tbuckley/cabot-search huggingface dataset:
Early prediction of proarrhythmic cardiotoxicity in the drug development process
Authors: E. P. Anyukhovsky
Journal: Cardiovascular Research (2011)

This editorial refers to ‘Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk’ by G.R. Mirams et al ., pp. 53–61, this issue. 

Drug-induced QT interval prolongation and the appearance of life-threatening Torsade de Pointes (TdP) arrhythmia are potential risks during treatment with a variety of drug compounds, including anti-arrhythmics and non-cardiovascular drugs.1–3 Because of this cardiotoxic side effect, a number of non-cardiovascular drugs have been withdrawn from the market, and the development of several compounds has been aborted in the late phases of the development programmes.2–6 The late detection of cardiotoxic side effects induced by compounds of pharmacological interest can significantly obstruct drug discovery and development projects and increase their cost. Consequently, it is desirable to identify the potential proarrhythmic cardiotoxicity of compounds at an early stage of drug development.

In the majority of cases, drugs that prolong the QT interval preferentially inhibit the rapid component of the delayed rectifier potassium current I Kr (or hERG, the α-subunit of I Kr channels). It is the major repolarizing current of the cardiac action potential that is exceptionally susceptible to blockade by many different compounds. Drugs that block I Kr prolong the action potential duration and …
Otomycosis in the Tropics
Authors: H. C. Highet
Journal: BMJ (1900)

Progress-The patient remained in fair healtlh until August, l896, when she had an attack of peritcnitis, and in my absence fronm town consulted Sir Spencer Wells, and later on Mr. Alban voran, both of whom advised ag&inst operative measures.During the following ten months she had little to complain of, and continued at herbusiness, being able to take long walks and look after her house.On June 28th, however, she met with an accident, being knocked down by a cart when crossing the road.She was much bruised on the abdomen, thighs, legs, and arms, and narrowly escaped being killed.The accident was followed by abdominal pain, and from that date she rapidly lost ground.Repeated Aspirations-The tumours became tender, emaciation was marked, and on August 24th free fluid was detected in the abdonmen.By September x3th she was much distended, and z8 pints of clear amber- coloured fluid were removed by aspiration.On September 24th she was again relieved, 20 pints being withdrawn At the end of two weeks, on October 6th, the aspirator was again necessary, and about 20 pints were evacuated.On October 25th the patient was admitted intothe Grosvenor Hospital for Women, Westminster, and two days later she was for the fourth time aspirated, 21 pints being removed.The reaccumulation of fluid, however, was so rapid that on November 2nd about 14 pints were taken away.Operation.-Thepatient now decided to have the tumours removed.Accordingly on November 6th 1 operated.On openiing the abdomen about
Neurovascular mechanisms as a possible cause of remission of rheumatoid arthritis in hemiparetic limbs
Authors: G Keyszer
Journal: Annals of the Rheumatic Diseases (2004)

In patients with rheumatoid arthritis (RA), ischaemic stroke frequently leads to an unexplained remission of the arthritis in the paretic limb. Here we present two cases which suggest that neurovascular mechanisms contribute to the asymmetry of inflammation by impairing the microcirculation in the paretic extremity.

A 47 year old man developed RA in 1988. In 1990, he had an apoplectic insult, resulting in a complete, left sided hemiplegia. The right hand had a marked ulnar drift of the metacarpophalangeal (MCP) joints and an inflamed wrist with impaired motion, whereas the left hand showed no inflammation or deformity. An x ray analysis of the right hand demonstrated carpal ankylosis and subluxation and erosion of all MCP joints. The left hand showed no erosive changes (fig 1A). Thermal imaging indicated marked temperature differences between both hands, most obvious at the wrists (fig 1B). Duplex sonography measured no detectable flow …
Response to: ‘Detection of antinuclear antibodies: added-value of solid phase assay?’ by Bossuyt and Fieuws
Authors: Nancy Agmon-Levin, Jan Damoiseaux, Yehuda Shoenfeld
Journal: Annals of the Rheumatic Diseases (2013)

We have read the letter by Bossuyt and Fieuws entitled ‘Detection of anti-nuclear antibodies, added-value of solid phase assay?’ with great interest.1 In this letter, the authors described a comparison between anti-nuclear antibodies (ANA) performed by indirect immunofluorescent assay (IIFA) and by an automated method (fluoroenzymeimmunoassay; EliA CTD screen, Thermo Fisher) using samples obtained from patients with systemic lupus erythematosus (SLE), systemic sclerosis, Sjogren's syndrome (SS) and healthy controls. The authors concluded that the favourable method for ANA detection is disease dependent and that combining IIFA with solid phase assay can increase the diagnostic accuracy.

These points, raised by Bossuyt and Fieuws, may be regarded in the perspective of the international recommendations for ANA detection that we have recently published.2 Indeed, our recommendations support the use of IIFA as …
A Randomized Controlled Trial of Cognitive Behavioral Therapy for Adherence and Depression (CBT-AD) in Patients With Uncontrolled Type 2 Diabetes
Authors: Steven A. Safren, Jeffrey S. Gonzalez, Deborah J. Wexler, Christina Psaros, Linda M. Delahanty, Aaron J. Blashill, Aleksandra I. Margolina, Enrico Cagliero
Journal: Diabetes Care (2013)

To test cognitive behavioral therapy for adherence and depression (CBT-AD) in type 2 diabetes. We hypothesized that CBT-AD would improve adherence; depression; and, secondarily, hemoglobin A1c (A1C).Eighty-seven adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual (ETAU), including medication adherence, self-monitoring of blood glucose (SMBG), and lifestyle counseling; a provider letter documented psychiatric diagnoses. Those randomized to the intervention arm also received 9-11 sessions of CBT-AD.Immediately after acute treatment (4 months), adjusting for baseline, CBT-AD had 20.7 percentage points greater oral medication adherence on electronic pill cap (95% CI -31.14 to -10.22, P = 0.000); 30.2 percentage points greater SMBG adherence through glucometer downloads (95% CI -42.95 to -17.37, P = 0.000); 6.44 points lower depression scores on the Montgomery-Asberg Depression Rating Scale (95% CI 2.33-10.56, P = 0.002); 0.74 points lower on the Clinical Global Impression (95% CI 0.16-1.32, P = 0.01); and 0.72 units lower A1C (95% CI 0.29-1.15, P = 0.001) relative to ETAU. Analyses of 4-, 8-, and 12-month follow-up time points indicated that CBT-AD maintained 24.3 percentage points higher medication adherence (95% CI -38.2 to -10.3, P = 0.001); 16.9 percentage points greater SMBG adherence (95% CI -33.3 to -0.5, P = 0.043); and 0.63 units lower A1C (95% CI 0.06-1.2, P = 0.03) after acute treatment ended. For depression, there was some evidence of continued improvement posttreatment, but no between-group differences.CBT-AD is an effective intervention for adherence, depression, and glycemic control, with enduring and clinically meaningful benefits for diabetes self-management and glycemic control in adults with type 2 diabetes and depression.
Randomised trial of endoscopic argon laser photocoagulation in bleeding peptic ulcers.
Authors: A G Vallon, P B Cotton, B H Laurence, J R Armengol Miro, J C Salord Oses
Journal: Gut (1981)

Emergency endoscopy on 332 patients with acute upper gastrointestinal bleeding showed that 178 had peptic ulcers; 28 of these were actively bleeding (spurting) and 108 showed stigmata of recent haemorrhage (vessels or spots in the ulcer base) suggesting a risk of rebleeding. These 136 patients were randomly allocated to Argon laser photocoagulation or to no additional therapy (controls) at the time of initial endoscopy. All patients received conventional management, and the controlling clinicians did not know whether or not the laser had been used in any individual patients. The laser system proved both simple and safe in use. Initial haemostasis was achieved by the laser in 10 of 15 9spurting vessels9, but four of 13 9control9 spurting vessels also stopped bleeding spontaneously. Overall, there were no statistically significant differences between the laser treated and control groups in terms of rebleeding, the need for surgical intervention, or death. These results require amplification in larger trials, and comparison with other studies using different protocols and other haemostatic methods.
Identification of a genetic marker of Helicobacter pylori strains involved in gastric extranodal marginal zone B cell lymphoma of the MALT-type
Authors: P Lehours
Journal: Gut (2004)

<h3>Abstract</h3> Use of organic manures to meet the nutrient requirement of crop would be an inevitable practice in the years to come for sustainable agriculture since organic manures generally improve the soil physical, chemical and biological properties. Hence, field experiments were carried out in 2017 and 2018 to compare the impact of different organic manures and NPK fertilizer on soil properties, growth, yield, proximate and mineral contents of okra (<i>Abelmoschus esculentus</i> L.). The treatments each year 2017 and 2018 consisted of: rabbit manure, cow dung, poultry manure, green manure [Mexican sunflower (<i>Tithonia diversifolia</i> Asteraceae)], pig manure, NPK 15-15-15 fertilizer applied at 120 kg N ha<sup>−1</sup> and a control (no manure/ inorganic fertilizer). The seven treatments were laid out in a randomized complete block design with three replication. Organic manures and NPK fertilizer increased the soil organic matter (OM), N, P, K, Ca and Mg (NPK fertilizer did not increase OM, Ca and Mg significantly), growth, yield, minerals, protein, ash, carbohydrate and mucilage contents of okra fruit as compared with control. Organic manures improved okra yield compared with NPK fertilizer. Okra growth and yield parameters were significantly higher in 2018 compared with 2017. Control, rabbit manure, cow dung, poultry manure, green manure, pig manure and NPK fertilizer in 2018 increased the pod yield of okra by 9.7%, 35.3%, 57.9%, 36.2%, 39.2%, 45.5% and 3.2%, respectively compare with the same treatment in 2017. Amongst various organic manures, poultry manure produced significantly higher plant growth, yield, mineral and proximate composition of okra because of its high soil chemical properties which could be related to its lowest C: N ratio, lignin and lignin: N ratio. Results also showed that okra grown during high intensity rainfall has higher yield but with reduced quality except its mucilage content. Therefore, planting of okra with poultry manure under moderate rainfall will enhance the health benefit from the fruit, however, those that desire its mucilage content planting during high rainfall is recommended.
Role of Antibody and Complement in the Immune Clearance and Destruction of Erythrocytes I. IN VIVO EFFECTS OF IgG AND IgM COMPLEMENT-FIXING SITES
Authors: Aland D. Schreiber, Michael M. Frank
Journal: Journal of Clinical Investigation (1972)

A model which permits evaluation in molecular terms of the role of antibody and of complement in the immune destruction of erythrocytes was established in the guinea pig. IgM and IgG immunoglobulins were isolated from rabbit anti-guinea pig erythrocyte antisera and were used to sensitize (51)Cr-labeled guinea pig erythrocytes. The average number of complement-fixing sites per erythrocyte formed by antibody was determined for each of the various preparations by the Cla fixation and transfer test. The rate of clearance and of organ localization was determined for cells sensitized with either IgM or IgG antibodies, and dose-response curves were established in normal guinea pigs and guinea pigs with a genetically controlled, complete absence of the fourth component of complement (C4). At least 60 complement-fixing sites per cell were required for accelerated clearance of IgM-sensitized erythrocytes. The bulk of cells with IgM sites were cleared by the liver within 5 min after injection and were then slowly returned to the circulation where they survived normally. There was no accelerated clearance whatsoever of IgM-sensitized erythrocytes in C4-deficient guinea pigs. As few as 1.4 IgG complement-fixing sites per cell resulted in decreased erythrocyte survival. There was no evidence of immediate tissue sequestration and release. Progressive trapping and destruction of erythrocytes by the spleen was responsible for most of the clearance of IgG-sensitized cells. Clearance of IgG-sensitized cells was markedly impaired in guinea pigs with C4 deficiency; however, there was some decrease over normal survival. The data indicate that IgG and IgM antibodies interact with complement in vivo by mechanisms which are qualitatively or quantitatively different and produce different biologic effects.
Relation between door-to-balloon times and mortality after primary percutaneous coronary intervention over time: a retrospective study
Authors: Brahmajee K Nallamothu, Sharon-Lise T Normand, Yongfei Wang, Timothy P Hofer, John E Brush, John C Messenger, Elizabeth H Bradley, John S Rumsfeld, Harlan M Krumholz
Journal: The Lancet (2014)
Metabolic signaling pathways asociated with fatty acid synthase activity
Authors: Steven J. Kridel, Joy L. Little
Journal: Cancer Research (2005)

5479   Fatty Acid Synthase (FAS) is the enzyme responsible for the synthesis of the 16-carbon fatty acid, palmitate. FAS is overexpressed in many cancers including prostate, breast, colorectal, and ovarian, with little or no expression in corresponding normal tissues. In addition, FAS expression correlates with poor prognosis and aggressive disease. Because of the marked relationship between FAS expression and tumor status, FAS has become an attractive target for anti-tumor therapy. Inhibition of FAS by the newly described drug orlistat causes cell death in breast and prostate cancer cell lines and inhibits tumor growth in a xenograft model of prostate cancer. In the effort to characterize the mechanism of cell death caused by inhibition of FAS, various anti-apoptotic agents were tested in concert with orlistat. Neither Bcl-2, FADD-dN, nor the pan-caspase inhibitor, zVAD.fmk rescues cell death caused by orlistat. Because fatty acid synthesis and oxidation can modulate the ATP balance of a cell, we asked whether FAS inhibition affected AMP-activated kinase (AMPK) signaling. Inhibition of FAS by orlistat induces phosphorylation of AMPK indicating that ATP levels are depleted. When AMPK is active, energy consuming processes of the cell are blocked in favor of ATP production. One potential downstream target of AMPK is mTOR, the Ser/Thr kinase that also acts as a sensor for ATP and amino acid levels to balance nutrients for cell growth. Inhibition of FAS by orlistat induces phosphorylation of mTOR. Because mTOR plays a role in translational regulation, we asked whether cap-dependent translation may also be affected. Indeed, FAS inhibition by orlistat causes phosphorylation of eIF2α. Accordingly, orlistat treatment inhibits new protein synthesis which may lead to cell cycle arrest and apoptosis. Phosphorylation of eIF2α indicates that FAS inhibition may induce ER stress. Together these data indicate that FAS activity may serve to regulate several metabolic pathways, including those involved in ATP production and protein synthesis, to promote prostate cancer survival.
Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2.
Authors: G Strassmann, V Patil-Koota, F Finkelman, M Fong, T Kambayashi
Journal: The Journal of Experimental Medicine (1994)

Among other effects, prostaglandins (PG) of the E series are known to inhibit several acute and chronic inflammatory conditions in vivo and proinflammatory cytokine production by activated macrophages in culture. The research presented here demonstrates that the inhibitory effect of PGE2 on tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production by lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages involves IL-10. In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-alpha and IL-6, but not of lactate or nitric oxide. The decrease in the level of these cytokines is inversely proportional to the increase in immunoreactive IL-10. This differential inhibitory effect of PGE2 is mimicked by agents that elevate intracellular levels of cAMP, but not cGMP. Neutralizing anti IL-10 antibody but not neutralizing antibodies against other macrophage secretory products (IL-6, leukemia inhibitory factor, and transforming growth factor beta [TGF-beta]), significantly reverse the potent inhibitory effect of PGE2. In vivo, the administration of PGE2 before LPS challenge significantly reduces circulating TNF-alpha and IL-6 levels. Anti-IL-10 antibody substantially enhanced the LPS-induced TNF-alpha and IL-6 levels in mice that received either LPS alone or LPS plus PGE2. These results suggest that the anti-inflammatory effect of PGE2 on mononuclear phagocytes is mediated in part by an autocrine feedback mechanism involving IL-10.
Nuclear Magnetic Resonance Studies of Cationic and Energetic Alterations With Oxidant Stress in the Perfused Heart
Authors: S. Yanagida, C.S. Luo, M. Doyle, G.M. Pohost, M.M. Pike
Journal: Circulation Research (1995)

Abstract The postischemic generation of oxygen-derived free radicals may contribute to myocardial reperfusion injury by affecting sarcolemmal ion transport. Recent evidence indicates that exposure to reactive oxygen intermediates induces rapid increases in myocardial cytosolic free Ca 2+ (Ca 2+ i ). The mechanism is undetermined but may involve disturbances in Na + homeostasis. We tested this hypothesis by interleaving 23 Na and 31 P nuclear magnetic resonance (NMR) measurements of Na + i and high-energy phosphates in glucose-perfused rat hearts exposed to hydroxyl radicals generated from H 2 O 2 and Fe 3+ . In separate experiments, K + i and Ca 2+ i were measured with 39 K and 19 F NMR, respectively. The hearts rapidly exhibited contracture. Threefold Na + i increases and substantial K + i depletion were observed. Glycolytic inhibition was indicated by rapid sugar phosphate accumulation and cellular energy depletion. Notably, however, severe functional and energetic deterioration and substantial elevation of Ca 2+ i occurred before substantial Na + i accumulation or K + i depletion was observed. Further experiments investigated the ability of pyruvate to scavenge H 2 O 2 and to protect the myocardium from oxidant stress. Pyruvate (1 or 2.5 mmol/L) dramatically attenuated functional and energetic alterations and alterations in Na + i and K + i , whereas acetate (2.5 mmol/L) offered no protection. Unlike pyruvate, lactate (5 mmol/L) has little or no capacity to scavenge H 2 O 2 but has similar protective effects. In conclusion, pyruvate effectively protects against H 2 O 2 /Fe 3+ , largely by direct H 2 O 2 scavenging. Protection with lactate may involve intracellular pyruvate augmentation. Without exogenous pyruvate or lactate, myocardial Na + homeostasis can be substantially altered by oxidant stress, possibly via cellular energy depletion. Excess Na + i accumulation may, in turn, hasten metabolic and functional deterioration, but a causal link with the initial alterations in function or Ca 2+ i was not supported.
Tracers for assessing exposure to environmental tobacco smoke: what are they tracing?
Authors: J M Daisey
Journal: Environmental Health Perspectives (1999)

The effectiveness of various tracers for measurements of exposure to environmental tobacco smoke (ETS) as a complex chemical mixture is based on the physicochemical properties of four major organic components and their dynamic behavior in indoor environments. For the particulate matter (PM) component and the very volatile organic compounds, emission and ventilation rates are generally the most important processes controlling indoor concentrations and exposures of nonsmokers. For the volatile organic compounds (VOCs) and semivolatile organic compounds (SVOCs), sorption on and desorption from indoor surfaces are additional processes that influence exposures. Laboratory and modeling studies of the dynamic behavior of nicotine, an SVOC, and PM indicate that nicotine can be used to estimate PM exposures from ETS in indoor environments when certain criteria are met: (italic>a(/italic>) smoking occurs regularly in the environment, (italic>b(/italic>) the system is near quasi-steady state, and (italic>c(/italic>) sampling time is longer than the characteristic times for removal processes. Measurements in residential and workplace buildings also support the use of nicotine as a tracer for PM in ETS. Recent laboratory and field data indicate that the VOCs from ETS can be traced using compounds with similar physicochemical properties, such as 3-ethenylpyridine, pyrrole, or pyridine. The effectiveness of nicotine for estimating exposures to the VOCs and SVOCs has not been determined, although these constitute major mass fractions of ETS.
An Intervention to Decrease Catheter-Related Bloodstream Infections in the ICU
Authors: Peter Pronovost, Dale Needham, Sean Berenholtz, David Sinopoli, Haitao Chu, Sara Cosgrove, Bryan Sexton, Robert Hyzy, Robert Welsh, Gary Roth, Joseph Bander, John Kepros, Christine Goeschel
Journal: New England Journal of Medicine (2006)

Catheter-related bloodstream infections occurring in the intensive care unit (ICU) are common, costly, and potentially lethal.
Oral Health in the United States: The Post-Fluoride Generation
Authors: P. Milgrom, S. Reisine
Journal: Annual Review of Public Health (2000)

▪ Abstract Tremendous strides have been made in reducing the incidence of tooth decay, periodontal diseases, and associated loss of teeth in adults and children since the inception of community water fluoridation programs. Yet the disadvantaged and poor have not fully shared in the benefits. Other challenges to oral health remain. Oral cancer and related smoking and smokeless tobacco use remain major public health problems. Access to preventive and therapeutic dental care is far from universal. Public health programs similar in commitment to the approach of community water fluoridation programs initiated in the 1950s and 1960s are needed to address neglected oral health needs of underserved and high-risk populations in the United States.
Diseases Due to Abnormalities of Hemoglobin Structure
Authors: E R Huehns
Journal: Annual Review of Medicine (1970)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More