tbuckley/cabot-search huggingface dataset:
FOXO transcription factors regulate innate immune mechanisms in respiratory epithelial cells
Authors: Frederik Seiler, Philipp Lepper, Jan Hellberg, Frank Langer, Markus Bischoff, Robert Bals, Christoph Beisswenger
Journal: European Respiratory Journal (2012)

Background: Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. FOXO transcription factors are key regulators of cellular metabolism, proliferation and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells.  Methods: Bronchial epithelial cells were transfected with siRNA specific for FOXO1 and FOXO3 and infected with  Haemophilus influenza  and  Pseudomonas aeruginosa . Expression of inflammatory cytokines and antimicrobial peptides were determined. Epithelial uptake of bacteria was examined. FOXO3 was detected in human bronchial tissue.  Results: Infection with bacterial pathogens potently activated FOXO transcription factors in respiratory epithelial cells  in vivo  and  in vitro . Active FOXO was also detectable in bronchial tissue of subjects with different infection-related lung diseases. siRNA mediated knock down of FOXO in epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines under basal conditions and upon infection. FOXO deficiency further affected internalization of  Haemophilus influenzae  in bronchial epithelial cells. TLR3 activated innate immune responses in a FOXO-dependent manner.  Conclusion: FOXO transcription factors are involved in the cellular responses to bacterial stimuli and possess a central role in regulating innate immune functions of respiratory epithelial cells.
The Object of the Berlin Leprosy Conference.
Authors: Albert S. Ashmead
Journal: JAMA (1897)

New York, Feb. 16, 1897. <h3>To the Editor:</h3> —In a correspondence with Dr. Goldschmidt, December, 1895, a plan was devised by the writer for the formation of an International World's Committee, composed of delegates of all governments. This plan was submitted to Dr. Hansen, who approved of it, and submitted it to the Norwegian government through his chief, Dr. Holmboe. The answer came back that before Norway issued the invitation, it was necessary to obtain a general opinion of the leading leprologists. Dr. Hansen said that his government would probably ask a credit of parliament for the expenses of the Congress. The Provisional Committee was formed of Goldschmidt, Hansen and Ashmead. The plan was explained to the public in medical newspapers, and was brought to the attention of the leprologists through private correspondence. It seemed to be generally approved. It remained to determine the seat of the Congress. Here there
Irbesartan did not reduce all-cause death or CV hospitalization in heart failure and preserved ejection fraction
Authors: Justin A. Ezekowitz
Journal: Annals of Internal Medicine (2009)

ACP Journal Club19 May 2009Irbesartan did not reduce all-cause death or CV hospitalization in heart failure and preserved ejection fractionJustin A. Ezekowitz, MD, Finlay A. McAlister, MDJustin A. Ezekowitz, MDUniversity of Alberta,, Edmonton, Alberta, Canada (J.A.E., F.A.M.)Search for more papers by this author, Finlay A. McAlister, MDUniversity of Alberta,, Edmonton, Alberta, Canada (J.A.E., F.A.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-150-10-200905190-02010 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationMassie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-67. https://pubmed.ncbi.nlm.nih.gov/19001508Clinical Impact RatingsGIM/FP/GP: Cardiology: References1 McAlister FA, Teo KK, Taher M, et al. Insights into the contemporary epidemiology and outpatient management of congestive heart failure. Am Heart J. 1999;138:87-94. [PMID: 10385769] Google Scholar2 Ezekowitz JA, Lee DS, Tu JV, Newman AM, McAlister FA. Comparison of one-year outcome (death and rehospitalization) in hospitalized heart failure patients with left ventricular ejection fraction >50% versus those with ejection fraction <50%. Am J Cardiol. 2008;102:79-83. [PMID: 18572040] Google Scholar3 Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-81. [PMID: 13678871] Google Scholar4 Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338-45. [PMID: 16963472] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Alberta,, Edmonton, Alberta, Canada (J.A.E., F.A.M.)This article was published at Annals.org on 5 May 2009. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byBeta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fractionBeta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction 19 May 2009Volume 150, Issue 10Page: JC5-10KeywordsACE inhibitorsEjection fractionHeart failureHospitalizationsHypertensionLongitudinal studiesMorbidityMyocardial infarction ePublished: 19 May 2009 Issue Published: 19 May 2009 Copyright & PermissionsCopyright © 2009 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Child poverty in rich countries rose during financial crisis
Authors: A. Gulland
Journal: BMJ (2014)

The proportion of children living in poverty has risen in rich countries since the worldwide financial crisis of 2008, concludes a new report by Unicef, the United Nations’ children’s agency.1

The report looked at the 41 richest countries in the world and found that in more than half (23) the number of children living below the poverty line (classed as living in a household earning 50% to 60% of average income, or less) has increased since 2008. This means that around 76.5 million children live in poverty in the world’s richest countries.

The largest increase in the childhood poverty rate was seen in Iceland, where in 2012 32% of children lived below the poverty line, …
Microbe Hunters--Then and Now
Authors: B. Dixon
Journal: BMJ (1996)

Ed Hilary Koprowski, Michael B A Oldstone Medi-Ed Press, £16.99, pp 456 ISBN 0 936741 11 2

Since it first appeared in 1926, Paul de Kruif's Microbe Hunters must have drawn hundreds of thousands of young people into either biology or medicine. Nowadays, its rumbustious portraits of Pasteur, Koch, and their peers seem not so much inspirational as over the top. Yet this was an enthralling and accessible account, for readers of all ages, of one of the great episodes in the development of modern medical science.

The title and dust jacket of this new work, produced by 45 authors, will …
Williams Textbook of Endocrinology
Authors: Sheldon Stoffer
Journal: JAMA (1992)

The first edition of this famous textbook, published in 1950, was written by Robert H. Williams and 11 contributors. Williams stated then that "the authors chosen to collaborate in writing this book are men who have maintained intimate contact with progress in both basic and clinical investigations, and who have had great experience in the practical application of this information." "[In 1950] the main clinical tests for the evaluation of thyroid function were listed as basal metabolic rate, protein bound iodine, radioiodine studies, creatine tolerance, and blood cholesterol." The main object of the text, in Williams' words, was to "provide a condensed and authoritative discussion of the management of clinical endocrinopathies, based on the application of fundamental information obtained from chemical and physiologic investigations." In short, this text was to serve as "a bridge between basic science and clinical endocrinology." It is informative for the modern clinician to peruse that
An RNA interference model of RPS19 deficiency in Diamond-Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone-responsive genes by microarray
Authors: Benjamin L. Ebert, Michele M. Lee, Jennifer L. Pretz, Aravind Subramanian, Raymond Mak, Todd R. Golub, Colin A. Sieff
Journal: Blood (2005)
The dangers of attacking disease programmes for developing countries
Authors: Simon Collins, Brook K Baker, Gregg Gonsales, Marco Gomes
Journal: BMJ (2007)

Roger England has launched yet another broadside attack on programmes for priority diseases in poor countries ( BMJ 2007;335:565 doi: 10.1136/bmj.39335.520463.94 and 2007;334:344 doi: 10.1136/bmj.39113.402361.94). In his latest Personal View, he claims that “disease specific global programmes [are] not the way to help Africa,” instead that they cause “big problems for recipients,” and that money for HIV/AIDS is “the worst.” He claims that off-budget money leads to distortions; that there are duplications of plans, operations, and monitoring; and that priority disease programmes are neither cost effective nor sustainable.

His evidence that little is being achieved is one statistic: HIV prophylaxis is reaching only 9% (actually it is 11%) of pregnancies of HIV positive women. He blames the warped prioritisation of disease programmes on international lobby groups from rich countries.

England's prescription for change says that (1) governments must stop funding global programmes that do not go through countries' planning and budgeting processes; (2) the Global Fund to Fight AIDS, Tuberculosis, and Malaria must disband and be reconstituted as a global health fund; (3) countries must reform their systems and outsource service provision from the government to the private sector; and (4) everyone should drop the millennium development goals because they are more trouble than they are worth.

The evidence on hand rebuts or at least moderates many of England's claims and recommendations.

(1) Contrary to England's claims, priority disease programmes have shown considerable progress in a relatively short period of time. Currently, the Global Fund contributes two thirds of international funding for tuberculosis and malaria, and about 20% of global resources for HIV/AIDS, for example. In its short life it has funded programmes that have already saved more than 1.8 million lives; provided antiretroviral treatment to …
Pharmacokinetics of all‐<i>trans</i> retinoic acid in acute promyelocytic leukemia patients on dialysis
Authors: Kimitaka Takitani, Koichi Nagai, Eiki Kanbe, Akiko Inoue, Chihiro Kawakami, Tomoko Kuno, Hiroshi Tamai
Journal: American Journal of Hematology (2003)
Delayed Onset of Infectious Mononucleosis Associated with Acquired Agammaglobulinemia and Red Cell Aplasia
Authors: DAVID T. PURTILO
Journal: Annals of Internal Medicine (1984)

In 1974, an 11-year-old white boy with the X-linked lymphoproliferative syndrome developed hyper-IgM after becoming infected with Epstein-Barr virus. However, he failed to develop normal immune responses against the virus. In December 1981, when red cell aplasia occurred, he was given packed erythrocytes and gammaglobulin. Nine weeks later, acute infectious mononucleosis developed. Concurrently, his T4/T8 helper/suppressor ratio decreased from 2.7 to 0.2, and IgM antibodies to Epstein-Barr virus appeared. Subsequently, circulating B cells became undetectable in his blood, and agammaglobulinemia appeared. Red cell aplasia abated transiently. This patient's course was complicated by Haemophilus influenzae and Mycobacterium tuberculosis pneumonias, and red cell aplasia and agammaglobulinemia have persisted. Epstein-Barr virus acting as a slow virus probably induced the red cell aplasia and agammaglobulinemia because of the aberrant immune responses to Epstein-Barr virus. Immunodeficient responses to Epstein-Barr virus should be sought in other patients with the diseases documented in our patient.
An Analysis of 1962 Poliomyelitis Cases
Authors: Reimert T. Ravenholt
Journal: JAMA (1963)

<h3>To the Editor:</h3> —In my previous communication, "Studies of Poliomyelitis in Seattle" (<i>JAMA</i><b>184</b>:663 [May 25] 1963), I indicated that "severity of paralysis did not correlate with Salk vaccination status, suggesting that such vaccination provides all-or-none protection from paralytic poliomyelitis." Since then, the Communicable Disease Center, USPHS, has published an analysis of all poliomyelitis cases reported to CDC during 1962 from the entire US (<i>Poliomyelitis Surveillance Rep</i>, No. 277, June 7, 1963). The 1962 national experience provides considerable support for the concept that immunization with Salk vaccine gives all-or-none protection against paralytic poliomyelitis, as indicated by these data: The distribution of all paralytic cases and of fatal cases (the most severely paralyzed) according to immunization status was remarkably similar— with 62.2% of all persons paralyzed and 63.8% of all persons succumbing to poliomyelitis having had no inactivated vaccine; and 10.1% of the former group and 12.8% of the latter
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
Authors: Aurélien Marabelle, Holbrook Kohrt, Idit Sagiv-Barfi, Bahareh Ajami, Robert C. Axtell, Gang Zhou, Ranjani Rajapaksa, Michael R. Green, James Torchia, Joshua Brody, Richard Luong, Michael D. Rosenblum, Lawrence Steinman, Hyam I. Levitsky, Victor Tse, Ronald Levy
Journal: Journal of Clinical Investigation (2013)

Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
A memorable patient: You only see what you know
Authors: S. Schafer
Journal: BMJ (2003)

I was in my first year of residency at the university department of cardiology when a 58 year old woman was admitted to the ward because of slowly progressing exertional dyspnoea and fatigue. As requested by the referring physician, I made a thorough cardiological examination. Except for mildly increased serum cholesterol concentrations, she had no cardiovascular risk factors. However, she confirmed that over the past few months she had had increasing difficulty climbing the stairs to her second floor apartment. I noticed no irregularities during her physical examination, but her electrocardiogram showed first degree atrioventricular block and borderline left ventricular hypertrophy. Echocardiography showed moderate left ventricular enlargement and diffusely reduced systolic function. After ruling out relevant coronary macroangiopathy, the diagnosis …
Assessing Health-Related Quality of Life for Advanced Basal Cell Carcinoma and Basal Cell Carcinoma Nevus Syndrome
Authors: Susan D. Mathias, Mary-Margaret Chren, Hilary H. Colwell, Yeun Mi Yim, Carolina Reyes, Diana M. Chen, Scott W. Fosko
Journal: JAMA Dermatology (2013)

<h3>Importance</h3> Little is known about patients' experiences of advanced basal cell carcinoma (aBCC) and basal cell carcinoma nevus syndrome (BCCNS), a rare genetic disorder that greatly increases the number of BCCs. <h3>Objective</h3> To develop a questionnaire to measure patient-reported outcomes (PROs) in these populations. <h3>Design, Setting, and Participants</h3> Concept elicitation interviews were conducted with patients with aBCC and BCCNS from 5 US clinical sites and the BCCNS Life Support Network and 4 physicians. The PRO questionnaires were drafted based on results from a literature review and findings from these interviews. Questionnaires were finalized after cognitive debriefing interviews were conducted with patients. Concept elicitation interviews were conducted with 30 patients (14 with aBCC, 16 with BCCNS) and 4 physicians (2 dermatologists, 1 Mohs surgeon, and 1 oncologist) in the United States. A subset of 10 of these patients (5 with aBCC, 5 with BCCNS) took part in cognitive debriefing interviews. <h3>Main Outcomes and Measures</h3> Development of 2 questionnaires to allow clinicians to assess the emotional, social, and physical impacts of the disease on patients with aBCC and BCCNS. <h3>Results</h3> Most concept elicitation interview patients were male (63%) and white (93%); their mean age was 57 years. There were impacts on emotional, social, and physical functioning in both conditions. Patients were unable to do many activities and avoided other activities. Seventy-nine percent of patients with aBCC and all patients with BCCNS reported scarring. Physician interviews revealed similar findings. During cognitive debriefing interviews, the questionnaires were found to be relevant, clear, and comprehensive. <h3>Conclusions and Relevance</h3> Advanced BCC and BCCNS affect patients in unique and substantial ways. These PRO questionnaires were developed with patient and clinician input and measure the key areas that have an impact on patients with these conditions.
Germinal Center Centroblasts Transition to a Centrocyte Phenotype According to a Timed Program and Depend on the Dark Zone for Effective Selection
Authors: Oliver Bannard, Robert M. Horton, Christopher D.C. Allen, Jinping An, Takashi Nagasawa, Jason G. Cyster
Journal: Immunity (2013)

Germinal center (GC) B cells cycle between the dark zone (DZ) and light zone (LZ) during antibody affinity maturation. Whether this movement is necessary for GC function has not been tested. Here we show that CXCR4-deficient GC B cells, which are restricted to the LZ, are gradually outcompeted by WT cells indicating an essential role for DZ access. Remarkably, the transition between DZ centroblast and LZ centrocyte phenotypes occurred independently of positioning. However, CXCR4-deficient cells carried fewer mutations and were overrepresented in the CD73(+) memory compartment. These findings are consistent with a model where GC B cells change from DZ to LZ phenotype according to a timed cellular program but suggest that spatial separation of DZ cells facilitates more effective rounds of mutation and selection. Finally, we identify a network of DZ CXCL12-expressing reticular cells that likely support DZ functions.
Random sampling versus random allocation
Authors: P. Sedgwick
Journal: BMJ (2011)

Researchers investigated the effects of providing people with evidence based information about colorectal cancer and screening. A randomised controlled study design was used. The intervention was a brochure that included personalised risk of colorectal cancer, available screening options with possible benefits and harm, plus information on prevention of colorectal cancer. People also had access to two optional interactive internet modules on risk and diagnostic tests. The control treatment was the official information leaflet of the German colorectal cancer screening programme. Primary outcome measures included “informed choice” based on knowledge and attitude, plus the planned and actual uptake of screening.1

Potential trial participants were people insured by a large German statutory health insurance scheme who were aged 50-75 years and had no history of colorectal cancer. A total of 7946 people were eligible. A random sample of about 4000 people was drawn and invited to participate in the trial. In total, 1577 agreed and were randomly allocated to the intervention (n=785) or control (n=792).

The researchers …
Partnerships in Medical Education
Authors: Carlos J. M. Martini
Journal: JAMA (1991)

We frequently hear that the United States has one of the best—if not<i>the</i>best—medical education systems in the world. However, with the same frequency, detractors complain about the system's resistance to improvements and change. As Alvin Tarlov, MD,<sup>1</sup>recently observed, from a sociologic perspective, medical institutions may reach a level of maturity that leaves them paralyzed and unable to reform themselves. After years of experimentation and discussion, modifications are just now being made to a stable and entrenched medical education establishment, notorious for rejecting innovation. The following discussion is intended as a reminder of critical issues that have attracted the interest of the medical education community during the past year. Some of the very factors that make the US system successful also deter change. A conglomerate of connected but relatively independent components, medical education thrives on the American traditions of decentralization and autonomy. But national efforts, such as
Genetic changes likely to predict response to immunotherapy in bowel cancer are identified
Authors: S. Mayor
Journal: BMJ (2015)

Genetic changes associated with how the immune system responds to bowel cancer have been identified by researchers, from the results of a study published in Oncoimmunology that could help to identify patients likely to respond to different targeted immunotherapy treatments.1

The density of tumour infiltrating lymphocytes is prognostic and predictive in colorectal cancer, but the genetic factors driving this immune response have previously been unclear. Researchers analysed data on 195 patients with colorectal cancer in the Cancer …
<i>Pseudomonas aeruginosa</i>Exotoxin A
Authors: Matthew Pollack
Journal: New England Journal of Medicine (1980)

Pseudomonas aeruginosa is an opportunistic pathogen that causes more than 100,000 infections in the United States each year. Pseudomonas infections are associated with considerable morbidity and mortality despite the use of modern antibiotics.1 Recognition of the limitations of existing therapy for pseudomonas disease has stimulated renewed interest in its pathogenesis and in immunologic approaches to prophylaxis and treatment.During the past century Charrin2 and Bouchard3 postulated the role of a toxin in pseudomonas disease. Their hypothesis lay dormant until the 1960's when Liu et al. discovered and later purified a lethal factor in pseudomonas cultures that they called exotoxin A. . . .