tbuckley/cabot-search huggingface dataset:
Single-Arm Study of Bridging Therapy With Low-Molecular-Weight Heparin for Patients at Risk of Arterial Embolism Who Require Temporary Interruption of Warfarin
Authors: M.J. Kovacs, C. Kearon, M. Rodger, D.R. Anderson, A.G.G. Turpie, S.M. Bates, L. Desjardins, J. Douketis, S.R. Kahn, S. Solymoss, P.S. Wells
Journal: Circulation (2004)

Background— When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital. Methods and Results— This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths. Conclusions— Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.
Prognostic Biomarkers in Phase II Trial of Cetuximab-Containing Induction and Chemoradiation in Resectable HNSCC: Eastern Cooperative Oncology Group E2303
Authors: Amanda Psyrri, Ju-Whei Lee, Eirini Pectasides, Maria Vassilakopoulou, Efstratios K. Kosmidis, Barbara A. Burtness, David L. Rimm, Harold J. Wanebo, Arlene A. Forastiere
Journal: Clinical Cancer Research (2014)

We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial.
Release of chemoattractants for human monocytes from endothelial cells by interaction with neutrophils
Authors: P Schratzberger
Journal: Cardiovascular Research (1998)

Objectives: The release of monocyte chemoattractant protein-1 (MCP-1) in the vessel wall may lead to accumulation of monocytes in the subendothelial space. The role of neutrophils (PMNL) in the initiation of this process is unknown. We tested whether PMNL are able to induce the production and release of MCP-1 in endothelial cells. Methods: PMNL were allowed to interact with human umbilical vein endothelial cell (HUVEC) monolayers in culture. Culture media were collected and assessed for chemotactic activity on mononuclear leukocytes (MNC) or purified monocytes in a modified Boyden chamber assay. Additionally, MCP-1 levels in supernatants were quantified by ELISA. Results: Media from unstimulated HUVEC culture supernatants induced a slight increase (1.2-fold) of MNC and purified monocyte chemotaxis, which was significantly augmented by addition of PMNL for 1 h (1.4-fold; P<0.05). The increase in chemotaxis was time- and dose-dependent and could be blocked by an anti-MCP-1 monoclonal antibody. Media obtained after coculture of PMNL and HUVEC for 1–5 h contained increased amounts of MCP-1 as measured by ELISA; addition of cycloheximide abolished this response. Conclusions: Interaction of PMNL with endothelium induces the release of functionally active MCP-1 suggesting that in the vascular wall, PMNL may play a role in the recruitment of MNC.
Severity scores for CAP. 'Much workload for the next bias'
Authors: S. Ewig, A. Torres
Journal: Thorax (2010)

Tools for the assessment of severity of patients with community-acquired pneumonia (CAP) have attracted much interest in the recent past. In this issue of Thorax ( see page 878 ) two systematic reviews and meta-analyses address the value of such tools including no less than 401 and 23 studies.2 Despite different inclusion strategies and statistical approaches, both studies report two main and similar conclusions. First, both the most extensively investigated tools (Pneumonia Severity Index (PSI) and CURB-65/CRB-65) have remarkably favourable power to predict mortality. Secondly, whereas PSI is somewhat better in predicting patients at low risk, the reverse is true for CURB-65/CRB-65. However, these differences are of questionable clinical relevance. Thus, both tools can be regarded as equivalent. CRB-65 is the simplest tool and can easily be remembered and also applied in the outpatient setting. These straightforward conclusions are the result of a decade of intensive and successful work to establish clinically useful tools of severity assessment. So far success is impressive; clinicians now can use a very simple tool as an adjunct to clinical judgement, and studies on patients with CAP can rely on a validated tool for severity stratification.3

At this point, it is worthwhile having a look at the perspectives beyond: where do we have to go from here? Actually, there are many issues that still must be addressed concerning validation in intervention studies and still insufficently recognised ambiguities inherent to the severity scores.

PSI has been prospectively validated in independent populations as a tool to guide site of treatment decisions, and the use of the PSI was associated with a larger proportion of patients in PSI risk classes I and II who were treated in the outpatient environment without compromising their safety.4 No …
The structure and organization of the bile canalicular cytoskeleton with special reference to actin and actin-binding proteins
Authors: Nobuhiro Tsukada, Cameron A. Ackerley, M. James Phillips
Journal: Hepatology (1995)

The distribution of actin filaments and actin-binding proteins in the bile canaliculus (BC) of normal human hepatocytes was determined as a means of establishing the structure and organization of the BC cytoskeleton. Immunoblots demonstrated that actin, and the actin-binding proteins, myosin II, tropomyosin, vinculin, alpha-actinin, villin, were present, as were the non-actin-related proteins beta-tubulin, and cytokeratins. Three actin filament regions were identified: microvillus core filaments, a membrane-associated microfilamentous network, and a circumferential pericanalicular actin filament band. Actin-binding proteins were nonrandomly associated with actin in these regions. In the case of the pericanalicular band, there was also association with the zonula adherens junction. Intermediate filaments inserted into desmosomes. The ultrastructural localization of the actin-binding proteins was fundamentally linked to the arrangement and organization of the major canaliculus-associated microfilament structures. Structural organization of the cytoskeleton was also linked to distinct components of the intercellular junctions. It is notable that tropomyosin and a-actinin, which in muscle cells are regulatory proteins of contractile activity, and myosin II are associated with the pericanalicular actin microfilament band; it is the BC counterpart of the contractile actin filament band found in the apical region of other secretory cells. The outer sheath of noncontractile intermediate filaments likely stabilizes the canalicular compartment.
Neoadjuvant Vinorelbine-Capecitabine Versus Docetaxel-Doxorubicin-Cyclophosphamide in Early Nonresponsive Breast Cancer: Phase III Randomized GeparTrio Trial
Authors: G. von Minckwitz, S. Kummel, P. Vogel, C. Hanusch, H. Eidtmann, J. Hilfrich, B. Gerber, J. Huober, S. D. Costa, C. Jackisch, S. Loibl, K. Mehta, M. Kaufmann
Journal: JNCI Journal of the National Cancer Institute (2008)

Among breast cancer patients, nonresponse to initial neoadjuvant chemotherapy is associated with unfavorable outcome. We compared the response of nonresponding patients who continued the same treatment with that of patients who switched to a well-tolerated non–cross-resistant regimen. Previously untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m 2 , doxorubicin at 50 mg/m 2 , and cyclophosphamide at 500 mg/m 2 per day (TAC). Patients whose tumors did not decrease in size by at least 50% were randomly assigned to four additional cycles of TAC or to four cycles of vinorelbine at 25 mg/m 2 and capecitabine at 2000 mg/m 2 (NX). The outcome was sonographic response, defined as a reduction in the product of the two largest perpendicular diameters by at least 50%. A difference of 10% or less in the sonographic response qualified as noninferiority of the NX treatment. Pathological complete response was defined as no invasive or in situ residual tumor masses in the breast and lymph nodes. Toxic effects were assessed. All statistical tests were two-sided. Of 2090 patients enrolled in the GeparTrio study, 622 (29.8%) who did not respond to two initial cycles of TAC were randomly assigned to an additional four cycles of TAC (n = 321) or to four cycles of NX (n = 301). Sonographic response rate was 50.5% for the TAC arm and 51.2% for the NX arm. The difference of 0.7% (95% confidence interval = −7.1% to 8.5%) demonstrated noninferiority of NX ( P = .008). Similar numbers of patients in both arms received breast-conserving surgery (184 [57.3%] in the TAC arm vs 180 [59.8%] in the NX arm) and had a pathological complete response (5.3% vs 6.0%). Fewer patients in the NX arm than in the TAC arm had hematologic toxic effects, mucositis, infections, and nail changes, but more had hand–foot syndrome and sensory neuropathy. Pathological complete responses to both regimens were marginal. Among patients who did not respond to the initial neoadjuvant TAC treatment, similar efficacy but better tolerability was observed by switching to NX than continuing with TAC.
Endoscopic Ultrasound–Guided Fine-Needle Aspiration in the Diagnosis and Staging of Lung Cancer and Its Impact on Surgical Staging
Authors: Jouke T. Annema, Michel I. Versteegh, Maud Veseliç, Pieter Voigt, Klaus F. Rabe
Journal: Journal of Clinical Oncology (2005)

The diagnosis and staging of lung cancer critically depends on surgical procedures. Endoscopic ultrasound (EUS) -guided fine-needle aspiration (FNA) is an accurate, safe, and minimally invasive technique for the analysis of mediastinal lymph nodes (LNs) and can additionally detect tumor invasion (T4) in patients with centrally located tumors. The goal of this study was to assess to what extent EUS-FNA could prevent surgical interventions.Two hundred forty two consecutive patients with suspected (n = 142) or proven (n = 100) lung cancer and enlarged (> 1 cm) mediastinal LNs at chest computed tomography were scheduled for mediastinoscopy/tomy (94%) or exploratory thoracotomy (6%). Before surgery, all patients underwent EUS-FNA. If EUS-FNA established LN metastases, tumor invasion, or small-cell lung cancer (SCLC), scheduled surgical interventions were cancelled. Surgical-pathologic verification occurred when EUS-FNA did not demonstrate advanced disease. Cancelled surgical interventions because of EUS findings was the primary end point.EUS-FNA prevented 70% of scheduled surgical procedures because of the demonstration of LN metastases in non-small-cell lung cancer (52%), tumor invasion (T4) (4%), tumor invasion and LN metastases (5%), SCLC (8%), or benign diagnoses (1%). Sensitivity, specificity, and accuracy for EUS in mediastinal analysis were 91%, 100% and 93%, respectively. No complications were recorded.EUS-FNA qualifies as the initial staging procedure of choice for patients with (suspected) lung cancer and enlarged mediastinal LNs. Implementation of EUS-FNA in staging algorithms for lung cancer might reduce the number of surgical staging procedures considerably.
A paediatric tube and capsule for suction biopsy of the small intestinal mucosa designed for direct nasogastric intubation
Authors: R. E. Schneider, R. Chang
Journal: Gut (1971)

The use of a modified paediatric tube and capsule for suction biopsy of the mucosa of the small intestine is discussed. The tube is small in diameter and can be introduced through the nose without local trauma and with minimal discomfort. The intubation technique was followed in 72 instances to obtain suction biopsies from the proximal mucosa of the small intestine in protein-calorie malnourished children, and the results obtained with this instrument are also presented.
All is not Toll: new pathways in DNA recognition
Authors: Hermann Wagner, Stefan Bauer
Journal: The Journal of Experimental Medicine (2006)

Immunological defense depends on the ability of the innate immune system to recognize invading microbes as foreign and thus eliminate them. The Toll-like receptors (TLRs) help detect foreign invaders by sensing various pathogen-associated molecules, including microbial RNA and DNA. At present, it is unclear whether and how the immune system distinguishes between microbial and self nucleic acids, as host-derived RNA and DNA also stimulate TLRs. In addition, recent studies have revealed the existence of TLR-independent pathways that are activated in response to microbial and host nucleic acids.
End-Organ Dysfunction in Cystic Fibrosis
Authors: Peter D. Arkwright, Vera Pravica, Philip J. Geraghty, Maurice Super, A. Kevin Webb, Martin Schwarz, Ian V. Hutchinson
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The clinical course of patients with cystic fibrosis (CF) with functionally similar mutations in the CF transmembrane conductance regulator gene is variable and must therefore relate to secondary genetic and environmental factors. We examined the hypothesis that polymorphisms of certain inflammatory mediator and regulatory genes affect clinical outcome by influencing the degree of end-organ damage. By studying the possible association between clinical outcome and angiotensin I-converting enzyme (ACE) and cytokine genotypes by amplification refractory mutation system-polymerase chain reaction, using stored DNA from 261 white patients with CF, we found that ultrasound features of cirrhosis occurred more frequently in patients with the high-producer (DD) rather than the low-producer (II) ACE genotype (odds ratio [95% confidence interval], 3.7 [1.2 to 12]). Moreover, significant pulmonary dysfunction (age at which FEV1 < 50%) was associated with the high-producer ACE genotype (2.3 [1.2 to 4.5]) and transforming growth factor-beta1 genotype (2.6 [1.0 to 6.8]) as well as with age at first colonization with Pseudomonas aeruginosa (9.1 [1.1 to 72]). We conclude that the high-producer ACE genotype predicts patients with CF who have an increased chance of developing portal hypertension; and high-producer ACE and TGF-beta1 genotypes are secondary genetic factors contributing to pulmonary dysfunction in these patients.
Studies on Hemoglobin Biosynthesis: Asynchronous Synthesis of Hemoglobin A and Hemoglobin A2 by Erythrocyte Precursors *
Authors: Ronald F. Rieder, David J. Weatherall
Journal: Journal of Clinical Investigation (1965)

Hemoglobin A2 comprises less than 3.3% of the total hemoglobin of normal adults (1, 2).Elevated levels are found in many individuals with thalassemia minor (3, 4), in some patients with pernicious anemia in relapse (5), and in per- sons heterozygous for hemoglobin Zurich (6).Reduced levels are encountered in the newborn child (3), in some patients with anemia due to iron deficiency (5), and in persons with hereditary persistence of fetal hemoglobin (7, 8).In the study to be described, measurements were made of the relative rates of synthesis of hemoglobins A and A2 by red cell precursors of patients with certain hematologic disorders. MethodsBlood samples were drawn into tubes containing heparin, 0.2 mg per ml.Experiments were initiated within 2 hours except that blood from two patients with thalassemia major was transported in cooled containers and studied within 5 hours.Measurement of hemoglobin.The concentrations of hemoglobin solutions were compared by measuring op- tical densities of oxyhemoglobin at 415 m1A of cyan- methemoglobin or cyanhematin (9) at 543 mA.Synthesis of hemoglobins A and As by reticulocytes in vitro.Hemoglobin synthesis by reticulocytes in vitro was studied by incubating cells with Fe' citrate (1 jAg of Fe per ml; initial specific activity, approximately 30 /Ac per mg) or uniformly labeled leucine-C" (specific ac- tivity, 0.10 ,uc per 0.0348 mg) and measuring the specific activities of the purified hemoglobin fractions.In experiments employing radioactive iron, 1 ml of Fe' citrate (8 to 30 ,uc) was incubated with 4 ml of a type AB human serum having a high iron-binding ca- pacity.The final incubation medium was made by adding the Fe' serum to 5 ml of a modified Krebs-Henseleit *
Prospective Changes in Quality of Life After Ductal Carcinoma-in-Situ: Results From the Nurses' Health Study
Authors: Larissa Nekhlyudov, Candyce H. Kroenke, Inkyung Jung, Michelle D. Holmes, Graham A. Colditz
Journal: Journal of Clinical Oncology (2006)

The incidence of ductal carcinoma-in-situ (DCIS) of the breast has been increasing. However, uncertainties exist about its prognosis, optimal treatment, and effect on women's health-related quality-of-life (HRQoL). Our study assessed the prospective changes in HRQoL in women diagnosed with DCIS.Between 1992 and 2000, HRQoL was assessed at three 4-year intervals among women enrolled in two Nurses' Health Study cohorts using the Medical Outcomes Survey Short-Form 36 health survey. Using mixed effects and logistic regression modeling, we compared the prospective changes in HRQoL scores among women with and without DCIS.The study included 114,728 women; 510 were diagnosed with DCIS during the study period. During 4 years, women with DCIS had small, but statistically significantly greater declines in the domains of role limitations due to physical problems (-6.74; SE, 1.69), vitality (-2.06; SE, 0.78), and social functioning (-2.40; SE, 0.93) than women without DCIS. Among those with DCIS, clinically significant declines were more often observed within 6 months of the diagnosis in the domains of social functioning (odds ratio, 1.78; 95% CI, 1.03 to 3.07) and mental health (odds ratio, 2.03; 95% CI, 1.09 to 3.79) than after 6 months after diagnosis.Women with DCIS experienced small long-term declines in HRQoL, although these declines did not seem to be clinically important. Short-term clinically significant declines in the psychosocial domains were noted. In counseling women with DCIS, clinicians should provide reassurance but prepare them to deal with the short-term sequelae.
Peripheral Reticular Pigmentary Change Is Associated with Complement Factor H Polymorphism (Y402H) in Age-Related Macular Degeneration
Authors: R. Keith Shuler, Silke Schmidt, Paul Gallins, Michael A. Hauser, William K. Scott, Jennifer Caldwell, Anita Agarwal, Jonathan L. Haines, Margaret A. Pericak-Vance, Eric A. Postel
Journal: Ophthalmology (2007)
Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure
Authors: Sandra C. Mayer, Ralf Gilsbach, Sebastian Preissl, Elsa Beatriz Monroy Ordonez, Tilman Schnick, Nadine Beetz, Achim Lother, Carolin Rommel, Hannah Ihle, Heiko Bugger, Frank Rühle, Andrea Schrepper, Michael Schwarzer, Claudia Heilmann, Ulrike Bönisch, Shashi Kumar Gupta, Jochen Wilpert, Oliver Kretz, Dominik von Elverfeldt, Joachim Orth, Klaus Aktories, Friedhelm Beyersdorf, Christoph Bode, Brigitte Stiller, Markus Krüger, Thomas Thum, Torsten Doenst, Monika Stoll, Lutz Hein
Journal: Circulation Research (2015)

Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition. Objective: The aim of this study was to identify the mechanism of regulation of the methyl-CpG–binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading. Methods and Results: MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α 1 - and β 1 -adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload. Conclusions: These data connect adrenergic activation with a microRNA—MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure.
Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells
Authors: G Teng
Journal: Cardiovascular Research (2004)

The long QT syndrome, N629D HERG mutation, alters the pore selectivity signature sequence, GFGN to GFGD. Heterologous co-expression of N629D and the wildtype HERG resulted in a relative loss of the selectivity of K+ over Na+, but its physiologic relevance has not been assessed in cardiac myocytes.Accordingly, N629D was overexpressed, via adenoviral gene transfer, in cardiomyocytes derived from mouse stem cells. Three IKr phenotypes were observed: (1) the wildtype-like IKr showed inward rectification and a positive tail current; (2) the N629D-like IKr showed outward rectification and an inward tail current; and (3) intermediate IKr showed a small outward tail current. Action potentials (AP) were paired with the IKr measurements in each cell. Resting membrane potential (RMP) was critically dependent on the IKr phenotype. The resting membrane potential of the cells was -61 +/- 5 mV (n=40) in wildtype, -63 +/- 3 mV (n=18) in wildtype-like IKr phenotype, -30 +/- 2 mV (n=12) in N629D-like and -47 +/- 2 mV (n=24) in intermediate phenotype (p<0.00001). Triggered action potential durations (APD) were: 62 +/- 12 ms (n=6) in wildtype, 65 +/- 11 ms (n=6) in wildtype-like IKr phenotypes and 106 +/- 10 ms (n=6) (p<0.01) in intermediate IKr phenotypes. Lowering [K+]o hyperpolarized wildtype cells and cells with a wildtype-like IKr phenotype, but depolarized those with intermediate phenotype (from -45 +/- 1 to -35 +/- 0.5 mV (n=12), p<0.01). In 6 of 12 cells, with intermediate phenotype, the hypokalemia-induced depolarization resulted in triggered activity. TTX suppressed this triggered activity.Overexpression of N629D in cardiomyocytes derived from stem cells results in phenotypic variability in IKr, which was the critical determinant of the resting membrane potential, action potential duration and arrhythmogenic response to low [K+]o.