tbuckley/cabot-search huggingface dataset:
Scoring of radiographic progression in randomised clinical trials in ankylosing spondylitis: a preference for paired reading order
Authors: A Wanders
Journal: Annals of the Rheumatic Diseases (2004)

To describe the influence of the reading order (chronological v paired) on radiographic scoring results in ankylosing spondylitis. To investigate whether this method is sufficiently sensitive to change because paired reading is requested for establishing drug efficacy in clinical trials.Films obtained from 166 patients (at baseline, 1 year, and 2 years) were scored by one observer, using the modified Stoke Ankylosing Spondylitis Spinal Score. Films were first scored chronologically, and were scored paired 6 months later.Chronological reading showed significantly more progression than paired reading both at 1 year (mean (SD) progression 1.3 (2.6) v 0.5 (2.4) units) and at 2 years (2.1 (3.9) v 1.0 (2.9) units); between-method difference: p<0.001 at 1 year, and p<0.001 at 2 years. After 1 year, progression (>0 units) was found in 35/166 (21%) patients after paired reading and in 55/166 (33%) after chronological reading. After 2 years, these figures were 50/166 (30%) and 68/166 (41%), respectively. Sample size calculations showed that 94 patients in each treatment arm are required in a randomised clinical trial (RCT) to provide sufficient statistical power to detect a difference in 2 year progression if films are scored paired.Reading with chronological time order is more sensitive to change than reading with paired time order, but paired reading is sufficiently sensitive to pick up change with a follow up of 2 years, resulting in an acceptable sample size for RCTs.
Abstract 2914: Creation of a novel biochemical and biophysical assay suite to enable the identification of inhibitors targeting inactive kinases
Authors: Dennis S. France, Chang-Rung Chen, Erika Volckova, Sudharshan Eathiraj, Susan Cornell-Kennon, Li Huang, Denise McSweeney, Jeffrey Szwaya, Rocio Palma, Mark A. Ashwell, Thomas C.k. Chan
Journal: Cancer Research (2012)

Abstract We have recently reported the implementation of a structural biology-based drug design platform for the identification of protein kinase inhibitors which utilize hydrophobic clusters to stabilize the inactive state of a kinase. These clusters are not formed in active kinases and result in the conversion of the ATP binding cleft into a non-polar environment which is sterically and electrostatically incompatible with ATP binding. We have industrialized this approach, designated the ArQule Kinase Inhibitor Platform (AKIPTM), and synthesized a library of more than 15,000 small molecules through the application of an in silico guided process. This has allowed us to rapidly generate leads to a variety of kinases, including receptor tyrosine kinases, non-receptor tyrosine kinases, and serine-threonine kinases. By virtue of their unique binding modes, many of these inhibitors would not be identified in standard assays using highly activated kinases. We have therefore deliberately re-engineered standard biochemical kinase assays using unphosphorylated inactive kinases to aid in the optimization of these inhibitors. In addition to these biochemical assays, we have also implemented a variety of well-established technologies not commonly used early in the hit generation process, including a thermal shift assay (TSA), affinity mass spectrometry, endogenous tryptophan fluorescence detection, an ATP-exclusion assay using a non-hydrolyzable ATP analogue, classical kinetic analysis to assess ATP-dependence and mechanism-of-inhibition, X-ray crystallography, and finally, cross-competition experiments with known inhibitors. Using the cumulative knowledge gained from these technologies throughout the hit generation, hit-to-lead, and lead optimization stages has enabled us to make informed decisions and resulted in identification of many potent ATP-independent inhibitors. The AKIP technology to date has produced at least one clinical candidate, ARQ 092, which potently inhibits AKT with a high degree of selectivity amongst the human kinome. Further examples of the application of these various technologies will be provided for a diverse range of kinases, including c-Met, FGFR, Ack, and TNIK. 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 2914. doi:1538-7445.AM2012-2914
Changes in plasma haptoglobin and alpha-2-macroglobulin in hemophiliacs receiving factor replacement therapy
Authors: Gerald Shulman, James O. Ballard, M. Elaine Eyster
Journal: American Journal of Hematology (1985)

Plasma proteins were studied in 84 patients with hemophilia A, who were receiving factor replacement therapy. Compared with age-matched controls, 63 patients (75%) had subnormal haptoglobin and 58 (69%) had elevated alpha-2-macroglobulin. Causes for depressed haptoglobin were sought by correlating ABO blood types, liver function tests, factor VIII procoagulant levels, and intensity of yearly exposure to clotting factor products. Subnormal haptoglobin levels in chronically transfused patients may relate in part to hemolysis from AB incompatability. However, depressed haptoglobin levels were also found in group O hemophiliacs without other evidence of hemolysis. Most patients lacked evidence of active liver disease, making synthetic deficiency unlikely. There was close correlation between depressed haptoglobin and severity of clotting factor deficiency. The degree of alpha-2-macroglobulin elevation correlated with severity of procoagulant deficiency but not with intensity of clotting factor replacement therapy. Since alpha-2-macroglobulin plays a major role in the catabolism of fibrinogen, elevated levels may represent a compensatory increase in response to exogenous fibrinogen contained in the clotting factor concentrates. Alternatively, since alpha-2-macroglobulin has potent immunosuppressive properties, the elevation may represent a response to transfused alloantigens. Whatever the underlying cause, it is likely the elevations are due to endogenous production rather than to transfusions since clotting factor concentrates contain minimal amounts of alpha-2-macroglobulin.
Histidine supplementation for treatment of anaemia of uraemia.
Authors: M J Blumenkrantz, D J Shapiro, M E Swendseid, J D Kopple
Journal: BMJ (1975)

The effects of supplemental histidine on the anaemia of 16 chronically uraemic patients and 26 patients undergoing maintenance dialysis were assessed. Patients were given either L-histidine 4 g/day or placebo for a mean of 17-5 weeks in a randomized double-blind controlled study. Haemoglobin and packed cell volume increased slightly and to a similar degree in the patients on dialysis receiving placebo and histidine, but this change was statistically significant only in those on placebo. Plasma histidine rose significantly in the histidine-treated patients undergoing dialysis and decreased in the uraemic patients receiving placebo. These results suggest that supplementary L-histidine in patients with uraemia or patients undergoing maintenance dialysis does not improve anaemia.
Better Baby Burping
Authors: Julian P. Price
Journal: JAMA (1965)

<h3>To the Editor:—</h3> The Editor ofThe Journalis an internist. The lead editorial in the Nov 9 issue deals with baby burping—strictly a pediatric problem. What goes? When will these lesser-educated internists quit trying to horn in on the problems of their better-educated colleagues? If they must deal with burping, let them deal with their own beerdrinking patients. Let not their dirty hands touch or molest the birth bubble of air that lies in the bulging midsection of the innocent babe.
Oesophagus Bezoar Diagnosed and Removed Endoscopically
Authors: I. Szántó;, J. Kiss
Journal: Endoscopy (1976)

The authors describe the rare case of bezoar in the oesophagus. Their patient was sent to their Clinics with a diagnosed oesophageal tumor. The exact diagnosis was established by endoscopical examination. The bezoar was removed by endoscope, therefore, an operation was not necessary.
Effect of Continuous Glucose Infusion on the Glucose-6-Phosphatase Activity of the Liver in Rats
Authors: R. D. Hawkins, M. A. Ashworth, H. Sghaghter, R. E. Haist
Journal: New England Journal of Medicine (1959)

ASHMORE, Hastings and Nesbett1 reported that the glucose-6-phosphatase activity of the liver is elevated in the diabetic animal and that the administration of insulin to diabetic rats causes the elevated level of glucose-6-phosphatase activity in the liver to return to normal. Langdon and Weakley2 found that the injection of insulin into alloxan-diabetic rats twelve hours before death resulted in a return of liver glucose-6-phosphatase activity to normal levels. Ashmore et al.3 reported that the injection of insulin into normal rats caused a decrease in the glucose-6-phosphatase of the liver. Harper4 concluded from his study of the effect of hormonal treatment . . .
Adaptive Tolerance to Pulmonary Oxygen Toxicity After Hypoxia or Intermittent Hyperoxia.
Authors: E. Finder
Journal: Annals of Internal Medicine (1973)

Meeting Abstracts1 May 1973Adaptive Tolerance to Pulmonary Oxygen Toxicity After Hypoxia or Intermittent Hyperoxia.E. Finder, G. Simons, R.N., G. Huber, M.D.E. FinderSearch for more papers by this author, G. Simons, R.N.Search for more papers by this author, G. Huber, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-78-5-832_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTherapeutic use of oxygen at toxic concentrations is often essential in managing acute and chronic respiratory failure. The following experiments on administration of 100% oxygen [1] define a progressive, dose-dependent toxicity for pulmonary structure and function after continuous exposure to oxygen, [2] demonstrate complete prevention of these toxic manifestations if an equivalent toxic dose is given by intermittent rather than continuous exposure, and [3] introduce a concept of "oxygen tolerance" in which toxic manifestations of continuous exposure are markedly reduced in animals first adapted either on an intermittent basis to a high oxygen environment (Po2, 700 mm Hg) or continuously... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Massachusetts PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1973Volume 78, Issue 5Page: 832-832KeywordsAttentionHypoxiaOxygenPartial pressure of oxygenPulmonary functionRespiratory failureToxicity Issue Published: 1 May 1973 PDF downloadLoading ...
Scintigraphic Diagnosis of Prostaglandin Induced Periostitis
Authors: DENNIS W. WULFECK, TERRY E. WILLIAMS, STEVEN EBERLY
Journal: Clinical Nuclear Medicine (1995)

A 3-month-old infant with a history of meconium aspiration, coarctation, patent ductus arteriosus, mitral stenosis, aortic stenosis, pulmonary hypertension, and status post extra-corporeal membrane oxygenation is presented. The patient underwent 33 days of prostaglandin therapy. In view of the infant's critical state and positive urine culture for Candida alblcans, a screen for infection was performed with Ga-67 citrate.
Blood Alcohol Levels after Prolonged Use of Histamine-2-Receptor Antagonists
Authors: Alessandro Casini
Journal: Annals of Internal Medicine (1994)

Letters1 July 1994Blood Alcohol Levels after Prolonged Use of Histamine-2-Receptor AntagonistsAlessandro Casini, MD, Francesco Mari, PhD, and Calogero Surrenti, MDAlessandro Casini, MDUniversita di Firenze; Firenze; ItalySearch for more papers by this author, Francesco Mari, PhDUniversita di Firenze; Firenze; ItalySearch for more papers by this author, and Calogero Surrenti, MDUniversita di Firenze; Firenze; ItalySearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-121-1-199407010-00020 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Our in vivo study results do not negate the in vitro evidence but rather show that the potential inhibition of gastric alcohol dehydrogenase by H2-receptor antagonists has no effect on the systemic bioavailability of ethanol when used clinically. We found no difference in measured gastric alcohol dehydrogenase activity in patients before and after treatment. An important characteristic of our study was the demonstration of a significant first-pass metabolism of ethanol (53%) in all patients before entering the study. We can assume that differences in the area-under-the-curve reflect differences in first-pass metabolism of ethanol, and it is difficult to ...References1. Fraser AG, Hudson M, Sawyerr AM, Smith MS, Sercombe J, Rosalki SB, et al. Ranitidine has no effect on postbreakfast ethanol absorption. Am J Gastroenterol. 1993; 88:217-21. Google Scholar2. Raufman JP, Notar-Francesco V, Raffaniello RD, Straus EW. Histamine-2 receptor antagonists do not alter serum ethanol levels in fed, nonalcoholic men. Ann Intern Med. 1993; 118:488-94. Google Scholar3. Dauncey H, Chesher GB, Palmer RH. Cimetidine and ranitidine. Lack of effect on the pharmacokinetics of an acute ethanol dose. J Clin Gastroenterol. 1993; 17:189-94. Google Scholar4. Smith T, DeMaster EG, Furne JK, Springfield J, Levitt MD. First-pass gastric mucosal metabolism of ethanol is negligible in the rat. J Clin Invest. 1992; 89:1801-6. Google Scholar5. Levitt MD. Lack of clinical significance of the interaction between H2-receptor antagonists and ethanol. Aliment Pharmacol Ther. 1993; 7:131-8. Google Scholar Author, Article, and Disclosure InformationAffiliations: Universita di Firenze; Firenze; Italy PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 July 1994Volume 121, Issue 1Page: 73-74KeywordsAlcoholsBloodBlood alcohol concentrationDehydrogenasesDrug metabolismDrugsEthanolMental functioning ePublished: 15 August 2000 Issue Published: 1 July 1994 Copyright & PermissionsCopyright © 1994 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Cardiac complications observed in elderly patients following 2′‐deoxycoformycin therapy
Authors: Jean L. Grem, Susan A. King, Hoo G. Chun, Michael R. Grever
Journal: American Journal of Hematology (1991)

Abstract Deoxycoformycin (dCF) is an investigational nucleoside with significant activity in hairy cell leukemia, cutaneous T‐cell lymphoma, and chronic lymphocytic leukemia. During a 4‐year period, 11 patients have experienced cardiac events as a complication of dCF therapy under NCI sponsorship. The cases are presented and recommendations for the administration of dCF to patients with pre‐existing heart disease are made.
Overexpressed A <sub>1</sub> Adenosine Receptors Reduce Activation of Acetylcholine-Sensitive K <sup>+</sup> Current by Native Muscarinic M <sub>2</sub> Receptors in Rat Atrial Myocytes
Authors: Marie-Cécile Wellner-Kienitz, Kirsten Bender, Thomas Meyer, Moritz Bünemann, Lutz Pott
Journal: Circulation Research (2000)

Abstract —In adult rat atrial myocytes, muscarinic acetylcholine (ACh)-sensitive K + current activated by a saturating concentration of adenosine ( I K(ACh),(Ado) ) via A 1 receptors (A 1 Rs) amounts to only 30% of the current activated by a saturating concentration of ACh ( I K(ACh),(ACh) ) via muscarinic M 2 receptors. The half-time of activation of I K(ACh),(Ado) on a rapid exposure to agonist was ≈4-fold longer than that of I K(ACh),(ACh) . Furthermore, I K(ACh),(Ado) never showed fast desensitization. To study the importance of receptor density for A 1 R- I K(ACh),(Ado) signaling, adult atrial myocytes in vitro were transfected with cDNA encoding for rat brain A 1 R and enhanced green fluorescent protein (EGFP) as a reporter. Whole-cell current was measured on days 3 and 4 after transfection. Time-matched cells transfected with only the EGFP vector served as controls. In ≈30% of EGFP-positive cells (group I), the density of I K(ACh),(Ado) was increased by 72%, and its half-time of activation was reduced. Density and kinetic properties of I K(ACh),(ACh) were not affected in this fraction. In ≈70% of transfection-positive myocytes (group II), the density of I K(ACh),(ACh) was significantly reduced, its activation was slowed, and the fast desensitizing component was lost. Adenosine-induced currents were larger in group II than in group I, their activation rate was further increased, and a fast desensitizing component developed. These data indicate that in native myocytes the amplitude and activation kinetics of I K(ACh),(Ado) are limited by the expression of A 1 R. Overexpression of A 1 R negatively interferes with signal transduction via the muscarinic M 2 receptor–linked pathway, which might reflect a competition of receptors with a common pool of G proteins. Negative interference of an overexpressed receptor with physiological regulation of a target protein by a different receptor should be considered in attempts to use receptor overexpression for gene therapy.
A sunshine act for Europe
Authors: F. Godlee
Journal: BMJ (2011)

We have developed a mouse model in which a specific population of inhibitory neurons can be selectively ablated by the action of diphtheria toxin (DT). The model involves targeting the human DT receptor to the agouti-related protein (<i>Agrp</i>) locus so that systemic administration of DT kills all of the AgRP-expressing neurons, resulting in starvation of the mice. Ablation of AgRP neurons results in robust (5- to 10-fold) activation of <i>Fos</i> gene expression in many brain regions that are innervated by AgRP neurons, including the arcuate nucleus (ARC), the paraventricular nucleus, the medial preoptic area, the lateral septum, and nucleus of the solitary tract. As expected, there is robust increase in GFAP staining (astrocytes) as well as IBA1 and CD11b staining (microglia) in the ARC in response to AgRP neuron ablation. There is also a dramatic increase of these markers in most, but not all, postsynaptic targets of AgRP axons. We used a genetic approach to reduce melanocortin signaling, which attenuated <i>Fos</i> activation in some brain regions after ablation of AgRP neurons. We suggest that loss of inhibitory signaling onto target neurons results in unopposed excitation that is responsible for the activation of <i>Fos</i> and that dysregulation of these neuronal circuits is responsible for starvation. Furthermore, glial cell activation in target areas of AgRP neurons appears to be a result of excitotoxicity.
William Dawson Catto
Authors: Graeme Catto
Journal: BMJ (2006)

​FormerFormer general practitioner Aberdeen (b 1913; q Aberdeen 1939), died from a severe stroke on 4 December 2005. After serving with the Royal Army Medical Corps in India and the Middle East during the second world war, Bill Catto became a general practitioner in the Woodside district of Aberdeen, where he lived in the practice house for 20 years. A great sportsman in his youth he became an enthusiastic if modest golfer and was the club doctor when the local football team won the European Cup in 1983. He leaves a son and two grandchildren.



Figure 1
Mbeki forced to do a U turn over AIDS drugs
Authors: P. Sidley
Journal: BMJ (2002)

The South African government has, under pressure, relented on its HIV/AIDS policy and will supply certain antiretroviral drugs under specific and limited circumstances.

The policy shift follows a resurgence in the eccentric policies inspired by President Thabo Mbeki's doubts about the link between HIV and AIDS.

After a cabinet meeting a week ago, the government decided that it will put in place a national plan to supply nevirapine to HIV positive pregnant women and their babies to reduce the risk of transmission of the virus to the babies. Women who have been raped will also benefit from the shift in policy as all state hospitals will be able to offer …
5α-Reductase Inhibitors and Risk of High-Grade or Lethal Prostate Cancer
Authors: Mark A. Preston, Kathryn M. Wilson, Sarah C. Markt, Rongbin Ge, Christopher Morash, Meir J. Stampfer, Massimo Loda, Edward Giovannucci, Lorelei A. Mucci, Aria F. Olumi
Journal: JAMA Internal Medicine (2014)

5α-Reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear.To determine the association between 5ARI use and development of high-grade or lethal prostate cancer.Prospective observational study of 38,058 men followed up for prostate cancer diagnosis and outcomes between 1996 and 2010 in the Health Professionals Follow-up Study.Use of 5ARIs between 1996 and 2010.Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing.During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high grade (Gleason sum [GS] 8-10), 1238 were GS 7, and 1600 were low grade (GS 2-6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (hazard ratio [HR], 0.77; 95% CI, 0.65-0.91). 5ARI users had a reduced risk of GS 7 (HR, 0.67; 95% CI, 0.49-0.91) and low-grade (GS 2-6) prostate cancer (HR, 0.74; 95% CI, 0.57-0.95). 5ARI use was not associated with risk of high-grade (GS 8-10) prostate cancer (HR, 0.97; 95% CI, 0.64-1.46) or lethal disease (HR, 0.99; 95% CI, 0.58-1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use, 0.95; 95% CI, 0.92-0.99), localized (HR, 0.95; 95% CI, 0.90-1.00), and low-grade disease (HR, 0.92; 95% CI, 0.85-0.99). There was no association for lethal, high-grade, or grade 7 disease.While 5ARI use was not associated with developing high-grade or lethal prostate cancer, it was associated with a reduction in low-grade, GS 7, and overall prostate cancer. Because the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use.
Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study
Authors: J Kuusisto, K Koivisto, K Kervinen, L Mykkanen, E-L Helkala, M Vanhanen, T Hanninen, K Pyorala, Y A Kesaniemi, P Riekkinen, M Laasko
Journal: BMJ (1994)

<h3>Abstract</h3> <b>Objective</b>: To determine the association between the e4 allele of apolipoprotein E and Alzheimer9s disease in a randomly selected population sample. <b>Design</b>: Cross sectional population based study. <b>Subjects</b>: 980 people aged 69 to 78 (349 men, 631 women). <b>Setting</b>: Population of Kuopio, eastern Finland. <b>Main outcome measures</b>: Presence of e4 allele and diagnosis of Alzheimer9s disease by detailed neurological and neurophysiological evaluation. <b>Results</b>: 46 (4.7%) subjects were classified as having probable or possible Alzheimer9s disease. The frequency of the apolipoprotein E e4 allele was 0.359 in patients with Alzheimer9s disease and 0.165 in subjects without dementia (P&lt;0.0001). The prevalence of Alzheimer9s disease was 2.9% in subjects with no e4 alleles, 7.6% in subjects with one e4 allele, and 21.4% in subjects with two e4 alleles of apolipoprotein E. <b>Conclusions</b>: Allele e4 of apolipoprotein is associated with Alzheimer9s disease in a dose-response fashion in a randomly selected elderly population.