tbuckley/cabot-search huggingface dataset:
P230Metalloproteinases inhibition: a new approach to reduce hemorrhage and blood transfusions
Authors: J Orbe, JA Rodriguez, JA Sanchez, A Salicio, M Belzunce, A Ugarte, HCY Chang, O Rabal, J Oyarzabal, JA Paramo
Journal: Cardiovascular Research (2014)

Purpose: Bleeding can be a complication of surgery (e.g. cardiac surgery) leading to blood transfusion requirements and substantial morbidity and mortality having a great health and econimical impact. Hyperfibrinolysis is an integral component of bleeding in this condition, therefore administration of antifibrinolytics like tranexamic acid (TXA), is the strategy of choice. However, side effects associated with venous or arterial thrombosis and seizures, limit its use. We hypothesized that inhibition of metalloproteinases (MMPs) may represent a new therapeutic approach to control bleeding, based on its role on hemostasis. Methods: Through the implemented drug discovery process, based on in-vitro MMPs activity biochemical test and a functional thromboelastometry assay, synthesized compounds from a novel chemical series were prioritized to be assayed in-vivo. In particular , the compounds that show a 50 % significant delay in blood lysis time were tested in a tail bleeding model in mouse, and after partial hepatectomy as compared with TXA. Moreover, pathological studies were performed with a dose 10 times higher than the effective in ensuring the safety of the compound and discard thrombotic events. Finally the pharmacokinetics and toxicity of selected candidate was further analyzed. Results: After some iterations a lead compound was achieved: CM-352 significantly reduced the bleeding time by 89% in the hyperfibrinolytic tail bleeding model at a dose of 10 ug/Kg - 30,000 times lower than TXA. Moreover, CM-352 was also effective at reducing blood loss after liver laceration, where TXA had no significant effect. CM-352 showed optimal ADME/Tox and pharmacokinetic profile as well as cardiovascular safety; in addition, anatomopathological analysis (at 10 mg/kg) showed no thrombus formation in lung, brain, kidney or liver. Conclusions: Our findings demonstrate that CM-352 inhibits fibrinolysis and reduces blood loss safely and efficiently through a new mechanism of action, which underscores its potential for patients suffering major bleeding due to various medical and surgical conditions.
Comparison of degree and extent of coronary narrowing by atherosclerotic plaque in anterior and posterior transmural acute myocardial infarction.
Authors: F C Brosius, W C Roberts
Journal: Circulation (1981)

The percentage of cross-sectional area narrowing by atherosclerotic plaques in each 5-mm- long segment of the right, left main, left anterior descending and left circumflex coronary arteries was deter- mined at necropsy in 50 patients who died of a first acute transmural myocardial infarction (AMI).The amount and extent of the coronary narrowing were compared in the 22 patients with anterior wall AMI and in the 28 patients with posterior wall AMI.Although the percentage of coronary arteries narrowed 76-100% was similar in the anterior and posterior wall AMI patients (74% vs 75%; average 3.0 of 4 coronary arteries per patient), the patients with anterior wall AMI had less severe narrowing of each of the 5-mm segments of the four major coronary arteries than did the patients with posterior wall AMI.Of the 1166 5-mm coronary seg- ments examined in the 22 anterior wall AMI patients, 23% were narrowed 76-100% in cross-sectional area by atherosclerotic plaque, and of the 28 patients with posterior wall AMI, 39% of the segments were 76-100% narrowed (p < 0.001).Among the anterior AMI patients, a higher percentage of the 5-mm segments of the left anterior descending coronary artery was severely (> 75%) narrowed than either posterior perfusing cor- onary artery.The percentage of segments narrowed 76-100% for each of the major coronary arteries in the posterior AMI patients, however, was similar.Thus, our necropsy patients with posterior wall AMI had more extensive and severe coronary artery narrowing than did our patients with anterior wall AMI.If the coronary arteries had not been examined quantitatively, this difference in severity would not have been apparent.PATIENTS with acute myocardial infarction (AMI), with rare exception, have severe narrowing by atherosclerotic plaques of at least one and usually two or more of the four major epicardial coronary arter- ies.'-"Little information is available on the amount of coronary narrowing in patients who have anterior compared with those who have posterior ("inferior"') wall left ventricular infarcts.Little information is also available on the amount of narrowing by athero- sclerotic plaques in the four major coronary arteries in patients with either anterior or posterior left ven- tricular infarcts.7 AMI of the anterior left ventricular wall is believed by many to indicate a severe "lesion" in the left anterior descending coronary artery and ab-
Mechanism of defibrination in humans after envenomation by the eastern diamondback rattlesnake
Authors: Craig S. Kitchens, Lodewyk H. S. van Mierop
Journal: American Journal of Hematology (1983)

Abstract We prospectively studied the hemostatic system of ten persons bitten by the Eastern diamondback rattlesnake (Crotalus adamanteus) during 1978–1980. Blood was drawn when the patients arrived in the emergency room and every 6 hr thereafter. All envenomated victims developed incoagulable blood (defined by a thrombin time ≥ 120 sec, normal &lt; 20 sec). Platelet counts and plasma levels of antithrombin III and factors II and VIII were not drastically altered, which distinguished this disorder from classic disseminated intravascular coagulation. Fibrinogen levels were markedly decreased (mean coagulable level of 0 mg/dl and antigenic levels of 99 mg/dl). Plasminogen levels were 20% of normal, alpha‐2‐plasminogen inhibitor was 17% of normal, and plasminogen activator was 20 times normal. Levels of fibrin degradation products peaked at a mean of 7,680 μg/ml. The magnitude and duration of the coagulopathy were proportional to the clinical severity of envenomation. Treatment with antivenin blunted the coagulopathy. Because venom from the Eastern diamond‐back rattlesnake does not directly activate plasminogen, we conclude that coagulopathy following envenomation by that reptile appears to be due to partial proteolysis of fibrinogen with secondary activation of plasminogen by released plasminogen activator, probably of endothelial orgin.
Activation of Toll-like Receptor 4 on Tumor Cells<i>In vitro</i>Inhibits Subsequent Tumor Growth<i>In vivo</i>
Authors: Virginia Andreani, Gerardo Gatti, Lucio Simonella, Virginia Rivero, Mariana Maccioni
Journal: Cancer Research (2007)

Abstract Although an eruption of information on the role of Toll-like receptor 4 (TLR4), the main receptor for bacterial lipopolysaccharide, in activating macrophages and dendritic cells has emerged, very little is known about the role of TLR4 present on epithelial cells from sterile environments like tumors. The main goal of this work was to investigate the consequences of TLR4 activation present on tumor cells in two different animal models of cancer: the Dunning rat prostate cancer and the B16 murine melanoma models. We show that (a) activating TLR4 signaling in two different tumor cell lines in vitro modifies the tumor outgrowth in vivo; (b) this effect is not due to a direct consequence of TLR4 signaling on the proliferation/apoptosis balance of the tumor cells; (c) the T-cell compartment is somehow involved in the described phenomenon because the inhibitory effect observed is not seen in athymic nude mice; and (d) tumor-infiltrating lymphocytes purified from tumors induced by TLR4-activated cells show strong induction of IFNγ transcript in detriment of interleukin-10 transcript, suggesting a change in their functionality. We hypothesize that TLR4 signaling in tumor cells in vitro induces the expression of proinflammatory mediators, which could dramatically alter the maturation state of dendritic cells present at the site of inoculation, switching the type of immune response elicited against the tumor. These results open up new avenues for understanding the role of TLR4 in tumor cells and for identifying potential new therapy strategies for cancer. [Cancer Res 2007;67(21):10519–27]
Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia.
Authors: Y Fong, K J Tracey, L L Moldawer, D G Hesse, K B Manogue, J S Kenney, A T Lee, G C Kuo, A C Allison, S F Lowry
Journal: The Journal of Experimental Medicine (1989)

Cytokines secreted in response to invading micro-organisms are important mediators of detrimental hemodynamic and metabolic changes in the host. To test whether cachectin/TNF plays a role in triggering release of other cytokines in the setting of infection, anesthetized baboons were passively immunized against systemic cachectin/TNF before infusion of a LD100 dose of live Escherichia coli. Bacteremia led to significant increases in circulating levels of cachectin/TNF, IL-1 beta, and IL-6. Although bacterial endotoxin/lipopolysaccharide is a potent stimulus for the synthesis and release of IL-1 and IL-6 in vitro, specific neutralization of cachectin/TNF in vivo with mAb pretreatment significantly attenuated both the IL-1 beta and the IL-6 responses despite fulminant overwhelming bacteremia. These data suggest that cachectin/TNF is essential for the initiation or amplification of IL-1 and IL-6 release during lethal gram-negative septic shock syndrome.
Breakthrough on the consciousness front or much ado about nothing?
Authors: N. F. Dixon
Journal: Behavioral and Brain Sciences (1995)

Abstract Propositions as to the nature of consciousness, based on disorders of perception that result from brain damage, and taking insufficient account of the numerous ways in which normal subjects may deviate from that “usual” sequence of events (input → subjective awareness → output) risk increasing rather than diminishing any existing confusion about the function of consciousness.
Reconstructive Valve Surgery, From Valve Analysis to Valve ReconstructionCarpentierAlainAdamsDavid H.FilsoufiFarzanReconstructive Valve Surgery, From Valve Analysis to Valve Reconstruction 354 pages. Maryland Heights, MO: Saunders Elsevier, 2010. $199.00. ISBN: 978-0-7216-9168-8
Authors: Bruce J. Leavitt
Journal: Circulation (2011)
Macrolides inhibit cytokine production by alveolar macrophages in bronchiolitis obliterans organizing pneumonia
Authors: Miaotian Cai, Francesco Bonella, Huaping Dai, Rafael Sarria, Josune Guzman, Ulrich Costabel
Journal: European Respiratory Journal (2012)

Background and objective:  Bronchiolitis obliterans organizing pneumonia (BOOP) is a distinct clinicopathological entity histologically characterized by intra-alveolar granulation tissue and absence of extensive fibrotic lesions. Effective macrolide treatment of BOOP has been reported anecdotally. This study aimed to investigate whether alveolar macrophages (AMs) produce aberrant proinflammatory cytokines in BOOP and whether this can be inhibited by clarithromycin (CAM) or azithromycin (AZM).   Methods:  AMs collected by bronchoalveolar lavage (BAL) from 6 BOOP patients and 8 non-ILD controls were cultured for 24 hours in the presence or absence of CAM, AZM, lipopolysaccharide (LPS), or dexamethasone (DEX). Tumor necrosis factor alpha (TNF-α), soluble TNF receptor 1 (sTNFR1), sTNFR2, interleukin 1beta (IL-1β), IL-6, IL-8, IL-10, interferon gamma inducible protein 10 (IP-10) and CC chemokine ligand 18 (CCL18) were measured in the culture supernatant by ELISA.   Results:  The spontaneous and LPS-stimulated production of all investigated cytokines by AMs was significantly increased in BOOP compared to controls. CAM and AZM induced a dose-dependent suppression of spontaneous TNF-α, sTNFR2, IL-6, IL-8 and CCL18 production (p    Conclusions:  AMs from BOOP patients produce abundant proinflammatory cytokines which may be pivotal in the disease pathogenesis. Macrolides inhibit this cytokine production, CAM more efficiently than AZM.
Potential availability of cadaver organs for transplantation.
Authors: M A Salih, I Harvey, S Frankel, D J Coupe, M Webb, H A Cripps
Journal: BMJ (1991)

OBJECTIVE--To determine the potential number of cadaver kidney donors by applying defined donor criteria to people dying in hospital. DESIGN--Prospective study of all deaths occurring in 21 hospitals from 1 September 1988 to 31 August 1989. Questionnaires were administered to medical and nursing staff and families of potential donors aged 1-69. SETTING--Acute care hospitals in Gwent, South Glamorgan, Mid Glamorgan, West Glamorgan, Pembrokeshire, and East Dyfed health authorities, serving a population of 2.2 million. MAIN OUTCOME MEASURES--Cause of death, age, ventilation at time of death, diagnosis of brain death, and consideration of consent. RESULTS--Adequate data were available for 9840 of 10,095 hospital deaths (97.5% coverage). 188 patients aged 0-69 were identified as potential organ donors (widest definition), and of these 108 died without being ventilated at the time of death. Tests of brain stem death were formally completed in 57 cases, and organ donation was considered by the families of 47 of these potential donors. 26 patients became organ donors. Patients aged 50-69 with stroke were less likely to be ventilated than those aged less than or equal to 49 (21/96 v 24/34). Families of potential donors aged 20-39 were least likely to give permission. CONCLUSIONS--The supply of donor organs (specifically kidneys) could be increased by altering the management of patients aged 50-69 dying of severe cerebrovascular disease in general medical wards, in particular by increasing the proportion ventilated. The ethics of elective ventilation for the purposes of organ donation require discussion.
The Name of the Red-Eared Slider: Herpetologists in Slow Ferment
Authors: Kirk J. Banquer
Journal: JAMA (1986)

<h3>To the Editor.—</h3> The article entitled "Turtle-Associated Salmonellosis in Puerto Rico"<sup>1</sup>dealt with the exportation of pet turtles and the dissemination of human salmonellosis. The taxonomy of these turtles referred to should be brought up to date. Most herpetologists<sup>2,3</sup>now classify these red-eared sliders as<i>Chrysemys scripta-elegans</i>rather than<i>Pseudemys scripta-elegans</i>.
Knai and colleagues' response to comments of the Portman Group in news story about their research on the "responsibility deal" on alcohol
Authors: Cécile Knai, Mark Petticrew, Nicholas Mays, Mary Alison Durand, Elizabeth Eastmure
Journal: BMJ (2015)

Some statements from the Portman Group about our evaluation of the “responsibility deal” on alcohol are seriously misleading.1

The statement about our “track record of campaigning against voluntary agreements” is inaccurate. One of our first studies set out to understand the characteristics of effective voluntary agreements,2 which should be based on clearly defined, evidence based, and quantifiable targets; should push partners to go beyond “business as usual”; and should include penalties for not delivering the pledges. Our …
Augmentation of in vitro humoral immune responses in the mouse by an antibody to IgD.
Authors: F D Finkelham, V L Woods, S B Wilburn, J J Mond, K E Stein, A Berning, I Scher
Journal: The Journal of Experimental Medicine (1980)

Heterologous anti-delta-chain antibodies have an adjuvant effect on specific in vivo humoral immune responses to simultaneously, or subsequently, injected antigens in the rat and rhesus monkey. We have used a hybridoma-secreted antibody that binds murine delta-chain of the allotype (4.22aM delta a) to study this phenomenon in the mouse and to investigate the mechanism of this effect. Injection of 4.22aM delta a into BALB/c mice removes almost all surface IgD (sIgD) from splenic B lymphocites. sIgD does not reappear until the serum level of 4.22aM delta a decreased 5-7 d after injection. 4.22aM delta a fails to induce detectable proliferation or to raise total serum Ig levels substantially above control values. However, 4.22aM dalta a injected 24 h before antigen elicits an approximately twofold enhancement of serum IgM and a 3- to 10-fold enhancement of serum IgG anti-trintriphenyl (TNP) antibodies in response to immunization with optimal doses of TNP-Ficoll or TNP-sheep red blood cells (TNP-SRBC). 4.22aM delta a injected 1 wk before or 3 d after TNP-SRBC, however, has no effect on IgG anti-TNP levels. The adjuvant effect of anti-delta-chain antibody was markedly decreased when suboptimal antigen doses were used. Furthermore, even in the case of TNP-Ficoll, a relatively T-independent antigen, the ability of 4.22aM dalta a to enhance the anti-TNP antibody response was T cell dependent. Our data suggest that the binding of anti-delta-chain antibody to cell sIgD may partially activate B lymphocytes and make them more capable of differentiating into antibody-secreting cells when stimulated by antigen-specific T cell help.
Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL
Authors: Cristina Sobacchi, Annalisa Frattini, Matteo M Guerrini, Mario Abinun, Alessandra Pangrazio, Lucia Susani, Robbert Bredius, Grazia Mancini, Andrew Cant, Nick Bishop, Peter Grabowski, Andrea Del Fattore, Chiara Messina, Gabriella Errigo, Fraser P Coxon, Debbie I Scott, Anna Teti, Michael J Rogers, Paolo Vezzoni, Anna Villa, Miep H Helfrich
Journal: Nature Genetics (2007)
Features of epidermolysis bullosa simplex due to mutations in the ectodomain of type XVII collagen
Authors: A.M.G. Pasmooij, G. Van Der Steege, H.H. Pas, J.H.sillevis Smitt, A.M. Nijenhuis, J. Zuiderveen, M.F. Jonkman
Journal: British Journal of Dermatology (2004)

Journal Article Features of epidermolysis bullosa simplex due to mutations in the ectodomain of type XVII collagen Get access A.M.G. Pasmooij, A.M.G. Pasmooij Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar G. Van Der Steege, G. Van Der Steege Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar H.H. Pas, H.H. Pas Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J.H.sillevis Smitt, J.H.sillevis Smitt Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar A.M. Nijenhuis, A.M. Nijenhuis Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar J. Zuiderveen, J. Zuiderveen Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M.F. Jonkman M.F. Jonkman Centre for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital, Hanzeplein 1, NL‐9700 RB Groningen, the Netherlands *Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Professor M.F.Jonkman. E‐mail: m.f.jonkman@derm.azg.nl Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 151, Issue 3, 1 September 2004, Pages 669–674, https://doi.org/10.1111/j.1365-2133.2004.06041.x Published: 01 September 2004 Article history Accepted: 28 December 2003 Published: 01 September 2004
228. Secretory PTD Fusion Proteins
Authors: Paul A. Shaw, Ian R. Catchpole, William H. Colledge
Journal: Molecular Therapy (2005)

The field of gene therapy and DNA vaccination fundamentally rely on the same technology to deliver and express therapeutic DNA in target cells. To be efficacious in the clinic, many aspects need improving and a number of barriers overcome. One such barrier is the delivery of the gene to a sufficient number of cells to elicit a therapeutic response. A possible method to circumvent this problem would be to enable the expressed therapeutic protein to spread to neighboring cells, hence increasing the overall therapeutic response. In the literature a number of peptide sequences have been identified that aid transduction of full length proteins across cellular membranes. These short basic peptides are commonly referred to as Protein Transduction Domains (PTDs). Two heavily investigated PTDs are the HIV-1 encoded transactivator of transcription (TAT) protein and the Drosophila Antennapedia (Antp) homeoprotein.
Endocrine treatment of physiological gynaecomastia
Authors: H. N Khan
Journal: BMJ (2003)

Tamoxifen seems to be effective 

Gynecomastia is a common condition among normal healthy men of varying ages. Tenderness may be one of its symptoms, but the usual reason for presentation is that young men don't like having breasts and older men are worried about the possibility of cancer. Diagnosis is primarily by clinical examination and where necessary ultrasound and needle biopsy. Traditional methods of management of gynaecomastia have included simple analgesia for pain, and surgery. The most common reason for the patient to request surgery is cosmetic. However, although surgery in experienced hands is safe and effective, with minimal stay in hospital, the cosmetic results cannot always be guaranteed—noticeable scars, permanent pigment changes in the breast area, and mismatched breasts or nipples have been reported.1 …
Autoimmunity in Patients Treated With Levodopa
Authors: George C. Cotzias
Journal: JAMA (1969)

<h3>To the Editor:—</h3> During our early studies of Parkinsonism with D,L DOPA<sup>1</sup>and during those with the L-isomer<sup>2,3</sup>Coombs tests were performed frequently. Continuation of this practice was indicated both on general grounds<sup>4</sup>and on the basis of a precedent with a DOPA derivative, namely D,L-a-methyldopa. This latter compound is serving in the management of hypertension under the trade name Aldomet. A toxic manifestation of methyldopa is the development of a positive Coombs test usually unaccompanied by demonstrable hemolysis.<sup>5,6</sup>We have encountered a similar change during the long-term administration of levodopa (L-DOPA) in the large amounts presently necessary to control Parkinsonism. Among 43 individuals treated during the last 3 1/2 years with either or both forms of DOPA, positive direct Coombs tests recently developed in four. These individuals also displayed positive indirect tests the titers of which were low (1:0 to 1:8). In two patients these
Risk of psychiatric side effects with varenicline
Authors: T. J Moore, C. D Furberg
Journal: BMJ (2009)

Gunnell and colleagues report “no clear evidence” that varenicline, a drug to aid smoking cessation, is associated with suicidal behaviours.1 This finding is directly contradicted by a strong signal seen in the most recent data from the UK’s yellow card system (table⇓).2

View this table:

Numbers of psychiatric symptoms reported under UK yellow card …