tbuckley/cabot-search huggingface dataset:
Nucleotide sequence variations in the internal ribosome entry site of hepatitis C virus-1b: No association with efficacy of interferon therapy or serum HCV-RNA levels
Authors: C Yamamoto, N Enomoto, M Kurosaki, S Yu, J Tazawa, N Izumi, F Marumo, C Sato
Journal: Hepatology (1997)

The extreme 5'-proximal sequences of the hepatitis C virus (HCV) genome including the 5'untranslated region (5'UTR) and the first 30 nucleotides of the core region are highly conserved, and serve as an internal ribosome entry site (IRES) that initiates the cap-independent translation of HCV polyprotein. Mutations in the IRES sequence have been shown to cause changes in the efficiency of protein translation in vitro. However, the significance of genetic variations in the IRES is not fully known in clinical settings. Pretreatment sera of 25 patients with HCV-1b infection who were treated with interferon were amplified by polymerase chain reaction (PCR), and the IRES sequence was directly sequenced. Correlation of interferon responses or other clinical features with IRES sequence variability was studied. Eleven of 25 patients were sustained responders (SR) of interferon treatment (negative serum HCV RNA and normal alanine transaminase levels for 6 months after the end of interferon treatment), and the other 14 patients were nonresponders ([NR], defined as any patient with positive serum HCV RNA within 6 months after the end of interferon therapy). In each patient, one to four nucleotide substitutions were found compared with the consensus sequence of HCV-1b genotype. There were no differences in the number of nucleotide substitutions between either SR and NR (mean, 1.8 in SR, 2.1 in NR; P = .30), and no specific variations associated with SR or NR were observed. Although NR had significantly higher serum levels of pretreatment HCV RNA than SR (median, 16 vs. <0.5 Meq/mL; P = .02), there was no correlation between the HCV-RNA level and the number of nucleotide substitutions in the IRES (mean, 1.9 nucleotide substitutions in 12 patients with HCV RNA <0.5 Meq/ mL vs. 2.1 nucleotide substitutions in 13 patients with HCV RNA >0.5 Meq/mL; P = .61). Sequence variability of the IRES has no influence on interferon efficacy or serum HCV-RNA concentrations in patients with chronic HCV-1b infection.
Outcome After Conservative Management or Intervention for Unruptured Brain Arteriovenous Malformations
Authors: Rustam Al-Shahi Salman, Philip M. White, Carl E. Counsell, Johann du Plessis, Janneke van Beijnum, Colin B. Josephson, Tim Wilkinson, Catherine J. Wedderburn, Zoe Chandy, E. Jerome St. George, Robin J. Sellar, Charles P. Warlow
Journal: JAMA (2014)

<h3>Importance</h3> Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data. <h3>Objective</h3> To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. <h3>Design, Setting, and Population</h3> Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years. <h3>Exposures</h3> Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination). <h3>Main Outcomes and Measures</h3> Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention). <h3>Results</h3> Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events; 9.5 vs 9.8 per 100 person-years; adjusted hazard ratio, 0.59; 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events; 1.6 vs 3.3 per 100 person-years; adjusted hazard ratio, 0.37; 95% CI, 0.19-0.72). <h3>Conclusions and Relevance</h3> Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.
Gallstone Size and the Risk of Gallbladder Cancer-Reply
Authors: Andrew K. Diehl
Journal: JAMA (1984)

<h3>In Reply.—</h3> Trevino and Carter appropriately emphasize the importance of identifying "Hispanics" by national origin. The determination of Hispanic ethnicity is a complex and difficult task.<sup>1</sup>Data for this study were obtained from the review of hospital records. Ethnicity determination was based on a global assessment of information available in the chart, including descriptions of patient ethnicity by physicians and clerical staff as well as patient surname. Although this method of ethnicity assessment has not been validated, it appears to be largely accurate for the population living in south Texas. Furthermore, the 1980 census found that 92.6% of persons of "Spanish origin" in the San Antonio standard metropolitan statistical area were of Mexican descent.<sup>2</sup>Hence, the designation of patients in this study as Mexican-American can be accepted with reasonable confidence. Of the 29 persons included in this study who were born in Latin America, 27 were born in
Chronic Aortoiliac Thrombosis
Authors: Richard Beckwith, Elston R. Huffman, B. Eiseman, S. Gilbert Blount
Journal: New England Journal of Medicine (1958)

THE syndrome of chronic aortoiliac thrombosis is common. This fact has been recognized and reported with increasing frequency during recent years. The classic description of this disease provided by Leriche1 , 2 in 1940 resulted in frequent reference to the entity as the Leriche syndrome. As described by Leriche1 2 3 the typical symptom complex occurred in men in the third to sixth decades of life. Fatigue and weakness of the legs and inability to maintain a penile erection were emphasized as common complaints. Physical findings included absence of arterial pulses in the lower limbs, atrophy, pallor and absence of trophic changes. During the . . .
Dr Pod's Healthcast
Authors: Graham Easton
Journal: BMJ (2006)

P odcasting is all the rage at the moment, and it has the potential to become a faithful friend to the busy doctor. A podcast is really a radio programme, but instead of being broadcast over the airwaves at a set time and then lost in the ether, you can download it on to your computer or your personal iPod to listen to when and where you want.

There are now podcasts for all sorts of folk from car enthusiasts to sporting gamblers, but doctors more than most have good reason to tap into the new technology. Imagine being able to keep up to date as you drive to work, cycle to your house visits, or slurp a quick coffee in front of your computer. No wonder medical podcasts are springing up left right and centre; for example, the New England Journal of Medicine and the Journal of the American Medical Association already have regular audio …
Ian Michael Elliott
Authors: H. MacNab, J. Hillman, D. Hickson
Journal: BMJ (2001)

General practitioner Bridlington (b 1959; q Newcastle 1983), died suddenly on 20 July 2001 from a myocardial infarction while on call for his patients.

After qualifying, he did house jobs at the Freeman Hospital, Newcastle, and Middlesbrough General. He came to Bridlington in 1987. He developed an interest in dermatology and was the clinical assistant at the local hospital. He was a school governor and active in his local church. His main joy was taking his wife and children on cycle rides and country walks. In the last year of his life, he had started to learn the saxophone. He leaves a wife, Karen; and four children.
Do we need new antiarrhythmic compounds in the era of implantable cardiac devices and percutaneous ablation?
Authors: T CHRIST, U RAVENS
Journal: Cardiovascular Research (2005)

The past two decades have witnessed a major breakthrough in the treatment of cardiac arrhythmias. Owing to technical perfection of implantable cardioverter defibrillators (ICD), antitachycardic pacing (ATP), and radiofrequency catheter ablation, today's treatment of cardiac arrhythmias has reached an unprecedented level of efficacy and safety. At the same time, the use of antiarrhythmic drugs has declined because of their low efficacy and proarrhythmic potential.

Do we actually need new antiarrhythmic compounds in the era of ICDs and percutaneous ablation? If the answer is yes, many additional questions come up: Which pharmacological targets should be modified? Are we merely looking for greater efficacy and safety in conventional antiarrhythmic principles [1] or do we need conceptually new approaches? Clearly, the therapeutic goals and the methods by which they are achieved differ in ventricular and in atrial tachyarrhythmias (Fig. 1).



Fig. 1 
Schematic presentation of the relative importance (indicated by the size of the circles) of the therapeutic options for conversion of ventricular (VT/VF) and atrial (AF) tachyarrhythmias. While the use of an implantable cardioverter defibrillator (ICD) is unquestionably the therapy of choice for life-threatening ventricular tachyarrhythmias, its combination with ablation, antitachycardic pacing (ATP), and drugs may represent options for reducing the number of delivered shocks. Since atrial arrhythmia does not impose an acute threat to survival, atrial ICDs, though effective, are not acceptable. Therefore, conversion of this arrhythmia is the mainstay for drug therapy or ablation. ATP has been tried but appears to be ineffective.



Unless ventricular fibrillation (VF) is effectively terminated, death occurs within a few minutes. Therefore, ICDs are the mainstay among the therapeutic options for ventricular tachyarrhythmias (see Fig. 1). The ICD reduces mortality in patients who have survived a potentially life-threatening arrhythmia but also produces a clear survival benefit when used as primary prevention for sudden cardiac death …
THE BINDING OF MYOGLOBIN BY PLASMA PROTEIN
Authors: Willoughby Lathem
Journal: The Journal of Experimental Medicine (1960)

When added to dog plasma in vitro and in vivo, myoglobin was bound to plasma protein in a concentration which, maximally, averaged 21 +/- 6 mg. per cent. Electrophoretically, bound myoglobin was separated from free myoglobin and migrated between alpha-2 and beta globulin. The electrophoretic characteristics of protein-bound myoglobin were similar to, although not identical with, those of protein-bound hemoglobin. The maximal binding capacity of plasma for myoglobin was less than for hemoglobin, which averaged 123 mg. per cent. At concentrations below the maximal binding capacity, from 15 to 50 per cent of the myoglobin was in the free, unbound state, differing from hemoglobin which was completely bound at all concentrations below the binding capacity. When myoglobin and hemoglobin were added together to plasma, hemoglobin appeared to interfere with the binding of myoglobin or to replace it at the binding sites. Myoglobin, however, did not appear to interfere with the binding of hemoglobin. These observations suggested that myoglobin and hemoglobin were bound at least in part by the same protein. When myoglobin was given intravenously, free myoglobin was excreted in the urine, whereas protein-bound myoglobin was not excreted. This suggests that protein-binding contributes to or determines the apparent renal threshold to myoglobin.
Large trials, new knowledge: the changing face of COPD management
Authors: Anthony De Soyza, Peter M.A. Calverley
Journal: European Respiratory Journal (2015)

Large, well-designed, drug-treatment trials have allowed useful advances to be made in the treatment and diagnosis of chronic obstructive pulmonary disease (COPD). The two main clinical trial designs that provide evidence of effectiveness are randomised controlled trials (RCTs) and observational studies. RCTs are generally considered to provide more robust evidence than that obtained from observational studies and can generate informative secondary analyses in addition to the primary research query. In COPD, however, well-designed comparator-controlled RCTs, although successful, have been shown to have some limitations, such as a lack of generalisability. The findings of observational studies, whilst prone to bias, can generate valuable data and have also provided useful information relating to the efficacy of treatments in the current COPD management guidelines. This review focuses on major COPD studies published since 2007 (including UPLIFT, TIOSPIR, ECLIPSE and COPDGene), and assesses the influence such RCTs and large observational studies have had on our knowledge of COPD, and how these may impact future trial designs.
Newcastle Disease Virus as an Antineoplastic Agent: Induction of Tumor Necrosis Factor- and Augmentation of Its Cytotoxicity2
Authors: R. M. Lorence, P. A. Rood, K. W. Kelley
Journal: JNCI Journal of the National Cancer Institute (1988)

The oncolytic strain 73-T of Newcastle disease virus (NDV) has been reported to be beneficial in the treatment of cancer patients, but little is known about its mechanism of action. In this study, NDV strain 73-T and a wild-type isolate of NDV were found to be potent inducers of tumor necrosis factor (TNF) production by both human peripheral blood mononuclear cells (PBMCs) and rat splenocytes. Antibody inhibition experiments identified TNF-α as the major species of TNF induced by NDV in PBMCs. The effect of recombinant human TNF-α (rHuTNF-α) on human cancer cells was then examined. Neither rHuTNF-α nor supernatants from NDV-stimulated PBMCs were cytotoxic toward the TNF-resistant human malignant melanoma cell line MEL-14. However, when MEL-14 cells were treated with NDV strain 73-T, both rHuTNF-α and supernatants from NDV-stimulated PBMCs killed 48% and 55%, respectively, of these tumor cells. Treatment with NDV also conferred TNF susceptibility to the TNF-resistant human malignant melanoma cell line MEL-21 and the human myelogenous leukemia cell line K562. In contrast to its enhanced cytotoxicity toward NDV-treated cancer cells, rHuTNF-α had no effect on NDV-treated normal human PBMCs proliferating in response to concanavalin A. These results suggest two important mechanisms for the antineoplastic activity of NDV: (a) induction of TNF-α secretion by human PBMCs and (b) enhancement of the sensitivity of neoplastic cells to the cytolytic effects of TNF-α.
Significance of coronary arterial thrombus in transmural acute myocardial infarction. A study of 54 necropsy patients.
Authors: F C Brosius, W C Roberts
Journal: Circulation (1981)

In 54 necropsy patients with transmural acute myocardial infarction (AMI) and coronary arterial thrombi, histologic sections of coronary arteries that contained the thrombi were examined by video-planimetry to determine if the amount of luminal narrowing caused by thrombi was comparable to that produced by underlying atherosclerotic plaques, and to determine the amount of luminal narrowing by plaques immediately proximal and distal to the thrombi. The 54 coronary arteries in the 54 patients were narrowed 33-98% (mean 81%) by atherosclerotic plaque alone in cross-sectional area at the site of the thrombus (occlusive in 47 and nonocclusive in seven), from 26-98% (mean 75%) within the 2-cm segment proximal to the thrombus, and from 43-98% (mean 79%) within the 2-cm segment distal to the thrombus. Of the 54 arteries, 52 (96%) were narrowed 76-98% in cross-sectional area by atherosclerotic plaque alone at or immediately proximal or distal to the thrombus and 26 (48%) were narrowed 91-98% by plaque alone. The thrombi were 0.1--6.0 mm2 (mean 1.4 mm2) in cross-sectional area and the underlying atherosclerotic plaques were 3.0-21.0 mm2 (mean 8.7 mm2). Thus, among necropsy patients with transmural AMI, coronary thrombi occur at sites already severely narrowed by atherosclerotic plaques.
Receptor-mediated phagocytosis in human neutrophils is associated with increased formation of inositol phosphates and diacylglycerol. Elevation in cytosolic free calcium and formation of inositol phosphates can be dissociated from accumulation of diacylglycerol.
Authors: M Fällman, D P Lew, O Stendahl, T Andersson
Journal: Journal of Clinical Investigation (1989)

Phagocytosis of C3bi- or IgG-opsonized yeast particles in human neutrophils was found to be associated with an increased formation of inositol phosphates and diacylglycerol. Pertussis toxin only marginally affected phagocytosis of IgG- and C3bi-opsonized particles and the associated formation of second messengers. Forskolin, which induced a threefold rise of cellular cAMP, however, markedly inhibited both C3bi- and IgG-mediated phagocytosis as well as the particle-induced formation of inositol phosphates and diacylglycerol. These observations are in contrast to what was found to occur with chemotactic factors and indicate that chemotactic and phagocytic signaling can be regulated independently in human neutrophils. Since C3bi-mediated phagocytosis has been shown to occur at vanishingly low cytosolic free calcium levels, calcium-depleted cells were used to study the importance of the inositol cycle for the engulfment of C3bi-opsonized particles. Despite a total lack of receptor-induced formation of inositol phosphates, a significantly increased accumulation of diacylglycerol accompanied the ingestion of C3bi-opsonized particles. These data show that the engulfment of C3bi-opsonized particles can occur independently of both a calcium transient and an increased inositol phosphate production. However, the observed accumulation of diacylglycerol, not derived from phosphoinositides, suggests that this second messenger play a role in the control of the engulfment process.
Myasthenia Gravis and Penicillamine Therapy of Rheumatoid Arthritis
Authors: Tomas Bocanegra
Journal: JAMA (1980)

IN RECENT years, penicillamine has become an important drug in the treatment of patients with rheumatoid arthritis. Unfortunately, in approximately 35% of these individuals, severe side effects will develop, requiring withdrawal of the drug therapy.<sup>1</sup> Cutaneous, renal, and hematologic abnormalities are the most commonly recognized untoward effects. Recently, myasthenia gravis associated with penicillamine treatment has been reported.<sup>2</sup>A clear temporal relationship suggestive of a drug-induced effect between this neuromuscular syndrome and the administration of penicillamine and the resolution of symptoms after withdrawal of the drug therapy have been observed in most patients. In this report, we describe a patient whose myasthenic symptoms resolved after discontinuation of the drug treatment but spontaneously recurred six months later. We also discuss the possible mechanisms of penicillamine-induced myasthenia gravis. <h3>Report of a Case</h3> Rheumatoid arthritis developed in a 54-year-old man in 1972. He did well while receiving aspirin until March 1978, when
Abstract 4888: Decitabine and vorinostat cooperate to sensitize metastatic human colon carcinoma cells to Fas-mediated apoptosis
Authors: Christina M. Torres, Dafeng Yang, Mary Zimmerman, Kankana Bardhan, Kebin Liu
Journal: Cancer Research (2012)

Abstract The death receptor Fas and its physiological ligand, FasL, which is expressed on the surface of cytotoxic T-cells (CTLs), regulate apoptosis of cancerous cells. While normal colon epithelial cells express high levels of Fas, Fas expression is diminished in colon carcinomas. Metastatic colon cancers acquire an apopotosis-resistant phenotype often due to the loss of Fas expression and function. Previous studies have implicated Fas-mediated apoptosis as an important contributor of tumor regression. Therefore, targeting Fas resistance is of critical importance in treating colon cancer through Fas-based cancer therapy and immunotherapy. In this study, we explore whether epigenetic pharmacological agents can restore Fas expression and re-establish sensitivity to Fas-mediated apoptosis in metastatic human colon carcinoma cells. First we determined that the epigenetic drugs Decitabine, a DNA methyltransferase inhibitor, and Vorinostat, a HDAC inhibitor, each are capable of up-regulating Fas expression. When combined, these two inhibitors cooperate to increase Fas expression to an even greater extent than each agent alone. Pre-treatment with decitabine, vorinostat, or both drugs followed by incubation with FasL, was able to overcome resistance to FasL-induced apoptosis. Analysis of bisulfite-modified genomic DNA, isolated from human metastatic colon carcinoma cells revealed that the Fas promoter is sporadically methylated; therefore sensitization of Fas receptor expression on the cell surface by decitabine was unlikely through direct inhibition of Fas promoter meythlation. Although the Fas promoter was not heavily methylated, the promoters for BNIP3 and Bik, which are downstream of Fas signaling, were methylated. After treatment with these pharmacological epigenetic inhibitors, alone or in combination, protein levels of both BNIP3 and Bik were increased. Our data suggest that combined modalities of chemotherapy and Fas-based immunotherapy may be an effective approach for the suppression of colon cancer metastasis. 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 4888. doi:1538-7445.AM2012-4888
UK government consults on health research funding
Authors: Susan Mayor
Journal: BMJ (2006)

The UK government is exploring how best to administer a new single, ring fenced fund for health research, through a public consultation launched last week

The review will advise on the best design and institutional arrangements for the new funding system, which was announced in last month's budget. The new arrangement proposes merging the previously separate funding of the Medical Research Council (MRC) and the NHS research and development programme ( BMJ 2006;332:994, 29 Apr). Comments are invited from all those involved in health research in the United Kingdom.

Announcing the review's remit, the Treasury said that funding …
Paediatric Neurology for the Clinician
Authors: Charles M. Poser
Journal: JAMA (1977)

The author, obviously a clinician of wide and mature experience, has managed to compress in 280 pages an extraordinary wealth of information characterized by practicality and common sense. He is writing for the pediatrician who is now going to practice pediatric neurology himself, or at least, this is what the author sets out to do. On the whole he has achieved this goal with resounding success: indeed, the book is not only comprehensive, it is elegant in its organization and its language. This is, however, not a book to be skimmed; it must be read with great care to appreciate the dozens of clinical pearls that abound on nearly every page! The first chapters, dealing with the neurological examination, presenting signs and symptoms, disorders of mental development, specific disorders of learning, and disorders and diseases of the motor system, are particularly useful. The chapter on epilepsy is the only one