We review the evidence for mutation rate heterogeneity and explore its consequences by extending classic population genetic models to allow an arbitrary distribution of mutation rate among individuals, either with or without inheritance. With this general new framework, we rigorously establish the effects of heterogeneity at various evolutionary timescales. In a single generation, variation of mutation rate about the mean increases the probability of producing zero or many simultaneous mutations on a genome. Over multiple generations of mutation and selection, heterogeneity accelerates the appearance of both deleterious and beneficial multi-point mutants. At mutation-selection balance, higher-order mutant frequencies are likewise boosted, while lower-order mutants exhibit subtler effects; nonetheless, population mean fitness is always enhanced. We quantify the dependencies on moments of the mutation rate distribution and selection coefficients, and clarify the role of mutation rate inheritance. While typical methods of estimating mutation rate will recover only the population mean, analyses assuming mutation rate is fixed to this mean could underestimate the potential for multi-locus adaptation, including medically relevant evolution in pathogenic and cancerous populations. We discuss the potential to empirically parameterize mutation rate distributions, which have to date hardly been quantified.
Protein Expression Patterns of Candidate Genes Involved in Apoptosis and Cell Cycle Control in Genetic Subgroups of Chronic Lymphocytic Leukemia.
Authors: Christof Schneider, Dirk Winkler, Meike Loddenkemper, Alexander Krober, Peter Lichter, Hartmut Dohner, Stephan Stilgenbauer
Journal: Blood (2004)
ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5
Authors: Hui-Lung Sun, Ri Cui, JianKang Zhou, Kun-yu Teng, Yung-Hsuan Hsiao, Kotaro Nakanishi, Matteo Fassan, Zhenghua Luo, Guqin Shi, Esmerina Tili, Huban Kutay, Francesca Lovat, Caterina Vicentini, Han-Li Huang, Shih-Wei Wang, Taewan Kim, Nicola Zanesi, Young-Jun Jeon, Tae Jin Lee, Jih-Hwa Guh, Mien-Chie Hung, Kalpana Ghoshal, Che-Ming Teng, Yong Peng, Carlo M. Croce
Journal: Cancer Cell (2016)

Highlights•ERK phosphorylation followed by Pin1-mediated isomerization impairs XPO5 activity•Downregulation of miR-122 leads to taxol resistance through septin-9 and MARK4•XPO5 phosphorylation correlates with poor prognosis in HCC patients•Pin1 and MARK4 are potential targets for clinical intervention in liver cancerSummaryMicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.
Addition of Rituximab to First-Line MCP (Mitoxantrone, Chlorambucil, Prednisolone) Chemotherapy Prolongs Survival in Advanced Follicular Lymphoma - 4 Year Follow-Up Results of a Phase III Trial of the East German Study Group Hematology and Oncology (OSHO#39).
Authors: Michael Herold, Antje Haas, Stephanie Srock, Sabine Neser, Kathrin H. Al Ali, Andreas Neubauer, Gottfried Doelken, Ralph Naumann, Thomas Fietz, Mathias Freund, Robert Rohrberg, Klaus Hoeffken, Astrid Franke, Thomas H. Ittel, Erika Kettner
Journal: Blood (2006)
Twenty Years of Follow-Up among Survivors of Childhood and Young Adult Acute Myeloid Leukemia (AML): A Report from the Childhood Cancer Survivor Study (CCSS).
Authors: Daniel A. Mulrooney, Douglas C. Dover, Yutaka Yasui, Kirsten K. Ness, Ann C. Mertens, Joseph P. Neglia, Charles A. Sklar, Leslie L. Robison, Stella M. Davies
Journal: Blood (2006)
PTU-031 What is The Value of Performing An Endoscopy in Patients Under The Age of 50 With Symptoms of Gastro-Oesophageal Reflux Disease
Authors: R Preedy, S Phillpotts, T El Menabawey, K Besherdas
Journal: Gut (2016)

<h3>Introduction</h3> For gastro-esophageal reflux (GORD), upper endoscopy may be indicated in older men with chronic GORD symptoms (greater than 5 years) and additional risk factors such as elevated body mass index and tobacco use, to increase detection of Barretts oesophagus and esophageal adenocarcinoma. Upper endoscopy is indicated in patients with GORD and alarm symptoms such as dysphagia, weight loss, bleeding, anaemia and recurrent vomiting. Without alarm symptoms upper endoscopy is only indicated when symptoms of GORD persist or progress despite appropriate medical therapy. Inappropriate use of upper endoscopy does not improve the health of patients, exposes them to preventable harms, can lead to unnecessary interventions and result in unnecessary costs with no benefit. Our aim was to assess the findings at upper endoscopy performed in patients under the age of 50 presenting with GERD without alarm symptoms. <h3>Methods</h3> A single centre, retrospective analysis in a large London NHS Foundation Hospital was performed. All patients endoscoped for reflux were identified using Unisoft Endoscopy reporting software across a period of 10 years (June 2005-May2015). Data from the patients’ electronic records was reviewed for histological diagnosis of Barrett’s or cancer. <h3>Results</h3> 124 of the 1772 patients endoscoped for reflux symptoms alone were found to have Barrett’s (7%). 627 of the 1772 patients were under the age of 50 at time of endoscopy Out of the patients under the age of 50, 23 (3.6%) were identified as having Barrett’s at the time of endoscopy but histologically proven in only 13 (2%) the others were shown to have reflux oesophagitis only. No patients were found to have cancer of the oesophagus or stomach. Out of the 13 patients with proven Barrett’s 4 patients had a length longer than 3 cm with a maximum length of 6 cm. All other patients had short segments of Barrett’s (less than 3 cm) and none had evidence of dysphasia or malignancy. <h3>Conclusion</h3> The role of endoscopy in patients under the age of 50 with symptoms of GORD only would appear to be an inappropriate first line investigation. In our case series only 2% patients endoscoped under the age of 50 were identified a histological positive diagnosis of Barrett’s. Inview of current guidelines only 0.3% would require surveillance endoscopy but this in itself remains questionable. <h3>Disclosure of Interest</h3> None Declared
Implication of AML1/RUNX1 Function in the Homeostasis and Leukemic Transformation of Hematopoietic Stem Cells.
Authors: Motoshi Ichikawa, Masataka Takeshita, Susumu Goyama, Takashi Asai, Eriko Nitta, Masahiro Nakagawa, Masahito Kawazu, Shigeru Chiba, Seishi Ogawa, Mineo Kurokawa
Journal: Blood (2007)
FRI0347 Phenotypic Changes of Lymphocytes in Patients with Severe Systemic Lupus Erythematosus Treated with An Intensified B-Cell Depletion Therapy with Rituximab
Authors: S. Sciascia, S. Baldovino, E. Menegatti, L. Solfietti, D. Di Simone, D. Rossi, D. Roccatello
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> B cells (BC) play a critical role in systemic lupus erythematosus (SLE). BC depletion therapy still remains an attractive option, despite the disappointing results of randomized controlled trials. However, the effects of rituximab treatment on T –cells including regulatory T cells (Treg) in SLE have not been fully determined. <h3>Objectives</h3> We prospectively investigated the differentiation and phenotypic changes of peripheral B cells and T regulatory lymphocytes (Treg) in patients with SLE after an intensified B-Cell depletion therapy with Rituximab <h3>Methods</h3> Ten patients with sever SLE [2males, mean age 41.6 yrs (25–57)] with severe multiorgan involvement have been prospectively treated with IBCDT protocol due to their resistance or intolerance to previous therapy. Protocol: Rituximab (RTX) 375 mg/sm on days 1, 8, 15, 22, and 2 more doses after 1 and 2 months, associated with 2 IV administrations of 10 mg/kg of cyclophosphamide and 3 methylprednisolone pulses (15 mg/kg) followed by oral prednisone (0.8 mg/kg/day, rapidly tapered to 5mg/day by the end of the 3rd month after RTX). No further immunosuppressive maintenance therapy has been given. Circulating B cells and Treg in the peripheral blood were investigated by flow-cytometry at baseline, month 1, month 2, and every other month thereafter up to 1 year. Whole blood samples obtained in the morning, in EDTA, were stained with monoclonal antibodies against CD45, CD3, CD4 CD19, CD20, CD25 and FOXP3. Response was evaluated by assessing the changes in clinical signs and symptoms, laboratory parameters and SLEDAI score. <h3>Results</h3> All patients had complete peripheral blood-B cell depletion after IBCDT and the CD20+ B cells were not detectable in the circulation by the 12th month (detection limit of 0.005x10<sup>9</sup>/l). Upon detection of B cell depletion, we observed in 12 months a 4-fold increase in the circulating Treg (CD4+CD25+FOXP3+) (2% at baseline, 3% after 1 month, 4,5% at 6 month, 8% at 12 months). All patients achieved clinical remission after IBCTD and no flare were observed during the one-year follow-up. IBCDT resulted in a decrease of median global SLEDAI from 14.6 [11–23] to 4 [1–5] at 12 months (p&lt;0.01) <h3>Conclusions</h3> Our results suggest a phenotypic change of peripheral T lymphocytes as a result of B cells depletion obtained with IBCTD. Treg considered being essential in the maintenance of peripheral self-tolerance, progressively increased after B cell depletion. Such immunological re-assessment was observed in association with clinical remission in the absence of further disease flare. <h3>Disclosure of Interest</h3> None declared