tbuckley/cabot-search huggingface dataset:
Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology
Authors: Joshua M. Shulman, Kewei Chen, Brendan T. Keenan, Lori B. Chibnik, Adam Fleisher, Pradeep Thiyyagura, Auttawut Roontiva, Cristin McCabe, Nikolaos A. Patsopoulos, Jason J. Corneveaux, Lei Yu, Matthew J. Huentelman, Denis A. Evans, Julie A. Schneider, Eric M. Reiman, Philip L. De Jager, David A. Bennett
Journal: JAMA Neurology (2013)

While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques.To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait.Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers.A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir.Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition.These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
EVIDENCE THAT DIGITALIS INFLUENCES CONTRACTION OF THE HEART IN MAN
Authors: Alfred E. Cohn, Harold J. Stewart
Journal: Journal of Clinical Investigation (1924)

Since 1785, when digitalis was first used systematically in the treatment of human disease, the criteria which have been employed in the attempt to define precisely when the drug is indicated, have undergone changes depending on those aspects of the study of the heart which were current at the time.These 140 years fall almost naturally into distinct periods.At first a belief initiated by Withering (1785) in the efficacy of digitalis as a diuretic was general and almost unquestioned.His chief indication for the exhibition of the drug is dear from this description: " Further experience convinced me, that the diuretic effects of this medicine do not at all depend upon its exciting a nausea or vomiting; but, on the contrary, that though the increased secretion of urine will frequently succeed to, or exist along with these circumstances, yet they are so far from being friendly or necessary, that I have often known the discharge of urine checked, when the doses have been imprudently urged so as to occasion sickness."But Withering himself could make no distinction between edema due to failure of the heart and edema due to failure of the kidneys though he was well aware that it exercised "a.power over the motion of the heart;" that was naturally impossible before the days of Hope and of Bright.The ground for the belief in the efficiacy of the drug as a diuretic rested, however, securely on prolonged and detailed observation.Opinion in later years departed from this earlybelief on grounds which, as can be seen now, were scarcely sufficient substitutes for direct experience.Withering's observations were confirmed, and subsequently ex- panded by such observers as Ferriar (1799), K.inglake (1801), and Beddoes (1801) who noted that digitalis slows the pulse and strengthens it.In addition to its action in causing diuresis, another important effect of the drug was noticed.This was described by K.reysig (1814) who conduded that digitalis must contribute something to the energy of the heart, on account of the improve- ment which could be seen following its use.Throughout the century this "some- 1 Use has been made in the survey of excellent papers by A.
Role of Echocardiography in Evaluation of Patients With Staphylococcus aureusBacteremia: Experience in 103 Patients
Authors: Vance G Fowler, Jennifer Li, G.Ralph Corey, Jerry Boley, Kieren A Marr, Ajay K Gopal, Li Kuo Kong, Geoffrey Gottlieb, Carolyn L Donovan, Daniel J Sexton, Thomas Ryan
Journal: Journal of the American College of Cardiology (1997)
Why do you want to be a doctor?
Authors: M. E. Black
Journal: BMJ (2011)

Career day at my daughter’s school in London is cheaper than therapy. I recount my life story to teenagers who listen intently—some even take notes. Succumbing to temptation I soup it up a bit (don’t we all?). Hitchhiking across Alaska in the summer while visiting native health services goes down well, as do my Bosnian war exploits, and the bizarre late night cases as a junior doctor in Dublin. Even though I remind them that 80% of any job is routine, even boring, they go away convinced they …
RNAmotifs: prediction of multivalent RNA motifs that control alternative splicing
Authors: Matteo Cereda, Uberto Pozzoli, Gregor Rot, Peter Juvan, Anthony Schweitzer, Tyson Clark, Jernej Ule
Journal: Genome biology (2014)

Abstract RNA-binding proteins (RBPs) regulate splicing according to position-dependent principles, which can be exploited for analysis of regulatory motifs. Here we present RNAmotifs, a method that evaluates the sequence around differentially regulated alternative exons to identify clusters of short and degenerate sequences, referred to as multivalent RNA motifs. We show that diverse RBPs share basic positional principles, but differ in their propensity to enhance or repress exon inclusion. We assess exons differentially spliced between brain and heart, identifying known and new regulatory motifs, and predict the expression pattern of RBPs that bind these motifs. RNAmotifs is available at https://bitbucket.org/rogrro/rna_motifs .
Optimizing the exercise test for pharmacological investigations.
Authors: J Myers, V F Froelicher
Journal: Circulation (1990)

Exercise trials in cardiology are often hindered by inconsistent approaches to exercise testing. These inconsistencies include the choice of exercise protocol, exercise end points, points of analysis, and absence or misuse of gas exchange data. Gas exchange techniques greatly enhance the accuracy with which cardiopulmonary function is assessed by exercise. Commonly used protocols are not always appropriate for all patients or all studies. Both cardiovascular disease and the exercise protocol can have an important impact on the relation between changes in work rate and oxygen uptake. Ramp protocols appear to offer the greatest promise for assessing cardiopulmonary function. Analyzing hemodynamic and gas exchange responses at several points submaximally, in addition to those at peak exercise, can add important information concerning the efficacy of a drug. A great deal of confusion continues to hinder the application of the gas exchange anaerobic threshold, and many of the commonly used testing end points are not reliable.
Diagnostic Decision: Utility of the Routine Electrocardiogram Before Surgery and on General Hospital Admission: Critical Review and New Guidelines
Authors: ARY L. GOLDBERGER
Journal: Annals of Internal Medicine (1986)

No consensus has been reached regarding the need for a routine 12-lead electrocardiogram (ECG) preoperatively or on general admission in adult patients. Critical review of relevant studies reveals important weaknesses and gaps in the data needed to formulate definitive recommendations. Available data, however, do not support the necessity for obtaining a baseline or screening ECG in all adult patients before surgery involving general or regional anesthesia or on hospital admission for other indications. To reduce costs related to unnecessary tests and false-positive results, routine use of the ECG is warranted only in selected subsets of hospitalized patients, including those with cardiac signs or symptoms and those at risk for occult heart disease, particularly older patients.
Website of the week: Testing intelligence
Authors: T. Richards
Journal: BMJ (2001)

Few children escape having to take some form of intelligence test. How highly they score depends on a myriad of factors including birth weight, a finding confirmed by a study in this week's BMJ (p 310).

The intelligence quotient (IQ) test is well established as a reliable means of assessing mental ability, and a visit to www.iqtest.com provides information about how the test has been derived and what the scores mean. It is also possible to take an IQ test online and be diverted by a tempting link to “amazing (free) techniques” to improve your score.

Being categorised by your IQ may be threatening. This is acknowledged on the route to self testing, which is littered by protective pre-test counselling about the possible adverse effects of finding out how intelligent you are, and the importance of not overinterpreting the test result. “A high IQ,” the visitor is warned, “is not a guarantee that an individual will achieve happiness, maintain sanity, or obtain spiritual growth.” Quite so. And a low IQ? “Does not mean that the individual will be unsuccessful financially, emotionally, or morally.” And the reassurance does not stop there. “Even traditionally exalted groups, such as physicians, can have individuals who would be measured as having only ‘normal’ intelligence.” Who could dispute that?

Moving on a stone's throw via www.searchtheweb.com, you can click on to sites devoted to emotional intelligence, or EQ, which many judge to be as important a parameter as IQ. Further opportunities for self testing are presented, this time of temperament and self esteem.

When the desire for self knowledge has been sated it is worth checking out www.eiconsortium.org. The consortium aims to aid the advancement of research and practice related to the emotional intelligence of organisations. It is based on the eminently believable premise that self awareness, optimism, and empathy increase job satisfaction and productivity. Several august companies are listed as members, although—and there must be a message here—none appears to be related to health care.
ROLE OF CHA2DS2-VASC SCHEMA IN PREDICTION OF THROMBOEMBOLIC RISK IN PATIENT UNDERGOING TRANSESOPHAGEAL ECHO GUIDED CARDIOVERSION
Authors: Hirad Yarmohammadi, Tristan Klosterman, Gaganpreet Grewal, Jeremiah Depta, Rayan Yousefzai, Bruce Lindsay, Kevin Shrestha, Wilson Tang, Allan L. Klein
Journal: Journal of the American College of Cardiology (2011)
Abstract 4312: E3 ligase activity of XIAP RING domain is required for XIAP-mediated cancer cell migration but not for its RhoGDI binding activity
Authors: Yonghui Yu, Jinyi Liu, Dongyun Zhang, Wenjing Luo, Jianxiu Yu, Jingxia Li, Xinhai Zhang, Jingyuan Chen, Chuanshu Huang
Journal: Cancer Research (2012)

Abstract Although an increased expression level of XIAP is associated with cancer cell metastasis in individuals with various types of cancer, the molecular mechanism linking XIAP to cancer metastasis remains unexplored. Here we show that in XIAP depletion HCT116 cells (XIAP−/−), cell migration, invasion and actin polymerization are decreased, which could be rescued either by the introduction of XIAP RING domain or knockdown of RhoGDI. Subsequent studies demonstrate that this function of the XIAP RING domain depends on its inhibition of RhoGDI SUMOylation at K138. Furthermore, SUMO1-RhoGDI, but not un-sumoylated RhoGDI preferentially binds to Rho GTPase and downregulates the activities of GTPases, including RhoA, Cdc42 and Rac1, by which RhoGDI inhibits cancer cellular actin polymerization and motility. Taken together, our study reveals a novel post-translational modification (SUMOylation) of RhoGDI, and its physiological regulation by the RING domain of XIAP, which may account for XIAP modulation of cancer cell motility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4312. doi:1538-7445.AM2012-4312
Might money spent on statins be better spent?
Authors: A. J Jenkins
Journal: BMJ (2003)

EDITOR–As Abbasi argues in his Editor's choice, the benefits of publishing negative findings should be obvious.1

As a general practitioner I wonder how many million pounds sterling the NHS could save if the Medical Research Council, the British Heart Foundation, and the Lancet shared this view. An example is in the prescribing of statins. They are a major cost in my practice, as I am sure they are to many practitioners.

Even in general practice I recognised …
Topical calcitriol - studies on local tolerance and systemic safety
Authors: E. Rizova, M. Corroller
Journal: British Journal of Dermatology (2001)

Calcitriol 3 μg g−1 ointment (Silkis ointment®, Galderma Laboratories) is a new treatment for psoriasis. Calcitriol is the biologically active metabolite of vitamin D3. It induces keratinocyte differentiation, inhibits keratinocyte, T‐cell and fibroblast proliferation, and inhibits the production of some inflammatory mediators, all contributors to the pathogenesis of psoriasis. Preclinical studies have shown an effect of topical calcitriol on calcium homeostasis at doses higher than those in clinical use. No adverse local events were observed when calcitriol was applied to animal skin. Phase I clinical studies confirmed that calcitriol 3 μg g−1 ointment is well tolerated in humans. These studies have demonstrated that at the minimal effective concentration of 3 μg g−1, calcitriol ointment has no discernible photosensitizing or phototoxic potential and no skin irritant or allergic potential in healthy volunteers. Its low systemic absorption through human skin is unlikely to significantly affect calcium homeostasis. This paper summarizes the findings of the preclinical and early clinical studies that provided the foundation of the later Phase II and III clinical trials on efficacy and safety with topical calcitriol 3 μg g−1 ointment for the treatment of plaque psoriasis.
Scotland's liquor licensing changes: an assessment.
Authors: J C Duffy, M A Plant
Journal: BMJ (1986)

The impact of the changes in Scotland9s liquor licensing laws was assessed by comparing trends in alcohol related problems in Scotland with those in England and Wales. The study showed no appreciable effect on the level of alcohol related morbidity and mortality, though some improvements were noted in relation to the rates of convictions for drunkenness. The changes introduced since 1976 appeared to be popular and there was widespread perception that public drunkenness had become less common-place.
Single-center experience of encapsulating peritoneal sclerosis in patients on peritoneal dialysis for end-stage renal failure
Authors: Angela M. Summers, Marc J. Clancy, Fysal Syed, Nicola Harwood, Paul E.C. Brenchley, Titus Augustine, Hany Riad, Alastair J. Hutchison, Paul Taylor, Robert Pearson, Ram Gokal
Journal: Kidney International (2005)
Emerging Human Coronaviruses — Disease Potential and Preparedness
Authors: Larry J. Anderson, Ralph S. Baric
Journal: New England Journal of Medicine (2012)

It is likely that novel zoonotic virus infections causing serious disease and death in humans will increasingly test our ability to respond appropriately. Changes in commercial and social practices, the environment, and travel will continually provide new opportunities for zoonotic pathogens to infect humans. In addition, ever more sophisticated tools to detect novel pathogens will increase the chance that we will identify sporadic infections that do not cause widespread disease. Zaki et al.1 now describe in the Journal the detection of a novel betacoronavirus (called HCoV-EMC) in a patient from Saudi Arabia who died of pneumonia and renal failure in . . .
Effect of Cancer Treatment on Skin Homograft Survival
Authors: John B. Graham, Natalija Petersons
Journal: JAMA (1964)

SOME PATIENTS with advanced cancer tolerate skin homografts longer than normal.<sup>1-2</sup>This is regarded as evidence of an impaired defense mechanism. We thought that perhaps a significant correlation could be found between the skin homograft rejection time and the clinical course of patients with cancer. Accordingly, we routinely applied skin grafts to all patients with primary cervical cancer admitted to the gynecology service. A full-thickness ellipse of skin, 0.6 × 1.0 cm, from another patient was applied to the forearm and held in place with a pressure dressing. The first sign of blanching or cyanosis was regarded as the end of survival. Grafts that survived 15 days or more were classified as prolonged. The frequency ofprolonged survival in various types of patients is indicated in Tables 1 and 2. There were 107 patients who received no cancer treatment before the graft was applied or while it was in
Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E ε2/ε3/ε4 genotype
Authors: Bernard Keavney, Sarah Parish, Alison Palmer, Sarah Clark, Linda Youngman, John Danesh, Colin McKenzie, Marc Delépine, Mark Lathrop, Richard Peto, Rory Collins
Journal: The Lancet (2003)
Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus–induced disease progression
Authors: Alagarraju Muthukumar, Aneta Wozniakowski, Marie-Claire Gauduin, Mirko Paiardini, Harold M. McClure, R. Paul Johnson, Guido Silvestri, Donald L. Sodora
Journal: Blood (2003)
Transdermal modification of platelet function. A dermal aspirin preparation selectively inhibits platelet cyclooxygenase and preserves prostacyclin biosynthesis.
Authors: R M Keimowitz, G Pulvermacher, G Mayo, D J Fitzgerald
Journal: Circulation (1993)

BACKGROUND Even low doses of oral aspirin inhibit prostacyclin (prostaglandin [PG] I2) formation and cause gastrointestinal toxicity. We examined the skin as a novel route for continuous low-dose aspirin administration and selective inhibition of platelet cyclooxygenase in humans. METHODS AND RESULTS Aspirin 250 or 750 mg/d for 10 days induced a dose-dependent inhibition of serum thromboxane (TX) B2. At the highest dose, five of six subjects responded, with a mean reduction in serum TXB2 of 95 +/- 3% (P = .003). Urinary 2,3-dinor TXB2, an index of in vivo TXA2 formation, decreased by 68 +/- 7% and recovered slowly, consistent with inhibition of platelet cyclooxygenase in vivo. In contrast, PGI2 biosynthesis, determined as excretion of 2,3-dinor-6-keto PGF1 alpha, was 81 +/- 5% of baseline at 10 days. Intravenous bradykinin increased PGI2 biosynthesis 5.1 +/- 1.6-fold (n = 4) before aspirin treatment. Oral aspirin 75 mg/d for 14 days abolished bradykinin-induced PGI2 formation, whereas dermal aspirin 750 mg/d had no effect despite similar inhibition of TXA2 biosynthesis. In five subjects, plasma aspirin and salicylate were determined after a single application of 750 mg. Aspirin was absorbed slowly, with peak levels of 0.24 +/- 0.11 micrograms/mL at 3 hours. Salicylate levels peaked at 6 to 12 hours, with plasma levels of 0.79 +/- 0.14 micrograms/mL. CONCLUSIONS Thus, it is possible to achieve selective inhibition of platelet cyclooxygenase by aspirin applied to the skin. This approach may be applicable to other antiplatelet agents and be useful in patients at risk for gastrointestinal bleeding or toxicity.
Kaposi's Sarcoma–Associated Herpesvirus-Encoded Interleukin-6 and G-Protein–Coupled Receptor Regulate Angiopoietin-2 Expression in Lymphatic Endothelial Cells
Authors: Richard J. Vart, Leonid L. Nikitenko, Dimitrios Lagos, Matthew W.B. Trotter, Mark Cannon, Dimitra Bourboulia, Fiona Gratrix, Yasuhiro Takeuchi, Chris Boshoff
Journal: Cancer Research (2007)

Abstract Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma–associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection up-regulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein–coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm. [Cancer Res 2007;67(9):4042–50]
Determination of the size of airborne flour particles
Authors: C. P. Sandiford, M. J. Nieuwenhuijsen, R. D. Tee, A. J. Newman Taylor
Journal: Allergy (1994)

Air sampling was done in a UK bakery and a flour mill with an eight-stage cascade impactor to determine the size of airborne flour particles. The concentration of captured material was determined by a competitive inhibition radioimmunoassay. Comparison of the different sites revealed that 8.79% and 52.14% of the particles in the bakery dough-brake and roll-production areas had a diameter < or = 6.0 microns, respectively, and 19.7% of the particles in the flour mill packing area were of this size. We conclude that in dusty areas up to 20% of the airborne flour particles are of a diameter likely to allow them to be deposited in the bronchial airways and alveoli.
Watching the Doctor
Authors: Albert R. Jonsen
Journal: New England Journal of Medicine (1983)

IN some cultures, it is said, villagers cluster around a healer and a patient, eagerly listening to their conversation and observing their actions. In our culture, with its intensely private ways, we are deprived of this spectator sport. Only persons with certain sorts of licenses or roles or duties are allowed to observe the intimacies of the "doctor–patient relationship." In recent years, certain persons have arranged to watch from a distance. The number of these spectators seems to have grown. They are usually academic people, sociologists, anthropologists, economists, or even philosophers. They do not have a license to look and . . .