tbuckley/cabot-search huggingface dataset:
Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting
Authors: Alexander Kulik, Michel R. Le May, Pierre Voisine, Jean-Claude Tardif, Robert DeLarochelliere, Sarika Naidoo, George A. Wells, Thierry G. Mesana, Marc Ruel
Journal: Circulation (2010)

Background— Clopidogrel inhibits intimal hyperplasia in animal studies and therefore may reduce saphenous vein graft (SVG) intimal hyperplasia after coronary artery bypass grafting. The Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) study was undertaken to evaluate whether the addition of clopidogrel to aspirin inhibits SVG disease after coronary artery bypass grafting, as assessed at 1 year by intravascular ultrasound. Methods and Results— In this double-blind phase II trial, 113 patients undergoing coronary artery bypass grafting with SVGs were randomized to receive aspirin 162 mg plus clopidogrel 75 mg daily or aspirin 162 mg plus placebo daily for 1 year. The primary outcome was SVG intimal hyperplasia (mean intimal area) as determined by intravascular ultrasound at 1 year. Secondary outcomes were graft patency, major adverse cardiovascular events, and major bleeding. One-year intravascular ultrasound and coronary angiography were performed in 92 patients (81.4%). At 1 year, SVG intimal area did not differ significantly between the 2 groups (4.1±2.0 versus 4.5±2.1 mm 2 , aspirin-clopidogrel versus aspirin-placebo, P =0.44). Overall 1-year graft patency was 95.2% in the aspirin-clopidogrel group compared with 95.5% in the aspirin-placebo group ( P =0.90), and SVG patency was 94.3% in the aspirin-clopidogrel group versus 93.2% in the aspirin-placebo group ( P =0.69). Freedom from major adverse cardiovascular events at 1 year was 92.9±3.4% in the aspirin-clopidogrel group and 91.1±3.8% in the aspirin-placebo group ( P =0.76). The incidence of major bleeding at 1 year was similar for the 2 groups (1.8% versus 0%, aspirin-clopidogrel versus aspirin-placebo, P =0.50). Conclusions— Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia 1 year after coronary artery bypass grafting. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00228423.
Effects of Ventricular Premature Stimulus Coupling Interval on Blood Pressure and Heart Rate Turbulence
Authors: Mari A. Watanabe, Joseph E. Marine, Robert Sheldon, Mark E. Josephson
Journal: Circulation (2002)

Background — Heart rate turbulence (HRT) is a promising noninvasive risk stratifier for mortality after myocardial infarction. On the basis of a study of ventricular premature complex coupling interval and sympathetic nerve burst amplitude, we hypothesized that measures of HRT would increase with increased prematurity of the coupling interval. Methods and Results — Twenty-eight patients undergoing programmed electrical stimulation were studied (12 with prior myocardial infarction, aged 60±18 years). An extrastimulus was delivered from the right ventricular apex after 20 sinus beats with a V-S 2 coupling interval decremented by 20 to 30 ms until refractoriness was reached. Turbulence slope (TS), turbulence timing (TT), and turbulence onset were calculated for each extrastimulus, and the linear regressions of these parameters on coupling interval and compensatory pause were calculated. Arterial blood pressure was measured with arterial catheter or a noninvasive continuous blood pressure transducer (Buffington cuff). TS and turbulence onset were abnormal in 4 and 13 patients, respectively. HRT parameters were significantly correlated with coupling interval or compensatory pause in only 2 or 3 patients for a given regression analysis. This absence of correlation was found likely to be due to lack of correlation between compensatory pause and systolic blood pressure after the compensatory pause. Heart rate and TS were correlated: Patients with high heart rate had low TS and late TT (TS=−2.7+0.01×sinus cycle length, P =0.018; TT=8.8 to 0.005×sinus cycle length, P =0.013). Conclusions — HRT can be induced by programmed stimulation. In this setting, heart rate affects HRT but not ventricular premature complex prematurity. Induced HRT seems to be a valid method for measuring HRT parameters in patients with few ventricular premature complexes.
Early Growth Response Gene 1–mediated Apoptosis Is Essential for Transforming Growth Factor β1–induced Pulmonary Fibrosis
Authors: Chun Geun Lee, Soo Jung Cho, Min Jong Kang, Svetlana P. Chapoval, Patty J. Lee, Paul W. Noble, Teshome Yehualaeshet, Binfeng Lu, Richard A. Flavell, Jeffrey Milbrandt, Robert J. Homer, Jack A. Elias
Journal: The Journal of Experimental Medicine (2004)

Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-beta(1) has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-beta(1) in the lung and its roles in the pathogenesis of these responses are not completely understood. In addition, the relationships between apoptosis and other TGF-beta(1)-induced responses have not been defined. To address these issues, we targeted bioactive TGF-beta(1) to the murine lung using a novel externally regulatable, triple transgenic system. TGF-beta(1) produced a transient wave of epithelial apoptosis that was followed by mononuclear-rich inflammation, tissue fibrosis, myofibroblast and myocyte hyperplasia, and septal rupture with honeycombing. Studies of these mice highlighted the reversibility of this fibrotic response. They also demonstrated that a null mutation of early growth response gene (Egr)-1 or caspase inhibition blocked TGF-beta(1)-induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-beta(1)-induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-beta(1) in vivo and define the critical role of Egr-1 in the TGF-beta(1) phenotype. They also demonstrate that Egr-1-mediated apoptosis is a prerequisite for TGF-beta(1)-induced fibrosis and remodeling.
Comparison of intravenous alteplase with a combined intravenous–endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study
Authors: Mikael Mazighi, Jean-Michel Serfaty, Julien Labreuche, Jean-Pierre Laissy, Elena Meseguer, Philippa C Lavallée, Lucie Cabrejo, Tarik Slaoui, Céline Guidoux, Bertrand Lapergue, Isabelle F Klein, Jean-Marc Olivot, Halim Abboud, Olivier Simon, Philippe Niclot, Chantal Nifle, Pierre-Jean Touboul, Gai Raphaeli, Christiane Gohin, Elisabeth Schouman Claeys, Pierre Amarenco
Journal: The Lancet Neurology (2009)
Constrictive Bronchiolitis in Soldiers Returning from Iraq and Afghanistan
Authors: Matthew S. King, Rosana Eisenberg, John H. Newman, James J. Tolle, Frank E. Harrell, Hui Nian, Mathew Ninan, Eric S. Lambright, James R. Sheller, Joyce E. Johnson, Robert F. Miller
Journal: New England Journal of Medicine (2011)

In this descriptive case series, 80 soldiers from Fort Campbell, Kentucky, with inhalational exposures during service in Iraq and Afghanistan were evaluated for dyspnea on exertion that prevented them from meeting the U.S. Army's standards for physical fitness.The soldiers underwent extensive evaluation of their medical and exposure history, physical examination, pulmonary-function testing, and high-resolution computed tomography (CT). A total of 49 soldiers underwent thoracoscopic lung biopsy after noninvasive evaluation did not provide an explanation for their symptoms. Data on cardiopulmonary-exercise and pulmonary-function testing were compared with data obtained from historical military control subjects.Among the soldiers who were referred for evaluation, a history of inhalational exposure to a 2003 sulfur-mine fire in Iraq was common but not universal. Of the 49 soldiers who underwent lung biopsy, all biopsy samples were abnormal, with 38 soldiers having changes that were diagnostic of constrictive bronchiolitis. In the remaining 11 soldiers, diagnoses other than constrictive bronchiolitis that could explain the presenting dyspnea were established. All soldiers with constrictive bronchiolitis had normal results on chest radiography, but about one quarter were found to have mosaic air trapping or centrilobular nodules on chest CT. The results of pulmonary-function and cardiopulmonary-exercise testing were generally within normal population limits but were inferior to those of the military control subjects.In 49 previously healthy soldiers with unexplained exertional dyspnea and diminished exercise tolerance after deployment, an analysis of biopsy samples showed diffuse constrictive bronchiolitis, which was possibly associated with inhalational exposure, in 38 soldiers.
Effects of Acute versus Chronic Hypoxia on DNA Damage Responses and Genomic Instability
Authors: Isabel M. Pires, Zuzana Bencokova, Manuela Milani, Lisa K. Folkes, Ji-Liang Li, Mike R. Stratford, Adrian L. Harris, Ester M. Hammond
Journal: Cancer Research (2010)

Questions exist concerning the effects of acute versus chronic hypoxic conditions on DNA replication and genomic stability that may influence tumorigenesis. Severe hypoxia causes replication arrest independent of S-phase checkpoint, DNA damage response, or transformation status. Arrests occur during both the initiation and elongation phases of DNA replication, correlated with a rapid decrease in available deoxynucleotide triphosphates. With fluctuating oxygen tensions in tumors, arrested hypoxic cells may undergo rapid reperfusion and reoxygenation that leads to reoxygenation-induced DNA damage. In cells subjected to chronic hypoxia, we found that replicative restart was inhibited along with numerous replication factors, including MCM6 and RPA, the latter of which limits the hypoxia-induced DNA damage response. In contrast, in cells where replicative restart occurred, it was accompanied by extensive reoxygenation-induced DNA damage and compromised DNA repair. We found that cells reoxygenated after acute hypoxia underwent rapid p53-dependent apoptosis. Our findings suggest that cells lacking functional p53 are more susceptible to genomic instability and potentially tumorigenesis if they experience reoxygenation after acute exposure to hypoxia.
C<scp>hemokines in</scp>I<scp>nnate and</scp>A<scp>daptive</scp>H<scp>ost</scp>D<scp>efense</scp>: Basic Chemokinese Grammar for Immune Cells
Authors: Antal Rot, Ulrich H. von Andrian
Journal: Annual Review of Immunology (2004)

Chemokines compose a sophisticated communication system used by all our cell types, including immune cells. Chemokine messages are decoded by specific receptors that initiate signal transduction events leading to a multitude of cellular responses, leukocyte chemotaxis and adhesion in particular. Critical determinants of the in vivo activities of chemokines in the immune system include their presentation by endothelial cells and extracellular matrix molecules, as well as their cellular uptake via "silent" chemokine receptors (interceptors) leading either to their transcytosis or to degradation. These regulatory mechanisms of chemokine histotopography, as well as the promiscuous and overlapping receptor specificities of inflammation-induced chemokines, shape innate responses to infections and tissue damage. Conversely, the specific patterns of homeostatic chemokines, where each chemokine is perceived by a single receptor, are charting lymphocyte navigation routes for immune surveillance. This review presents our current understanding of the mechanisms that regulate the cellular perception and pathophysiologic meaning of chemokines.
PWE-162 Seasonal and diurnal variation in the presentation and severity of acute upper gastrointestinal bleeding
Authors: B R Disney, R Watson, A Blann, G Lip, C Tselepis, M Anderson
Journal: Gut (2012)

<h3>Introduction</h3> Acute upper gastrointestinal bleeding is a medical emergency associated with a significant health burden and risk of mortality. Previous studies have looked for diurnal and seasonal variations in presentation. No studies have addressed these issues in the UK population. <h3>Methods</h3> All patients admitted with acute upper gastrointestinal bleeding to Sandwell and West Birmingham Hospitals NHS Trust from 1 January 2009 to 31 December 2009 were included in the study. Diurnal and seasonal differences in presentation were analysed using the χ<sup>2</sup> test; differences in Rockall and Blatchford scores were analysed using the Kruskal–Wallis test followed by the Mann–Whitney U test, with Bonferroni correction, to assess differences between individual groups. <h3>Results</h3> Overall, 470 patients with acute upper gastrointestinal bleeding were admitted during the study period. Of these 67.2% were male and 32.8% female. The mean age of patients was 64.0±18.8 years. Significant differences were seen in both diurnal and seasonal variation. Patients were more likely to present between the hours of 12:01–18:00 (p&lt;0.001). Admission rates were lower during the winter months (p=0.028). The Rockall score showed significant diurnal variation (p=0.048). No diurnal variation was seen in the Blatchford score (p=0.39). <h3>Conclusion</h3> Acute upper gastrointestinal bleeding shows a significant diurnal and seasonal variation in presentation. Diurnal variation is observed in Rockall scores, although this is of doubtful clinical relevance. The variation in presentation of acute upper gastrointestinal bleeding may have implications for the provision of endoscopy services. <h3>Competing interests</h3> None declared.
Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor–β1
Authors: Ichiko Kinjyo, Hiromasa Inoue, Shinjiro Hamano, Satoru Fukuyama, Takeru Yoshimura, Keiko Koga, Hiromi Takaki, Kunisuke Himeno, Giichi Takaesu, Takashi Kobayashi, Akihiko Yoshimura
Journal: The Journal of Experimental Medicine (2006)

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell–specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4+ T cells produced more transforming growth factor (TGF)-β1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-β1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-β1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-β1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-β1 and IL-10 through modulating STAT3 activation.
Cysteine proteinase inhibitors decrease rankl and lps induced differentiation of human and mouse osteoclast progenitor cells
Authors: F Strålberg, P Henning, I Gjertson, B Kindlund, PPC Souza, E Persson, M Abrahamson, F Kasprzykowski, A Grubb, UH Lerner
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> The authors have previously reported that the cysteine proteinase inhibitor (CPI) cystatin C (CysC) reduces osteoclast formation induced by signal pathways activated by either PTH receptor, vitamin D receptor or gp130 in crude mouse bone marrow cultures (ref). In the present study, the authors have investigated if CysC, E-64 (fungal CPI) and the tetrapeptidyl derivative Z-RLVG-CHN<sub>2</sub> (representing Arg<sup>8</sup>-Leu<sup>9</sup>-Val<sup>10</sup>-Gly<sup>11</sup> of the aminoterminal end of CysC) can inhibit osteoclast formation using purified mouse and human osteoclast progenitors stimulated by either RANKL or LPS <i>Escherichia coli</i>. <h3>Results</h3> All three inhibitors concentration-dependently (IC<sub>50</sub> CysC=0.3 μM, E-64=3μM, Z-RLVG-CHN<sub>2</sub>=0.3 μM) inhibited RANKL induced osteoclast formation in mouse bone marrow macrophage (BMM) cultures; similar observations were made using human peripheral blood CD14<sup>+</sup> progenitors. These data were based upon (1) counting the number of TRAP<sup>+</sup> osteoclasts in cultures on plastic or (2) on bone, (3) assessing actin-ring expressing cells and (4) by analysing pit formation and release of CTX when progenitor cells were cultured on bone. The effect was induced early during differentiation as demonstrated by withdrawal and addition of CysC at different time points, by showing that a variety of RANKL induced osteoclastic genes (<i>Calcr, Acp5, Ctsk, Integrin b3, Mmp-9</i>) were downregulated and that BMM was maintained at a macrophage stage (capacity to phagocytose and increased <i>Irf-8</i>). The inhibitory effect was associated with decreased mRNA and protein expression of c-Fos and Nfatc1, and with decreased activation of NF-κB. Inhibition was also associated with decreased mRNA and protein expression of RANK, with no effect on c-Fms. However, CysC inhibited osteoclast formation also in BMM cultures overexpressing <i>Rank</i> due to transfection with a lentivirus containing the <i>Rank</i> gene. Using fluorescent labelled CysC, the authors observed that CysC was taken up intracellularly in BMM by a process facilitated by RANKL. Similarly, all three CPIs decreased also LPS induced osteoclast formation. <h3>Conclusions</h3> These data show that CPIs decrease osteoclast formation induced by either RANKL or LPS by interfering with early steps in signal transduction pathways downstream RANK or Toll-like receptor 4.
Density and duration of experimental human pneumococcal carriage
Authors: J.F. Gritzfeld, A.J.H. Cremers, G. Ferwerda, D.M. Ferreira, A. Kadioglu, P.W.M. Hermans, S.B. Gordon
Journal: Clinical Microbiology and Infection (2014)

The density and duration of pneumococcal carriage are considered to affect the likelihood of transmission and invasive disease. Because of its importance in both spreading and causing disease, carriage has been suggested as an endpoint in future vaccine studies. Culture is the current gold standard for detection, but may not be sensitive enough to detect changes at low density. Healthy adult volunteers received an intranasal inoculation of Streptococcus pneumoniae serotype 6B. Pneumococcal density in nasal washes collected at six time-points post-inoculation was determined by culture and quantitative PCR (qPCR). Natural pneumococcal carriers detected at initial screening were followed in parallel. In 331 nasal washes from 79 volunteers, the sensitivity and specificity of pneumococcal detection by qPCR, as compared with culture, were 92.3% and 75.9%. The estimation of pneumococcal density by culture and qPCR was highly correlated (rs = 0.73, p <0.0001), although qPCR had a lower detection limit. Pneumococcal density fluctuated within a carriage episode, and occasionally fell below the detection limit of both methods. The duration of carriage episodes was underestimated when only one method was used. Similar fluctuations in density were observed in natural carriers. Pneumococcal carriage is a dynamic event. Culture and qPCR are complementary for surveying the density and duration of pneumococcal carriage episodes.
Nonaminoglycoside compounds induce readthrough of nonsense mutations
Authors: Liutao Du, Robert Damoiseaux, Shareef Nahas, Kun Gao, Hailiang Hu, Julianne M. Pollard, Jimena Goldstine, Michael E. Jung, Susanne M. Henning, Carmen Bertoni, Richard A. Gatti
Journal: The Journal of Experimental Medicine (2009)

Large numbers of genetic disorders are caused by nonsense mutations for which compound-induced readthrough of premature termination codons (PTCs) might be exploited as a potential treatment strategy. We have successfully developed a sensitive and quantitative high-throughput screening (HTS) assay, protein transcription/translation (PTT)–enzyme-linked immunosorbent assay (ELISA), for identifying novel PTC-readthrough compounds using ataxia-telangiectasia (A-T) as a genetic disease model. This HTS PTT-ELISA assay is based on a coupled PTT that uses plasmid templates containing prototypic A-T mutated (ATM) mutations for HTS. The assay is luciferase independent. We screened ∼34,000 compounds and identified 12 low-molecular-mass nonaminoglycosides with potential PTC-readthrough activity. From these, two leading compounds consistently induced functional ATM protein in ATM-deficient cells containing disease-causing nonsense mutations, as demonstrated by direct measurement of ATM protein, restored ATM kinase activity, and colony survival assays for cellular radiosensitivity. The two compounds also demonstrated readthrough activity in mdx mouse myotube cells carrying a nonsense mutation and induced significant amounts of dystrophin protein.
Army Clinical Psychiatry in the Combat Zone-1967-1968
Authors: H. SPENCER BLOCH
Journal: American Journal of Psychiatry (1969)

The author, who served in Viet Nam, outlines the present approach to treating U. S. Army psychiatric casualties there, based on the principles of immediacy, proximity, and expectancy. He also describes the Army psychiatric facilities; the principal resources are two neuropsychiatric specialty teams. Statistics are cited to show the effectiveness of the current treatment approach in returning men to active duty, and some typical case examples are included.
Prostaglandins and the control of blood flow in the canine myocardium.
Authors: T H Hintze, G Kaley
Journal: Circulation Research (1977)

A comprehensive study was undertaken to evaluate the effects of inhibition of prostaglandin (PG) synthesis on a variety of reactions in the coronary vascular bed of anesthetized, open-chest dogs. In 23 dogs an electromagnetic flow probe (EMFP) and hydraulic occluder were placed around either the left anterior descending or circumflex branches of the coronary artery and a needle was inserted distral to the EMFP. Injections into the coronary artery of arachidonic acid (AA), bradykinin, adenosine, angiotensin, and PGE2 were given before and after inhibition of PG synthesis by indomethacin (IND) or meclofenamate (MF). The effects of the inhibitors on reactive hyperemia resulting from 5-, 10-, 15-, and 20-second occlusions and the dilation resulting from 90-second exposure to 8% O2 were also examined. In each experiment, inhibition of PG synthesis was ascertained by the elimination of vasodilation to AA. After administration of IND or MF, while baseline coronary blood flow was slightly reduced, the total increment of blood flow to vasodilator agents was not significantly altered. Whereas the peak dilation and volume of reactive hyperemia were decreased, the percent flow debt repaid was unchanged and total increment of coronary flow due to hypoxia-induced vasodilation was not significantly modified. Vasoconstrictor responses to angiotensin were also unchanged. These results indicate that while inhibitors of PG synthesis increase coronary resistance, they do not adversely affect vascular responsiveness. We conclude that prostaglandins play little, if any, role in modulating coronary blood flow.