tbuckley/cabot-search huggingface dataset:
Is Clopidogrel Cardiovascular Medicine’s Double-Edged Sword?
Authors: Anthony A. Bavry, A. Michael Lincoff
Journal: Circulation (2006)

ntiplatelet therapy with aspirin has been unequivocally demonstrated to reduce the risk of ischemic complications across a broad spectrum of patients with vascular disease. 1 This agent is also an important pharmacological adjunct to percutaneous and surgical coronary revascularization procedures.Administration of aspirin after coronary bypass graft operations had been the standard of care for many years, although early experience suggested that this agent would increase hemorrhagic complications if administered before surgery. 2 However, subsequent evidence showed that preoperative aspirin improves survival without an appreciable increase in surgical bleeding. 3More recently, concerns regarding surgical bleeding risk have resurfaced with the introduction into clinical practice of a newer class of platelet inhibitors: the thienopyridines, ticlopidine and clopidogrel. Article p 1667Thienopyridines interfere with platelet activation by selectively and irreversibly blocking a subunit of the adenosine diphosphate receptor.This provides an antiplatelet effect that is additive to the inhibition of the thromboxane A 2 pathway by aspirin.The clinical benefit derived from the combination of aspirin and a thienopyridine first became apparent with trials demonstrating the efficacy of these agents in preventing subacute thrombosis after coronary stenting. 4Subsequently, large-scale clinical studies showed that long-term therapy (9 to 12 months) with aspirin and clopidogrel reduces ischemic complications compared with aspirin alone among patients with acute coronary syndromes 5 or after percutaneous coronary revascularization. 6In the population of patients with acute coronary syndromes, dual antiplatelet therapy begins to reduce adverse outcomes as early as 2 hours after administration, and the magnitude of benefit expands over the following 9 months. 5Moreover, several lines of evidence suggest that the greatest suppression of ischemic events among patients undergoing percutaneous coronary revascularization is achieved if a 300-to 600-mg loading dose of clopidogrel is administered 2 to 6 hours before the interventional procedure is started. 6 -8 This pretreatment period likely
Local appendiceal dysbiosis: the missing link between the appendix and ulcerative colitis?
Authors: X Roblin, C Neut, A Darfeuille-Michaud, J F Colombel
Journal: Gut (2011)

We read with great interest the article by Swidsinski et al reporting on a possible link between acute appendicitis and a local invasion by Fusobacteria. Investigating sections of 70 appendixes with confirmed appendicitis using rRNA-based fluorescence in situ hybridisation, the authors found bacteria deeply infiltrating the appendix. Fusobacteria (mainly Fusobacterium nucleatum/necrophorum ) were specific components of epithelial and submucosal infiltrates in 62% of patients and were not found in various controls. The presence of Fusobacteria correlated positively with the severity of appendicitis. Conversely, main faecal microbiota including Faecalibacterium prausnitzii groups were significantly decreased with an inverse relationship with the severity of the disease.1

Altogether, these observations point to the presence …
Studying human airway pharmacology in microsections: application of videomicrometry
Authors: D.T. Schmidt, G. Dent, E. Rühlmann, N.M. Muñoz, A.R. Leff, K.F. Rabe
Journal: European Respiratory Journal (2002)

The influence of endogenously-released mediators and activated eosinophils on the airway lumen and the effect of passive sensitization on anti-immunoglobulin (Ig)-E-induced contractile responses was investigated by videomicrometry. Human bronchial sections of 2–3 mm internal diameter, placed in 250 µL Hank's balanced salt solution on microtitre plates, were monitored and recorded by digitized image analysis. Airway preparations exhibited a spontaneous narrowing (mean±sem −33±5% of the luminal area). Removal of the bronchial epithelium almost completely prevented the development of spontaneuous narrowing (−6±3%; p&lt;0.001). The addition of platelet-activating factor stimulated human eosinophils to the bronchial sections led to significant narrowing of the airway lumen (−39±9%; p&lt;0.05). Passive sensitization induced hyperresponsiveness to polyclonal anti-IgE (−35±8%; p&lt;0.01). It is concluded that videomicrometry is suitable for studying interactions between human airways and inflammatory cells, as well as the effect of passive sensitization on smooth muscle reactivity in vitro , without the imposition of preload. Under these conditions, human airways exhibited a spontaneous decrease of the airway lumen over time suggesting a role for epithelium-derived mediators because the development of spontaneous tone was epithelium dependent.
Antigen persistence is required throughout the expansion phase of a CD4+ T cell response
Authors: Reinhard Obst, Hisse-Martien van Santen, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2005)

For CD8(+) T cells, a relatively short antigen pulse seems sufficient for antigen-presenting cells to drive clonal expansion and differentiation. It is unknown whether the requirement for antigen is similarly ephemeral for CD4(+) T cells. To study the dependence of a CD4(+) T cell response on antigen persistence in a quantitatively and temporally controlled manner in vivo, we engineered a mouse line expressing a major histocompatibility complex class II-restricted epitope in dendritic cells under the control of a tetracycline-inducible promoter. Experiments tracking the proliferation of CD4(+) T cells exposed to their cognate antigen in various amounts for different time periods revealed that the division of such cells was contingent on the presence of antigen throughout their expansion phase, even in the presence of an inflammatory stimulus. This previously unrecognized feature of a CD4(+) T cell response contrasts with the proliferative behavior of CD8(+) T cells that has been documented, and it implies that the two T cell subsets might require different strategies for efficient vaccination.
Absence of CD9 Enhances Adhesion-Dependent Morphologic Differentiation, Survival, and Matrix Metalloproteinase-2 Production in Small Cell Lung Cancer Cells
Authors: Yoshiyuki Saito, Isao Tachibana, Yoshito Takeda, Hiroyuki Yamane, Ping He, Mayumi Suzuki, Seigo Minami, Takashi Kijima, Mitsuhiro Yoshida, Toru Kumagai, Tadashi Osaki, Ichiro Kawase
Journal: Cancer Research (2006)

Abstract While adhering to extracellular matrix proteins in vitro and in vivo, small cell lung cancer (SCLC) cells frequently show morphologic differentiation and are protected from apoptosis. Integrin β1–mediated protein phosphorylation is suggested to be an essential signaling event in these processes. CD9 is an almost ubiquitously expressed tetraspanin protein that suppresses tumor progression by regulating cell motility and signaling through complex formation with β1 integrins. We reported previously that, among tetraspanins, CD9 is selectively absent in most SCLC cells and that ectopic expression of CD9 suppresses their motility. Here, we show that the ectopic expression of CD9 suppressed neurite-like process outgrowth and promoted apoptotic death of SCLC cells that were adherent to fibronectin in serum-starved conditions. This correlated with attenuation of adhesion-dependent phosphorylation of Akt but not that of focal adhesion kinase or c-Jun NH2-terminal kinase. Treatment of CD9− parent cells with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, inhibited process outgrowth and survival, suggesting that PI3K/Akt signaling is required for the morphologic change and cell survival. Production of matrix metalloproteinase (MMP)-2 was likewise suppressed in the CD9 transfectants and in LY294002-treated parent cells. These results suggest that the absence of CD9 in SCLC cells may contribute to postadhesive morphologic differentiation, survival, and MMP-2 production via PI3K/Akt pathway. (Cancer Res 2006; 66(19): 9557-65)
Induction of the CXC Chemokine Interferon-γ-Inducible Protein 10 Regulates the Reparative Response Following Myocardial Infarction
Authors: Marcin Bujak, Marcin Dobaczewski, Carlos Gonzalez-Quesada, Ying Xia, Thorsten Leucker, Pawel Zymek, Vikas Veeranna, Andrew M. Tager, Andrew D. Luster, Nikolaos G. Frangogiannis
Journal: Circulation Research (2009)

Rationale: Interferon-γ-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. Objective: To study the role of IP-10 in cardiac repair and remodeling. Methods and Results: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10 −/− hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10 −/− infarcts had more intense infiltration with CD45 + leukocytes, Mac-2 + macrophages, and α-smooth muscle actin (α-SMA) + myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and α-SMA + cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. Conclusions: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.
A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia
Authors: Donald E. Tsai, Selina M. Luger, Charalambos Andreadis, Dan T. Vogl, Allison Kemner, Melissa Potuzak, Ami Goradia, Alison W. Loren, Alexander E. Perl, Stephen J. Schuster, David L. Porter, Edward A. Stadtmauer, Steven C. Goldstein, James E. Thompson, Cezary Swider, Adam Bagg, Anthony R. Mato, Martin Carroll
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML). Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m2 until evidence of disease progression or unacceptable adverse events occurred. Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m2), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m2. Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to ≤5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived &amp;gt;1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome. Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m2/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.
Fasudil, a Rho-Kinase Inhibitor, Attenuates Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice by Inhibiting Apoptosis and Proteolysis
Authors: Yi-Xin Wang, Baby Martin-McNulty, Valdeci da Cunha, Jon Vincelette, Xiangru Lu, Qingping Feng, Meredith Halks-Miller, Mithra Mahmoudi, Miriam Schroeder, Babu Subramanyam, Jih-Lie Tseng, Gary D. Deng, Sabine Schirm, Anthony Johns, Katalin Kauser, William P. Dole, David R. Light
Journal: Circulation (2005)

Angiotensin II (Ang II) accelerates atherosclerosis and induces abdominal aortic aneurysm (AAA) in an experimental mouse model. Agonism of a G protein-coupled receptor by Ang II activates Rho-kinase and other signaling pathways and results in activation of proteolysis and apoptosis. Enhanced proteolysis and smooth muscle cell apoptosis are important mechanisms associated with AAA. In this study, we tested the hypothesis that fasudil, a Rho-kinase inhibitor, could attenuate Ang II-induced AAA formation by inhibiting vascular wall apoptosis and extracellular matrix proteolysis.Six-month-old apolipoprotein E-deficient mice were infused with Ang II (1.44 mg x kg(-1) x d(-1)) for 1 month. Animals were randomly assigned to treatment with fasudil (136 or 213 mg x kg(-1) x d(-1) in drinking water) or tap water. Ang II infusion induced AAA formation in 75% of the mice, which was accompanied by an increase in proteolysis detected by zymographic analysis and quantified by active matrix metalloproteinase-2 activity, as well as apoptosis detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and quantified by both caspase-3 activity and histone-associated DNA fragmentation. The level of DNA fragmentation in the suprarenal aorta correlated with AAA diameter. Ang II also increased atherosclerotic lesion area and blood pressure. Fasudil treatment resulted in a dose-dependent reduction in both the incidence and severity of AAA. At the higher dose, fasudil decreased AAA by 45% while significantly inhibiting both apoptosis and proteolysis, without affecting atherosclerosis or blood pressure.These data demonstrate that inhibition of Rho-kinase by fasudil attenuated Ang II-induced AAA through inhibition of both apoptosis and proteolysis pathways.
Changes in muscle tendon unit stiffness with increasing running speed
Authors: C Salvidge, P R Hayes
Journal: British Journal of Sports Medicine (2010)

The spring mass model of running proposes that with increases in running speed there will be decreases in ground contact time and concomitant increases in muscle tendon unit (MTU) stiffness. Previous studies examining these relationships have used either a limited number of running speeds or low numbers of participants. To date equivocal results have been found between changes in MTU stiffness and running speed. The purpose of this study was to examine changes in MTU stiffness with changes in running speed. After institutional ethical approval 18 physically active males (aged 20.8±0.9 years; stature 1.77±0.18 m; body mass 75.4±11.1 kg) completed the maximal anaerobic running test (MART). The MART test began at 11.9 km/h with each stage increasing by 1.37 km/h until participants could no longer complete a 20 s stage. Throughout the test ground contact time (Tc) was recorded at 1000 Hz using the Optojump Next system. Ground Tcs were used to calculate MTU stiffness using the method of Morin et al 1. Regression analysis revealed near perfect relationships with running speed for both Tc (F 1, 8=295.101; p&lt;0.001; R 2 =0.970; SEE=0.007 ms) and MTU stiffness (F 1, 8=725.844; p&lt;0.001; R 2 =0.988; SEE=0.798 kN/m). This study has used more participants and a wider range of participants than previous literature. These results provide strong supporting evidence for the spring mass model of running.
Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure
Authors: Ilan Goldenberg, Valentina Kutyifa, Helmut U Klein, David S Cannom, Mary W Brown, Ariela Dan, James P Daubert, N A Mark Estes, Elyse Foster, Henry Greenberg, Josef Kautzner, Robert Klempfner, Malte Kuniss, Bela Merkely, Marc A Pfeffer, Aurelio Quesada, Sami Viskin, Scott McNitt, Bronislava Polonsky, Ali Ghanem, Scott D Solomon, David Wilber, Wojciech Zareba, Arthur J Moss
Journal: New England Journal of Medicine (2014)

The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone.We evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis.At 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval [CI], 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundle-branch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P=0.04; P<0.001 for interaction of treatment with QRS morphologic findings).Our findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271, NCT01294449, and NCT02060110.).
Pulmonary hypertension and lung transplantation:<i>Thorax</i>publication activity review 2008–2010
Authors: Helmy Haja Mydin, Andrew J Fisher
Journal: Thorax (2011)

AbstractA review is presented on articles published in Thorax between 2008 and 2010 relating to lung transplantation and pulmonary hypertension.Lung transplantationpulmonary hypertensionairway epitheliumbronchiectasiscystic fibrosiscytokine biologyinnate immunityinterstitial fibrosislung proteaseslung transplantationlung physiologyprimary pulmonary hypertension
Local denaturation of collagen fibres during the mechanical rupture of collagenous fibrous tissue.
Authors: R J Minns, F S Steven
Journal: Annals of the Rheumatic Diseases (1980)

Human extensor tendons of the hand were pulled to rupture, and the torn ends, when observed in the scanning electron microscope, appeared to be knotted, possibly owing to the denaturation of the collagen. This confirmed by fluorimetry assays of both the ruptured ends and the middle unbroken sections of the same tendons. The use of a proteolytic enzyme, trypsin, to remove the denatured material and enhance the repair of organised collagen fibres from both ends is suggested if the ruptured ends have the denatured knotted appearance commonly observed clinically.
CD45RC− γδ+ T-cell infiltration is associated with immunologic unresponsiveness induced by prior donor-specific blood transfusion in rat hepatic allografts
Authors: Kazutoshi Okabe, Yasuo Yamaguchi, Eiji Takai, Hajime Ohshiro, Jia-Lin Zhang, Hideki Hidaka, Kohjiroh Ishihara, Shinichiro Uchino, Takashi Furuhashi, Shinwa Yamada, Katsutaka Mori, Michio Ogawa
Journal: Hepatology (2001)

Little is known regarding the role of gammadelta(+) T cells in organ transplantation. We previously reported that immunologic unresponsiveness is induced by prior donor-specific blood transfusion (DST) in rat hepatic allografts. We investigated the phenotype and distribution of gammadelta(+) T cells in the hepatic allograft, spleen, and peripheral blood of recipient rats with immunologic unresponsiveness induced by DST. gammadelta(+) T cells were enumerated in allograft livers and spleens by immunostaining and in blood by flow cytometric analysis. The phenotype of gammadelta(+) T cells was determined using CD45RC isoforms derived from alternative mRNA splicing. The cytokine profile of CD45RC(+) and CD45RC(-) gammadelta(+) T cells was analyzed by reverse transcription polymerase chain reaction. The number of gammadelta(+) T cells in hepatic infiltrates in recipient rats pretreated with DST was significantly greater than in untreated animals. This correlated with significantly higher levels of gammadelta T cell receptor (TCR) mRNA in hepatic allografts of DST-treated rats as compared with untreated animals. The gammadelta(+) T cell/alphabeta(+) T-cell ratio increased in hepatic infiltrates in DST-treated recipient rats but not in untreated animals. CD45RC(-)gammadelta(+) T cells were predominantly increased in DST-treated hepatic allografts compared with untreated allografts. Most of the intestinal intraepithelial T cells were CD45RC(-)gammadelta(+). Interleukin (IL)-10 and IL-4 mRNA were detected more in CD45RC(-)gammadelta(+) T cells than CD45RC(+)gammadelta(+) T cells. CD45RC(-)gammadelta(+) T cells infiltrating liver allografts produce Th2-type cytokines and are associated with immunologic unresponsiveness induced by DST.