tbuckley/cabot-search huggingface dataset:
Abstract 4784: Selective bioluminogenic HDAC activity assays for profiling HDAC inhibitors
Authors: Kevin R. Kupcho, Nathan J. Evans, Andrew L. Niles, Thomas A. Kirkland, Dan F. Lazar
Journal: Cancer Research (2014)

Abstract Histone deacetylases (HDACs) play critical roles in the regulation of gene transcription and cell signaling events by deacetylating histones and other important non-histone substrates. Aberrant increases in HDAC enzyme activities are therefore implicated in a number of human infirmities, including cancers, metabolic disease and neurodegeneration. Fortunately, HDAC enzymes represent attractive pharmacological targets because they are readily tractable with small molecule inhibitors. In fact, several HDAC inhibitors (HDACi) have recently proceeded through (or are near) the FDA approval process for the treatment of hematologic malignancies. However, the promise of clinical HDACi therapy has been hampered by significant dose-limiting toxicities. These off-target effects have led to a renewed focus on basic HDAC biology and the development of isoenzyme-specific HDAC inhibitors which could avoid off-target effects. To help facilitate the discovery of compounds with better defined selectivity profiles, we have developed lysine deacetylase assays that selectively measure specific isoenzyme activities in cells, extracts, or purified recombinant preparations. These assays are based on substrates that are selective due to a combination of extended peptide sequence and novel chemical modifications. Deacetylase activity is measured by delivering a single, pro-luminogenic, homogeneous assay reagent to assay wells, resulting in luminescence proportional to HDAC activity. In addition to being isoenzyme selective, these novel substrates are cell permeable allowing for lytic and non-lytic cell-based HDAC assays. Lastly, these assays are also fully compatible with fluorescent viability and/or cytotoxicity assays. This provides additional flexibility for multiplexed formats which examine not only selective HDAC inhibition, but the functional consequences they exert on cell health. Citation Format: Kevin R. Kupcho, Nathan J. Evans, Andrew L. Niles, Thomas A. Kirkland, Dan F. Lazar. Selective bioluminogenic HDAC activity assays for profiling HDAC inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4784. doi:10.1158/1538-7445.AM2014-4784
Suicide and Cocaine
Authors: Michael J. Clarke
Journal: JAMA (1988)

To the Editor.—  As Dr Sperry 1 shows, the phenomenon of cocaine suicide is an uncommon aspect of modern cocaine addiction. However, the cases reported  recent years are not the first examples of this.  In the British medical press, at least two cases of suspected suicide by hypodermic injection of cocaine were reported  the early part of the 20th century. 2,3 In one of these the deceased, a medical practitioner, was said to be in the habit of injecting cocaine solution. 2 In addition, the mortality statistics of England and Wales show 28 suicides by cocaine prior to 1950. 4 Although the proportion of these that involved cocaine addicts or the intravenous use of the drug cannot be discerned, we would expect that they do represent some such deaths.
Loeffler endocarditis: What have we learned?
Authors: Juan Benezet‐Mazuecos, Adolfo de la Fuente, Pedro Marcos‐Alberca, Jeronimo Farre
Journal: American Journal of Hematology (2007)

Abstract Loeffler endocarditis, eosinophilic endomyocardial disease or fibroplastic endocarditis appears to be a subcategory of the Hypereosinophilic syndrome in which the heart is predominantly involved. It is an uncommon myocardial disease, thought to be secondary to eosinophils damage, characterized by fibrous thickening of the endocardium of one or both ventricles, leading to apical obliteration and multiple cardiovascular complications. Despite all the efforts, the ultimate responsible mechanisms of this entity remain unresolved. Many theories have been raised trying to explain this phenomenon, but nowadays the enigma in relation to the different patterns of evolution continues. In this concise review we discuss the different pathophysiologic theories postulated and the management of the cardiovascular complications. Perhaps it will serve to assist in recognition of patients with the same condition around the world. Am. J. Hematol. 82:861–862, 2007. © 2007 Wiley‐Liss, Inc.
Media are too eager to link silicone to disease
Authors: N. Collis, C. T K Khoo, D. T Sharpe
Journal: BMJ (1998)

See pp 403, 417

Editor—Legal aid has been granted to a woman who alleges that her child's stomach cramps, skin problems, and food allergies are due to a silicone breast implant. The controversy surrounding silicone breast implants continues despite epidemiological studies finding no connection with neurological and connective tissue diseases.

Use of silicone is common. Some teats of infant bottles are made of silicone (box), and all are lubricated with silicone oil; baby milk formulas contain silicone. Silicone in breast milk is independent of …
Winter is coming: vaccine negotiations should be concluded swiftly
Authors: L. Glennie, C. Wright, C. Head
Journal: BMJ (2014)

The Meningitis Research Foundation welcomes publication of Christensen and colleagues’ model,1 which enables comparison with their original study2 and the interim opinion of the Joint Committee on Vaccination and Immunisation (JCVI),3 and shows a range of cost effective options.

However, this model undervalues the impact of meningococcal B infection. As we previously argued,4 the MOSAIC study,5 which underlies many parameters in this model, is a snapshot that inevitably underestimates disease burden.

In addition, …
Liver‐primed CD8 <sup>+</sup> T cells suppress antiviral adaptive immunity through galectin‐9‐independent T‐Cell immunoglobulin and mucin 3 engagement of high‐mobility group box 1 in mice
Authors: Joseph S. Dolina, Thomas J. Braciale, Young S. Hahn
Journal: Hepatology (2013)

The liver is a tolerogenic environment exploited by persistent infections, such as hepatitis B (HBV) and C (HCV) viruses. In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8(+) T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8(+) T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8(+) T cells also appear to have a T-regulatory (Treg) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (Teff ) cells in vitro and in vivo via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8(+) Treg cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8(+) Treg cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1).Virus-specific Tim-3(+) CD8(+) T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections.
Physostigmine Salicylate in the Treatment of Tricyclic Antidepressant Overdosage
Authors: Ray W. Newton
Journal: JAMA (1975)

Following intravenous administration of physostigmine salicylate for tricyclic antidepressant poisoning in 21 patients, convulsions occurred in two patients, and severe cholinergic manifestations occurred in two others. Because of these untoward effects and the very short duration of its beneficial action, it is very doubtful that physostigmine has any place in the routine management of tricyclic antidepressant poisoning.
Vagal slowing of the heart during haemorrhage: observations from 20 consecutive hypotensive patients.
Authors: K Sander-Jensen, N H Secher, P Bie, J Warberg, T W Schwartz
Journal: BMJ (1986)

Heart rate and arterial blood pressure were monitored in 20 consecutive patients during resuscitation from haemorrhagic shock. The mean blood loss (2.3 (SEM 0.3) 1) corresponded to 36(4)% of their estimated mean blood volume. During shock the mean blood pressure was 81/55 (3/2) mm Hg and heart rate 73 (3) beats/min. Administration of blood and crystalloids resulted in immediate increases to 111/72 (2/2) mm Hg and 102 (3) beats/min followed by steady state values of 131/79 (6/3) mm Hg and 82 (2) beats/min. In three otherwise healthy patients plasma concentrations of the vagally regulated hormone pancreatic polypeptide rose from resting values of 64-77 pmol/l (272-327 pg/ml) to 198-280 pmol/l (842-1190 pg/ml). These findings suggest that reversible hypotensive hypovolaemic shock is characterised by a decrease in heart rate conceivably reflecting an increase in vagal tone.
Ethanol and Angina Pectoris
Authors: ROBERT R. FENICHEL
Journal: Annals of Internal Medicine (1976)

ExcerptTo the Editor:Orlando and associates, in "Effect of Ethanol on Angina Pectoris" (Ann Intern Med 84:652-655, 1976), appear to believe that 100-proof vodka is 100% ethanol. It is not. One hundred proof was originally that concentration of ethanol that, when mixed with gunpowder and ignited, would burn rather than explode or fizzle. Proof is now defined more simply: X% ethanol is 2X proof.Throughout their paper, Orlando and associates assert that their subjects consumed 2 or 5 ounces of ethanol on various occasions, and they further assert that these are quantities within the ordinary range of social drinking. While...
THE RELATION BETWEEN ANTIANAPHYLAXIS AND ANTIBODY BALANCE
Authors: Marion C. Morris
Journal: The Journal of Experimental Medicine (1936)

It has been shown that antianaphylaxis is not caused by a partial saturation of cellular or humoral antibodies by the following facts. 1. Guinea pigs passively sensitized with anti-horse or antipneumococcus serum and specifically desensitized do not manifest as great a reactivity upon resensitization with the same antiserum as upon the original sensitization. 2. Guinea pigs passively sensitized with anti-Friedländer Type B serum or antipneumococcus Type II serum and specifically desensitized do not attain the same degree of reactivity as normal animals when passively sensitized with anti-horse serum. 3. Guinea pigs passively sensitized with anti-Friedländer Type B serum and desensitized with the specific carbohydrate remain as resistant to infection with Friedlander's bacillus Type B as undesensitized guinea pigs. Since in this case, at least, it is agreed that type-specific immunity and type-specific hypersensitiveness are due to the same type-specific antibody, a change in anaphylactic response should be accompanied by a change in immune response, provided this change depends on antibody balance. 4. A determination of the antibody content of the serum of sensitized as well as of desensitized guinea pigs by mouse protection tests indicates that a loss of reactivity in desensitized animals cannot be adequately accounted for on the basis of depletion of circulating antibody. These experiments suggest that hypersensitiveness and resistance are different manifestations of the same antigen-antibody reaction while antianaphylaxis is a state of refractoriness which is due neither to excess of circulating antibody nor to antibody depletion, but is the result of secondary changes the true nature of which is still not definitely established.
Feasibility Study on Endoscopic Suture with the Combination of a Distal Attachment and a Rotatable Clip for Complications of Endoscopic Resection in the Large Intestine
Authors: H. Yoshikane, H. Hidano, A. Sakakibara, Y. Niwa, H. Goto
Journal: Endoscopy (2000)

Endoscopic resection has been more frequently performed for increasingly larger intramucosal tumors of the large intestine in recent years. It is reasonable to expect that the larger the resected mucosal surface, the greater is the likelihood of complications such as bleeding or perforation. The aim of this study was to explore the feasibility of endoscopic suture with a distal attachment and a rotatable clip-fixing device for complications of endoscopic resection in the large intestine.The study population consisted of 15 patients who underwent endoscopic clipping therapy following endoscopic resection for intramucosal tumors of the large intestine. With a distal attachment fitted to the distal end of the endoscope, the optimal position for clipping was ensured by pressing the intestinal wall and deflating the intraluminal air little by little. With a rotatable clip-fixing device, the resection site was endoscopically sutured clip by clip.Tumors were of the laterally spreading tumor type in six patients, small sessile polyps in three, and pedunculated polyps in six. The complications consisted of bleeding in 12 patients, overt perforation in one, and latent perforation in two; 14 of the 15 patients underwent successful suturing by this method. The number of clips used ranged from two to seven (mean 4.4). No patients had further complications after the treatment.We conclude that endoscopic suture with the combination of a distal attachment and a rotatable clip-fixing device is very useful for complications of endoscopic resection in the large intestine.
Schizophrenia-related phenomena that challenge prediction error as the basis of cognitive functioning
Authors: Steven M. Silverstein
Journal: Behavioral and Brain Sciences (2013)

Abstract There are aspects of schizophrenia that pose challenges for Clark's model. These include: (1) evidence for excitatory activity underlying self-organizing neural ensembles that support coordinating functions, and their impairment in schizophrenia; (2) evidence regarding hallucinations that suggest they are not due to excessive prediction error; and (3) the critical role of emotional factors as setting conditions for delusion formation.
Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.
Authors: C Bogardus, S Lillioja, B V Howard, G Reaven, D Mott
Journal: Journal of Clinical Investigation (1984)

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.
Science and the Practice of Medicine in the Nineteenth Century; Medicine in the Making of Modern Britain 1700-1920
Authors: F B Smith
Journal: BMJ (1994)

W F Bynum, Cambridge University Press, £12.95, pp 283 ISBN 0 521 27205 X

Christopher Lawrence Routledge, £6.99, pp 106 ISBN 0 415 09168 3

These two complementary studies draw on recent scholarship in the history of medicine and on current anxieties about the place of technical scientific medical practice in the prevention, cure, and palliation of ill health.

Bynum's survey is authoritative, wide ranging, and elegant. His approach is …
Study of Agglutination of the Gonococcus in Man
Authors: C. E. Jenkins
Journal: BMJ (1926)

tMUDmLJOouUA 11 in enucleating the enlargement, which the pathologist described as a fibroadenoma without any trace of malignancy.I took great care to remove all the shelf between the vesical and prostatic cavities; in fact I took away so mucll that my assistanit was
Cytomegalovirus Infection–Enhanced Cardiac Allograft Vasculopathy Is Abolished by DHPG Prophylaxis in the Rat
Authors: Karl Lemström, Roope Sihvola, Cathrien Bruggeman, Pekka Häyry, Petri Koskinen
Journal: Circulation (1997)

Background A wealth of clinical and experimental evidence exists for cytomegalovirus (CMV) infection as an accelerating factor in the development of cardiac allograft vasculopathy. In this study, the impact of 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) on rat CMV infection–enhanced cardiac allograft vasculopathy is investigated. Methods and Results Heterotopic rat cardiac allografts were performed from the DA to the WF rat strain, and the recipients were immunosuppressed with cyclosporine A 2 mg·kg −1 ·d −1 SC for a period of 90 days until the end of experiment. Two groups of recipients were infected intraperitoneally with 10 5 plaque-forming units of rat CMV, whereas one group was left noninfected and used as controls. One group of rat CMV–infected rats was treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day from 1 day before transplantation to 30 days after transplantation. Compared with noninfected rats, rat CMV infection was associated with a significant increase in intimal thickening, from 0.68±0.10 to 1.30±0.12 score units ( P &lt;.01), and double the number of vessels affected ( P &lt;.01). DHPG treatment significantly reduced intimal thickening in rat CMV–infected rats, from 1.30±0.12 to 0.68±0.13 score units ( P &lt;.01), and halved the number of vessels affected ( P &lt;.01). Conclusions The present results demonstrate that DHPG prophylaxis entirely abolishes the accelerating effect of rat CMV infection on cardiac allograft vasculopathy in immunosuppressed rat recipients, which is consistent with our earlier findings demonstrating a similar effect in nonimmunosuppressed rat aortic allografts. Taken together, these results suggest that DHPG might be useful in the prevention of CMV-accelerated cardiac allograft vasculopathy among heart transplant recipients.
Use of the Oral Neuraminidase Inhibitor Oseltamivir in Experimental Human Influenza
Authors: Frederick G. Hayden, John J. Treanor, R. Scott Fritz, Monica Lobo, Robert F. Betts, Madeline Miller, Nelson Kinnersley, Roger G. Mills, Penelope Ward, Stephen E. Straus
Journal: JAMA (1999)

Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered.To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans.Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997.Individual hotel rooms; 2 large US university medical schools.A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8).All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days.Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers.In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food.In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.
Tribulations of clinical trials: There's more inside the tablet
Authors: J. H Turney
Journal: BMJ (2000)

Several years ago I was invited to be the medical officer for a geological expedition to the Arctic. The attractions of the beauty and grandeur of the high Arctic in summer are somewhat diminished by swarms of mosquitoes, which are notable for their size and ferocity. Even the locals find the attentions of the cuculid hordes hard to bear, with the caribou preferring to rest on patches of snow, where the lower air temperature discourages the biters. There was at that time unfounded speculation that B vitamins acted as systemic insect repellants,12 possibly because of the aroma of yeast excreted via the sweat. It therefore seemed a good idea to conduct a randomised clinical trial of the effect of …