tbuckley/cabot-search huggingface dataset:
Mutations in the hepatitis C virus polymerase that increase RNA binding can confer resistance to cyclosporine A
Authors: Zhe Liu, John M. Robida, Sreedhar Chinnaswamy, Guanghui Yi, Jason M. Robotham, Heather B. Nelson, Andre Irsigler, Cheng C. Kao, Hengli Tang
Journal: Hepatology (2009)

Abstract Hepatitis C virus (HCV) infection leads to acute and chronic liver diseases, and new classes of anti-HCV therapeutics are needed. Cyclosporine A (CsA) inhibits HCV replication and CsA derivatives that lack the immunosuppressive function are currently in clinical trials as candidate anti-HCV drugs. Here we characterize several independently derived HCV replicons with varying levels of CsA resistance due to mutations in nonstructural protein 5B (NS5B), the HCV-encoded polymerase. Mutant HCV replicons engineered with these mutations showed resistance to CsA. The mutations reside in two distinct patches in the polymerase: the template channel and one face of a concave surface behind the template channel. Mutant NS5B made by cells expressing the HCV replicon had increased ability to bind to RNA in the presence of CsA. Purified recombinant NS5B proteins containing the mutations were better at de novo initiated RNA synthesis than the wild-type control. Furthermore, the mutant proteins were able to bind RNA with ≈8-fold higher affinity. Last, mutation near the template channel alleviated the lethal phenotype of a mutation in the concave patch, P540A. This intramolecular compensation for the HCV replicase function by amino acid changes in different domains was further confirmed in an infectious cell culture-derived virus system. Conclusion: An increased level of CsA resistance is associated with distinct mutations in the NS5B gene that increase RNA binding in the presence of CsA, and the intramolecular communications between residues of the thumb and the C-terminal domains are important for HCV replicase function. (Hepatology 2009.)
Prothrombin in Enzymology, Thrombosis and Hemophilia
Authors: Oscar D. Ratnoff
Journal: JAMA (1967)

<b>Blood Clotting Enzymology</b>, edited by Walter H. Seegers, 628 pp, with illus, $27.50, New York and London: Academic Press, Inc., 1967. Probably most of those interested in the physiology and pathology of blood clotting believe that coagulation is the end result of a series of enzymatic reactions involving numerous individual clotting factors. The "cascade" or "waterfall" hypothesis of blood coagulation, which envisions a series of catalytic reactions among these factors, is a tentative expression of this belief that has been fruitful in suggesting new experiments and new ideas. No proponent would claim more than that, for history shows that today's hypothesis is destined for tomorrow's waste basket. One of my acerbic colleagues points out that the solution of all clotting problems would leave him unemployed. Perhaps the greatest impetus to science is not curiosity but rather controversy among men who see the same facts through different lenses. Seegers, one of
Rhabdomyolysis after intramuscular iron-dextran in malabsorption.
Authors: W D Foulkes, C Sewry, J Calam, H J Hodgson
Journal: Annals of the Rheumatic Diseases (1991)

The case of a 59 year old white man who had chronic malabsorption and selective IgA deficiency with severe iron deficiency is reported. In addition, he was deficient in vitamin E and selenium, important antioxidants which protect against lipid peroxidation. He was intolerant of oral iron and when treated with iron-dextran developed symptoms suggestive of polymyositis with evidence of rhabdomyolysis. It is suggested that free iron within iron-dextran activated free radicals, initiating lipid peroxidation and leading to polymyositis, rhabdomyolysis, and myoglobulinuria.
Modulation of Lymphocyte Proliferation by Antioxidants in Chronic Beryllium Disease
Authors: Dave R. Dobis, Richard T. Sawyer, May M. Gillespie, Jie Huang, Lee S. Newman, Lisa A. Maier, Brian J. Day
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Occupational exposure to beryllium (Be) can result in chronic granulomatous inflammation characterized by the presence of Be-specific CD4+ T cells. Studies show that oxidative stress plays a role in the pathogenesis of chronic inflammatory disorders.We hypothesized that Be-induced oxidative stress modulates the proliferation of Be-specific CD4+ T cells.Thirty-three subjects with chronic beryllium disease (CBD), 15 subjects with beryllium sensitization, and 28 healthy normal control subjects were consecutively enrolled from the Occupational and Environmental Health Clinic of the National Jewish Medical and Research Center.All studies were performed with Ficoll-Hypaque-isolated peripheral blood mononuclear cells from subsets of the study subjects. Decreased intracellular levels of the thiol antioxidants, glutathione and cysteine, were observed in peripheral blood mononuclear cells from subjects with beryllium sensitization and CBD, as compared with healthy control subjects. Beryllium stimulation decreased intracellular thiol antioxidants by more than 40%, accompanied by increased reactive oxygen species levels and the proliferation of Be-specific blood CD4+ T cells from subjects with CBD. Be-induced T-cell proliferation was inhibited by treatment with the thiol antioxidant N-acetylcysteine or the catalytic antioxidant manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP). MnTBAP treatment also inhibited T-cell proliferation in response to the unrelated, MHC class II-restricted antigen tetanus toxoid. Treatment of CBD blood lymphocytes, but not antigen-presenting cells, with MnTBAP decreased Be-induced T-cell proliferation by more than 40%.Beryllium can mediate a thiol imbalance leading to oxidative stress that may modulate the proliferation and clonal expansion of Be-specific blood CD4+ T cells. These data suggest that Be-induced oxidative stress plays a role in the pathogenesis of granulomatous inflammation in CBD.
Angiotensin-Converting Enzyme Inhibition Attenuates Hypofibrinolysis and Reduces Cardiac Perivascular Fibrosis in Genetically Obese Diabetic Mice
Authors: A. K. M. Tarikuz Zaman, Satoshi Fujii, Hirotumi Sawa, Daisuke Goto, Naoki Ishimori, Keiko Watano, Takeaki Kaneko, Tomoo Furumoto, Taeko Sugawara, Ichiro Sakuma, Akira Kitabatake, Burton E. Sobel
Journal: Circulation (2001)

Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis.To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription-polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis.Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.
Wide-area 308-nm phototherapy with nonlaser light in the treatment of psoriasis: results of a pilot study
Authors: L. Mavilia, P. Campolmi, R. Rossi, M. Mori, N. Pimpinelli, P. Cappugi
Journal: British Journal of Dermatology (2005)

Conflicts of interest: none declared. Sir, The phototherapy‐based treatment of psoriasis has been greatly updated during the last decade. Among the newly introduced devices, the 308‐nm excimer laser1 has proved to be effective in terms of rapidity of action and stability of remissions.2, 3 For about 3 years4 we have been using a 308‐nm XeCl monochromatic excimer light (MEL) (Excilite®; Deka Mela, Florence, Italy), able to generate 308‐nm ultraviolet (UV) B radiation, to produce a power density of 50 mW cm−2 at a distance of 15 cm from source (decreasing to about 40 mW cm−2 at the periphery of the spot), and to have a maximum irradiating area of 504 cm2 (36 × 14 cm). Following the experience of Asawanonda et al.,5 we started a new protocol based on multiples of the minimal erythema dose (MED). Before treatment, all patients were phototested to determine the MED of 308‐nm UVB by exposing a small area of uninvolved skin on the buttocks to a geometric dose range between 150 and 500 mJ cm−2 (3–10 s). Sixty‐nine patients (44 men and 25 women) aged between 18 and 77 years, with Fitzpatrick skin type I‐IV, affected by both localized (< 30% of total skin) and diffuse psoriasis vulgaris (> 30% of total skin), were enrolled in this pilot study. Patients were required to discontinue any topical treatment for 4 weeks, and any phototherapy‐based or systemic treatment for at least 3 months before enrolment. The psoriasis severity was evaluated according to the Psoriasis Area and Severity Index (PASI 12–36). The dose at the first application varied from 2 to 4 MED, depending on the skin area to be treated and the features (thickness, scaling and erythema) of the psoriatic lesion (Table 1). Subsequent doses were increased by 150–500 mJ cm−2 (3–10 s) during the following sessions (one every 7–14 days), inversely depending on the erythema grading related to the preceding application (the less erythema, the higher increase). The lamp was always located at a distance of 15 cm from the skin area to be treated. Both patients and operators always wore protective goggles. Unaffected skin was always protected with white paper towels or a total‐block sunscreen cream. No additional treatments, except an emollient cream under occlusive dressing, were used by the patients during the study period. No mineral oil, usually used in excimer laser treatment, was applied in our protocol. Clinical evaluation was performed once monthly during and after the treatment period up to a maximum follow‐up of 13 months.
Brain organization for language from the perspective of electrical stimulation mapping
Authors: George A. Ojemann
Journal: Behavioral and Brain Sciences (1983)

Abstract A model for the organization of language in the adult humans brain is derived from electrical stimulation mapping of several language-related functions: naming, reading, short-term verbal memory, mimicry of orofacial movements, and phoneme identification during neurosurgical operations under local anesthesia. A common peri-Sylvian cortex for motor and language functions is identified in the language dominant hemisphere, including sites common to sequencing of movements and identification of phonemes that may represent an anatomic substrate for the “motor theory of speech perception.” This is surrounded by sites related to short-term verbal memory, with sites specialized for such language functions as naming or syntax at the interface between these motor and memory areas. Language functions are discretely and differentially localized in association cortex, including some differential localization of the same function, naming, in multiple languages. There is substantial individual variability in the exact location of sites related to a particular function, a variability which can be partly related to the patient's sex and overall language ability and which may depend on prior brain injury and, perhaps subtly, on prior experience. A common “specific alerting response” mechanism for motor and language functions is identified in the lateral thalamus of the language–dominant hemisphere, a mechanism that may select the cortical areas appropriate for a particular language function.
Community-Based Care and Treatment of Schizophrenia
Authors: M. J. Friedrich
Journal: JAMA (2014)

Adding community-based care to facility-based care is an effective strategy for treating individuals with schizophrenia in India, according to a study by researchers from India and the United Kingdom (Chatterjee S et al. Lancet. doi:10.1016/S0140-6736[13]62629-X [published online March 5, 2014]).
Lesson of the week: Persistent itching due to etherified starch plasma expander
Authors: E L. Speight, R. M MacSween, A. Stevens
Journal: BMJ (1997)

Coronary artery disease is the leading cause of death in most developed countries.In the United States alone, 500 000 deaths a year are caused by coronary artery disease, over half of which are due to sudden cardiac arrest. 1 Often cardiac arrest is the initial manifestation of coronary artery disease, so many of these patients if successfully resuscitated could have years of productive life remaining.Improvements in cardiopulmonary resuscitation therefore could have an appreciable impact on total mortality. Recent advances in cardiopulmonary resuscitationSudden cardiac arrest remains a major cause of death in developing countries Despite years of experience with cardiopulmonary resuscitation, survival after cardiac arrest continues to be quite low Automatic external defibrillators and bystander cardiopulmonary resuscitation improve survival after sudden cardiac arrest Doctors should identify and counsel those patients who are not candidates for cardiopulmonary resuscitation
Screening for cystic fibrosis Screening before pregnancy is preferred
Authors: J D A Cooper, A J Franks, D J H Brock, N Quereshi
Journal: BMJ (1994)

EDITOR, - The paper by Sean Livingstone and colleagues produces further evidence that the antenatal context provides a pragmatic answer to the debate about a model for cystic fibrosis screening.1 We wish to make two comments about the paper.

Firstly, the authors suggest (in table II) that a majority of women, whether entering the trial or not, preferred screening during pregnancy. This is not borne out by the results they present since, although small numbers are involved, 60.5% of the non-participants preferred screening before pregnancy, compared with 46% of the participants. A previous survey of pregnant women found that 98% preferred screening before pregnancy and 69% would accept carrier screening during pregnancy.2 There is actually substantial interest in prepregnancy screening. This is signficant because the acceptability of screening to the general population is likely to alter with the improving clinical picture for cystic fibrosis3 as well as gene therapy.

Secondly, the authors conclude that although prepregnancy screening “permits some reproductive choice” those choices are unlikely to be pursued. The experience from screening programmes for Tay-Sachs disease and thalassaemia are given as evidence. We doubt this for two reasons: the evidence, particularly from Tay-Sachs carrier screening, that carriers exercise reproductive choice by their choice of partner, and also because the examples quoted …
Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction
Authors: Ravikumar Muthuswamy, Liwen Wang, Jamie Pitteroff, Jeffrey R Gingrich, Pawel Kalinski
Journal: Journal for ImmunoTherapy of Cancer (2015)

BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8(+) T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs.Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data.Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage.The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases.
Barrett's oesophagus: epidemiology comes up with a surprise
Authors: R C Heading
Journal: Gut (2003)

Although the risk of oesophageal adenocarcinoma is increased, this cancer is an uncommon cause of death in patients with Barrett’s oesophagus

In a Gut Commentary in 1997, Spechler1 observed that neither the definition nor the pathogenesis of Barrett’s oesophagus were as straightforward as they had seemed only a few years earlier. Today, it looks as if oesophagologists need recourse to the black arts of journalistic spin if recent research on Barrett’s is to be portrayed as bringing clarity to the subject, because in truth it has not had much success in resolving the major uncertainties about pathogenesis, clinical significance, and optimum patient management. Regrettably, we are still unable to answer very many important scientific and practical questions. For example, why do some patients with gastro-oesophageal reflux disease (GORD) develop Barrett’s whereas others do not? What determines the length of the columnar segment? Why does it not lengthen with time despite continuing reflux? Is Barrett’s the important precursor of oesophageal adenocarcinoma or is severe reflux the real risk factor irrespective of overt metaplasia of the epithelium? Is endoscopic surveillance of Barrett’s oesophagus an essential part of good clinical practice or is it a waste of time and money? This is …
ON AUTO-HAEMAGGLUTINATION: A CONTRIBUTION TO THE PHYSIOLOGY AND PATHOLOGY OF THE BLOOD
Authors: C. J. Bond
Journal: BMJ (1920)

THE phenomena of haemagglutination ernployed by Land- steincr, -Mosso, Hirsclhfeld, and otlhers as a means of differentiatinlg hiuman individuals into different " blood groups " have hitlherto been thought to possess only a
Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor
Authors: Markus Tölle, Vera Jankowski, Mirjam Schuchardt, Annette Wiedon, Tao Huang, Franziska Hub, Joanna Kowalska, Jacek Jemielity, Andrzej Guranowski, Christoph Loddenkemper, Walter Zidek, Joachim Jankowski, Markus van der Giet
Journal: Circulation Research (2008)

Besides serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors still remains uncertain. The supernatant from mechanically stimulated human microvascular endothelial cells elicited a potent vasoconstrictive response in the isolated perfused rat kidney. Whereas a nonselective purinoceptor blocker blocked this vasoactivity most potently, the inhibition of the endothelin receptor by BQ123 weakly affected that vasoconstrictive response. As a compound responsible for that vasoconstrictive effect, we have isolated from HMECs and identified the mononucleotide adenosine 5′-tetraphosphate (AP4). This nucleotide proved to be the most potent vasoactive purinergic mediator identified to date, exerting the vasoconstriction predominantly through activation of the P2X1 receptor. The intraarterial application of AP4 in a Wistar–Kyoto rat induced a strong increase of the mean arterial pressure. The plasma concentration of AP4 is in the nanomolar range, which, in vivo, induces a significant change in the mean arterial pressure. To our knowledge, AP4, which exerts vasoactive effects, is the most potent endogenous mononucleotide identified to date in mammals. The effects of AP4, the plasma concentration of AP4, and its release suggest that this compound functions as an important vasoregulator.
Mosquitoes and Malaria
Authors: Joan Stephenson
Journal: JAMA (2003)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Beneficial long-term effect of intracoronary perfluorochemical on infarct size and ventricular function in a canine reperfusion model
Authors: Mervyn B. Forman, David W. Puett, B. Hadley Wilson, William K. Vaughn, Gottlieb C. Friesinger, Renu Virmani
Journal: Journal of the American College of Cardiology (1987)
Expression of the p14ARF tumor suppressor predicts survival in acute myeloid leukemia
Authors: C Müller-Tidow, S K Metzelder, H Buerger, J Packeisen, A Ganser, G Heil, K Kügler, G Adigüzel, J Schwäble, B Steffen, W-D Ludwig, A Heinecke, T Büchner, W E Berdel, H Serve
Journal: Leukemia (2004)
Preferential splenic CD8+ T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia
Authors: Sylvain Audia, Maxime Samson, Matthieu Mahévas, Christophe Ferrand, Malika Trad, Marion Ciudad, Alexandrine Gautheron, Famky Seaphanh, Vanessa Leguy, Sabine Berthier, Bruno Salles, Laurent Martin, Bernard Lorcerie, Pablo Ortega-Deballon, Olivier Facy, Denis Caillot, Agnès Soudry-Faure, Marc Michel, Bertrand Godeau, Nicolas Larmonier, Philippe Saas, Nona Janikashvili, Bernard Bonnotte
Journal: Blood (2013)