tbuckley/cabot-search huggingface dataset:
Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems
Authors: Gerald S. Levey, Stephen E. Epstein
Journal: Journal of Clinical Investigation (1969)

The mechanism responsible for the hyperdynamic circulatory state in hyperthyroidism has not been defined. Although certain cardiac manifestations resemble those caused by excessive adrenergic stimulation, recent evidence suggests that thyroid hormone exerts an effect on the heart that is independent of the adrenergic system. Since the inotropic and chronotropic effects of norepinephrine appear to be mediated by activation of adenyl cyclase, the possibility that thyroxine and triiodothyronine are also capable of activating adenyl cyclase was examined in the particulate fraction of cat heart homogenates.L-thyroxine and L-triiodothyronine increased the conversion of adenosine triphosphate-(32)P (ATP-(32)P) to cyclic 3',5'-adenosine monophosphate-(32)P (3',5'-AMP-(32)P) by 60 and 45% respectively (P < 0.01). A variety of compounds structurally related to the thyroid hormones, but devoid of thyromimetic activity did not activate adenyl cyclase: these included 3,5-diiodo-L-thyronine, L-thyronine, 3,5-diiodotyrosine, monoiodotyrosine, and tyrosine. D-thyroxine activated adenyl cyclase and half maximal activity was identical to that of the L-isomer. Although the beta adrenergic blocking agent propranolol abolished norepinephrine-induced activation of adenyl cyclase, it failed to alter activation caused by thyroxine. When maximal concentrations of L-thyroxine (5 x 10(-6) moles/liter) and norepinephrine (5 x 10(-5) moles/liter) were incubated together, an additive effect on cyclic 3',5'-AMP production resulted. THIS INVESTIGATION DEMONSTRATES: (a) thyroid hormone is capable of activating myocardial adenyl cyclase in vitro and (b) this effect is not mediated by the beta adrenergic receptor. Moreover, the additive effects of norepinephrine and thyroxine suggest that at least two separate adenyl cyclase systems are present in the heart, one responsive to norepinephrine, the other to thyroid hormone. These findings are compatible with the hypothesis that the cardiac manifestations of the hyperthyroid state may, in part, be caused by the direct activation of myocardial adenyl cyclase by thyroid hormone.
Selecting the Right Tool For the Job
Authors: Arthur L. Caplan, Carolyn Plunkett, Bruce Levin
Journal: The American Journal of Bioethics (2015)

There are competing ethical concerns when it comes to designing any clinical research study. Clinical trials of possible treatments for Ebola virus are no exception. If anything, the competing ethical concerns are exacerbated in trying to find answers to a deadly, rapidly spreading, infectious disease. The primary goal of current research is to identify experimental therapies that can cure Ebola or cure it with reasonable probability in infected individuals. Pursuit of that goal must be methodologically sound, practical and consistent with prevailing norms governing human subjects research. Some maintain that only randomized controlled trials (RCTs) with a placebo or standard-of-care arm can meet these conditions. We maintain that there are alternative trial designs that can do so as well and that sometimes these are preferable to RCTs.
Perifusion of rat pancreatic tissue in vitro: substrate modification of theophylline-induced biphasic insulin release
Authors: Ian M. Burr, Luc Balant, Werner Stauffacher, Albert E. Renold
Journal: Journal of Clinical Investigation (1970)

The immunoreactive insulin (IRI) release patterns produced by continuous theophylline stimulation of rat pancreas have been defined, using an in vitro perfusion system. In the presence of glucose, citrate, and pyruvate at concentrations which were nonstimulatory by themselves, continuous stimulation with theophylline produced a biphasic IRI release profile. In the absence of substrate, continuous theophylline stimulation produced only an abrupt and limited primary response. Of the substrates tested, only glucose significantly enhanced this primary response. With increasing theophylline concentrations, whether in the presence or absence of substrate, significant increases were noted in the primary response as estimated by either the maximum rate of IRI release attained or by the total amount of IRI released during this time. Similarly, the secondary responses to theophylline increased with theophylline concentration in the presence of either citrate or pyruvate. With glucose as substrate, however, increasing theophylline concentrations from 2.5 to 5, then 10 mM produced a progressive reduction in both indices of the secondary response, which was inversely related to the primary response. These findings suggest that cyclic AMP not only mediates IRI release in quantitative terms but is also implicated in the qualitative nature of the response pattern. They also indicate a possible metabolic basis for biphasic IRI release, the acute or primary response being dependent upon the basal state of the cell and the availability of endogenous energy sources, the secondary response upon the availability of exogenous substrate.
Association between anti-tumour necrosis factor therapy and risk of ischaemic stroke in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Registers-Rheumatoid Arthritis (BSRBR-RA)
Authors: Audrey SL Low, Mark Lunt, Louise K Mercer, James B Galloway, Rebecca Davies, Kath D Watson, Deborah P Symmons, William G Dixon, Kimme L Hyrich
Journal: The Lancet (2013)
Abstract 916: BRCA1 mutations impair breast epithelial differentiation through upregulation of the transcriptional repressor Slug
Authors: Theresa A. Proia, Patricia Keller, Piyush Gupta, Ina Klebba, Ainsley Jones, Maja Sedic, Hannah Gilmore, Nadine Tung, Stephen Naber, Stuart Schnitt, Eric Lander, Charlotte Kuperwasser
Journal: Cancer Research (2011)

Abstract Tumor histopathology is a strong predictor of patient mortality, although the molecular and cellular factors that are responsible for this phenotypic diversity remain poorly understood. Women with inherited mutations in the BRCA1 gene have increased risk for the development of breast cancer, but also exhibit a specific predisposition for the development of aggressive basal-like breast cancers. Here we study the interplay between inherited mutations in BRCA1 and tumor differentiation by examining the regulation of progenitor cell fate in disease-free breast tissues from BRCA1 mutation carriers. We demonstrate for the first time that cell populations derived from patients harboring mutations in BRCA1 (BRCA1mut/+) give rise to tumors with increased basal differentiation, relative to cells obtained from BRCA1+/+ patients. Molecular analysis of disease-free breast tissues from BRCA1mut/+ patients revealed significant defects in epithelial progenitor cells that are present prior to cancer incidence. Moreover, we discovered that the transcriptional repressor Slug is an important functional regulator of human breast progenitor cell lineage commitment and differentiation and that it is aberrantly expressed in BRCA1mut/+ tissues and cells prior to neoplastic transformation. In addition, Slug expression is necessary for the increased basal-like phenotypes prior to and following neoplastic transformation. These findings demonstrate that the genetic background of patient populations, in addition to affecting incidence rates, significantly impacts progenitor cell fate commitment and therefore, tumor phenotype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2011-916
Lungscape: Resected Non–Small-Cell Lung Cancer Outcome by Clinical and Pathological Parameters
Authors: Solange Peters, Walter Weder, Urania Dafni, Keith M. Kerr, Lukas Bubendorf, Peter Meldgaard, Kenneth J. O’Byrne, Anna Wrona, Johan Vansteenkiste, Enriqueta Felip, Antonio Marchetti, Spasenija Savic, Shun Lu, Egbert Smit, Anne-Marie Dingemans, Fiona H. Blackhall, Paul Baas, Carlos Camps, Rafael Rosell, Rolf A. Stahel
Journal: Journal of Thoracic Oncology (2014)
The Veterinarian in America 1625-1975
Authors: Lester S. King
Journal: JAMA (1976)

When physicians speak of medicine they ordinarily are referring to diseases of man. However, if they ignore the realm of veterinary medicine, they ignore those intimate relationships that exist between man and the lower animals, a relationship on which the very survival of man has depended and which forms such an important part of our cultural and economic patterns. Veterinary medicine concerns not only the diseases of animals and their cure, but it intermeshes with cultural history. This fascinating work of Dr Smithcors is actually far broader than its title might suggest, for the book provides much more than the story of veterinarians. The author offers what could be called a succession of vignettes that deal particularly with animal diseases but also reveal the interrelations between man and animals in America, from the early 17th century to the present. The exposition is rather episodic. In the aggregate, the various sections
Effect on gastric and duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis.
Authors: A S Taha, S McLaughlin, P J Holland, R W Kelly, R D Sturrock, R I Russell
Journal: Annals of the Rheumatic Diseases (1990)

The synthesis of gastric and duodenal mucosal prostaglandin E2, prostaglandin I2, and thromboxane B2 during a 60 minute incubation of biopsy specimens, the degree of endoscopic and histological damage, and the anti-inflammatory response were all studied after a four week, double blind study of therapeutic doses of two non-steroidal anti-inflammatory drugs, naproxen and etodolac, received by 27 patients with active rheumatoid arthritis (13 receiving naproxen, 14 etodolac). Prostaglandin values after treatment did not differ from the baseline levels when all the patients were analysed as one group. Subgroup analysis showed that naproxen suppressed gastric prostaglandin E2 from a median of 29 to 9 ng/mg protein, duodenal prostaglandin E2 from 34 to 11 ng/mg, and duodenal prostaglandin I2 from 62 to 15 ng/mg protein. No overall suppression occurred with etodolac. Also, on the second assessment patients receiving naproxen had lower gastric and duodenal prostaglandin E2 and prostaglandin I2, but higher values of duodenal thromboxane B2, than patients receiving etodolac. Both drugs had comparable anti-arthritic activity and caused microscopic gastritis in similar proportions of patients. No correlation was detected between prostaglandin values and the mucosal damage which developed in seven patients receiving naproxen (54%) and three receiving etodolac (21%). These findings indicate that, unlike naproxen, etodolac does not seem to affect gastric or duodenal prostaglandin synthesis; other mechanisms of injury need to be considered.
SOME UNUSUAL SYMPTOMS IN A CASE OF MYXEDEMA.
Authors: ARNOLD JOLLY
Journal: JAMA (1899)

I wish to present a report of a case of myxedema with some unusual symptoms: Mrs. R., aged 26 years, blonde. She never had any sickness save the ordinary diseases of childhood; has been married six years and has one child, about 5 years old. The beginning of this trouble was in June or July, 1897, when after accompanying her husband (who is a traveling salesman) through the mountains of the West, she apparently began to take on flesh rapidly. With the advent of the increase of flesh came a general indisposition, irritability, languor and exophthalmos. She seemed content to sit quiet and do nothing as compared to her former habits, although she was always up and around the house and entertained company. Her menses stopped in July, and soon after she applied to her physician for treatment for that trouble and for the unnatural flesh she had so rapidly
Fixed coupling: different mechanisms revealed by exercise-induced changes in cycle length.
Authors: E L Michelson, J Morganroth, J F Spear, J A Kastor, M E Josephson
Journal: Circulation (1978)

Fixed coupled ventricular premature depolarizations (VPDs) are usually considered reentrant; recent experimental models have demonstrated that parasystolic rhythms may also appear in fixed coupled patterns. To analyze the mechanisms of fixed coupled VPDs, 60 exercise tests were chosen to evaluate the response of VPD coupling intervals to changes in cycle length of the dominant supraventricular rhythm. Selection criteria included the presence of frequent, unifocal VPDs that were fixed coupled (variation less than or equal to 80 msec) at any one cycle length, with the persistence of VPDs at several different cycle lengths. Three patterns of response of coupling intervals to changes in cycle length were noted: 1) 32 patients with a direct linear relation (r greater than or equal to 0.9) of coupling intervals to cycle length; 2) 16 patients with coupling intervals fixed, independent of cycle length; and 3) 12 patients with no consistent relation over a wide range of cycle lengths. Two patients in group 2 and four in group 3 fulfilled criteria for parasystole with interectopic intervals that remained constant at different cycle lengths. These results suggest that VPDs in group 1 are reentrant, while some patients with group 2 or 3 responses have evidence for parasystolic rhythms. We conclude that 1) fixed coupling of VPDs is not diagnostic of reentry, and 2) changes in cycle length induced with exercise may be useful in the analysis of mechanisms of VPDs.
A 66 year old woman with breathlessness: case progression
Authors: Douglas Lowdon, Marion McMurdo
Journal: BMJ (2004)

Last week (20 March, p 698) we described the case of Mrs Dempsey, who was investigated for a two month history of breathlessness and swollen ankles. Despite the paucity of cardiovascular risk factors and normal electrocardiographic appearances, we made a presumptive diagnosis of cardiac failure because of her bilateral pleural effusions. She was prescribed an angiotensin converting enzyme inhibitor and her diuretic dose was doubled. Outpatient echocardiography was organised to define the pathology and quantify her cardiac dysfunction.

She was advised her breathlessness was probably a consequence of heart dysfunction. The cause of the potential cardiac failure, though, was not clear. She did not …
Pericardial Fat, Visceral Abdominal Fat, Cardiovascular Disease Risk Factors, and Vascular Calcification in a Community-Based Sample
Authors: Guido A. Rosito, Joseph M. Massaro, Udo Hoffmann, Frederick L. Ruberg, Amir A. Mahabadi, Ramachandran S. Vasan, Christopher J. O’Donnell, Caroline S. Fox
Journal: Circulation (2008)

Pericardial fat may be an important mediator of metabolic risk. Correlations with cardiovascular disease risk factors and vascular calcification in a community-based sample are lacking. We sought to examine associations between pericardial fat, metabolic risk factors, and vascular calcification.Participants free of cardiovascular disease from the Framingham Heart Study (n=1155, mean age 63 years, 54.8% women) who were part of a multidetector computed tomography study underwent quantification of intrathoracic fat, pericardial fat, visceral abdominal fat (VAT), coronary artery calcification, and aortic artery calcification. Intrathoracic and pericardial fat volumes were examined in relation to body mass index, waist circumference, VAT, metabolic risk factors, coronary artery calcification, and abdominal aortic calcification. Intrathoracic and pericardial fat were directly correlated with body mass index (r=0.41 to 0.51, P<0.001), waist circumference (r=0.43 to 0.53, P<0.001), and VAT (r=0.62 to 0.76, P<0.001). Both intrathoracic and pericardial fat were associated with higher triglycerides (P<0.0001), lower high-density lipoprotein (P<0.0001), hypertension (P<0.0001 to 0.01), impaired fasting glucose (P<0.0001 to 0.001), diabetes mellitus (P=0.0005 to 0.009), and metabolic syndrome (P<0.0001) after multivariable adjustment. Associations generally persisted after additional adjustment for body mass index and waist circumference but not after adjustment for VAT (all P>0.05). Pericardial fat, but not intrathoracic fat, was associated with coronary artery calcification after multivariable and VAT adjustment (odds ratio 1.21, 95% confidence interval 1.005 to 1.46, P=0.04), whereas intrathoracic fat, but not pericardial fat, was associated with abdominal aortic calcification (odds ratio 1.32, 95% confidence interval 1.03 to 1.67, P=0.03).Pericardial fat is correlated with multiple measures of adiposity and cardiovascular disease risk factors, but VAT is a stronger correlate of most metabolic risk factors. However, intrathoracic and pericardial fat are associated with vascular calcification, which suggests that these fat depots may exert local toxic effects on the vasculature.
Magnetic resonance imaging of human transplanted hearts with gadolinium-dota myocardial enhancement: Potential use for the detection of rejection
Authors: Elie Mousseaux, Dominique Farge, Romain Guillemain, Catherine Amrein, Claire Vulser, Patrick Bruneval, Jean-Claude Gaux, Alain Carpentier
Journal: Journal of the American College of Cardiology (1991)
Gallop Rhythm of the Heart
Authors: JOSEPH GRAYZEL
Journal: Circulation (1959)

The 2 fundamental types of gallop are ventricular gallop and atrial gallop. Adequate cardiac acceleration modifies these gallops and may produce a summation gallop, an augmented ventricular gallop, or an augmented atrial gallop. The summation and augmented gallops were examined and their relation to the 2 fundamental gallops was quantitated. The cardiac rate at which summation and augmentation occur is unique. A graph and 2 corresponding equations were derived which relate the summation cardiac rate and corresponding cycle length to familiar electrocardiographic and phonocardiographic intervals.
OBSERVATIONS WITH A NEW TRANSMISSIBLE STRAIN OF THE LEUCOSIS (LEUCEMIA) OF FOWLS
Authors: J. Furth
Journal: The Journal of Experimental Medicine (1931)

Myeloid leucosis and erythroleucosis can be transmitted from one bird to others by emulsions of infiltrated organs, whole blood cells, and plasma. Inoculation is more often successful with blood cells or with whole blood than with plasma or with emulsions of organs infiltrated as the result of leucosis. Inoculation with material from a bird with myeloid or with erythroleucosis produces both myeloid and erythroleucosis, and in many instances mixed forms with characters of both. Evidence is wanting that lymphoid leucosis is caused by the agent that transmits myeloid and erythroleucosis. The occurrence of lymphoid leucosis among the birds inoculated with material from myeloid or erythroleucosis may be explained as spontaneous disease. Injury to cellular structure by treatment with distilled water or by repeated freezing and thawing does not destroy the agent that transmits the disease. Berkefeld filtrates have failed to transmit regularly myeloid or erythroleucosis. The evidence obtained shows, however, that the transmissible agent is filterable, although there are technical difficulties in its filtration.
Quantitative studies of the delivery of hepatic-synthesized bilirubin to plasma utilizing δ-aminolevulinic acid-4-14C and bilirubin-3H in man
Authors: E. A. Jones, R. Shrager, J. R. Bloomer, P. D. Berk, R. B. Howe, N. I. Berlin
Journal: Journal of Clinical Investigation (1972)

After the simultaneous intravenous administration of unconjugated bilirubin-(3)H and delta-aminolevulinic acid-4-(14)C, the plasma disappearance curves of unconjugated bilirubin-(3)H and the plasma appearance curves of biosynthesized unconjugated bilirubin-(14)C have been defined in seven patients, three of whom had acute intermittent porphyria (AIP). The incorporation of (14)C into plasma unconjugated bilirubin, derived by an analysis which involves deconvolution of the two plasma curves, varied between 13.1 and 23.5% (mean 19.3%) of the injected dose in the nonporphyric patients and between 5.4 and 13.6% (mean 8.3%) of the injected dose in the porphyric patients. In five of the patients, the stercobilin-(14)C specific activity in a pooled specimen of feces was measured, enabling the following further values to be calculated: (a) the total (14)C radioactivity incorporated into bilirubin (21.0 and 25.3% [mean 23.2%] of the injected dose in two of the nonporphyric patients and between 8.5 and 25.3% [mean 14.2%] of the injected dose in the porphyric patients), and (b) the proportion of hepatic synthesized bilirubin delivered directly to plasma in the unconjugated form (between 0.520 and 0.904; mean for nonporphyric patients 0.712; mean for porphyric patients 0.614). The results demonstrate that a large proportion of bilirubin derived from hepatic hemes passes through the plasma in the unconjugated form before conjugation and secretion into bile.
Laetrile Toxicity: A Report of Two Cases
Authors: Frederick P. Smith
Journal: JAMA (1977)

<h3>To the Editor.—</h3> Laetrile (amygdalin), unproved as a remedy for cancer,<sup>1</sup>has been advocated by proponents as, at worst, a nontoxic placebo. We report two cases of laetrile-associated toxic reactions and challenge the present claims of safety. <h3>Report of Cases.—</h3> Case1.—A 48-year-old woman with lymphoma diagnosed in 1965 began taking laetrile in Mexico in February 1977. On her return to the United States she continued taking laetrile, 6 mg intravenously each week and 500-mg tablets orally three times a day. On April 25 she was admitted to Georgetown University Hospital with fever, malaise, headache, and severe abdominal cramps. She had a temperature of 38.8 °C, a diffuse macular erythematous rash, marked lymphadenopathy and hepatosplenomegaly, and abdominal tenderness without peritoneal signs. Cultures were obtained, and laetrile therapy was discontinued. Her symptoms cleared in two days; cultures were negative for pathogens. Against our advice she resumed the above regimen of
TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus
Authors: Pui Y. Lee, Yutaro Kumagai, Yi Li, Osamu Takeuchi, Hideo Yoshida, Jason Weinstein, Erinn S. Kellner, Dina Nacionales, Tolga Barker, Kindra Kelly-Scumpia, Nico van Rooijen, Himanshu Kumar, Taro Kawai, Minoru Satoh, Shizuo Akira, Westley H. Reeves
Journal: The Journal of Experimental Medicine (2008)

Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770–3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7– and myeloid differentiation factor 88 (MyD88)–dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fcγ receptors (FcγRs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by FcγRs.