tbuckley/cabot-search huggingface dataset:
Role of Small GTPases in Endothelial Cytoskeletal Dynamics and the Shear Stress Response
Authors: Eleni Tzima
Journal: Circulation Research (2006)

Fluid shear stress caused by blood flow is a major determinant of vascular remodeling and arterial tone and can lead to development of atherosclerosis. The endothelial monolayer in vivo acts as a signal transduction interface for hemodynamic forces; these forces determine the shape, cytoskeletal organization, and function of endothelial cells, allowing the vessels to cope with physiological or pathological conditions. The Ras superfamily of GTPases have been revealed to be master regulators of many cellular activities. In particular, the GTPases RhoA, Rac1, and Cdc42 are known to regulate cell shape changes through effects on the cytoskeleton, but their ability to influence polarity, microtubule dynamics, and transcription factor activity is just as significant. Shear stress modulates the activity of small GTPases, which are critical for both cytoskeletal reorganization and changes in gene expression in response to shear stress. The goal of this article is to review what is known about Ras and more so about Rho GTPases in mechanotransduction and the responses of cells to fluid flow. Several distinct signaling pathways can be coordinately activated by flow, and small GTPases are strongly implicated in some of them; thus possible connections will be explored and a unifying hypothesis offered.
Reducing violence in severe mental illness: randomised controlled trial of intensive case management compared with standard care
Authors: E. Walsh, C. Gilvarry, C. Samele, K. Harvey, C. Manley, P. Tyrer, F. Creed, R. Murray, T. Fahy
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To establish whether intensive case management reduces violence in patients with psychosis in comparison with standard case management. <b>Design:</b> Randomised controlled trial with two year follow up. <b>Setting:</b> Four inner city community mental health services. <b>Participants:</b> 708 patients with established psychotic illness allocated at random to intervention (353) or control (355) group. <b>Intervention:</b> Intensive case management (caseload 10–15 per case manager) for two years compared with standard case management (30-35 per case manager). <b>Main outcome measure:</b> Physical assault over two years measured by interviews with patients and case managers and examination of case notes. <b>Results:</b> No significant reduction in violence was found in the intensive case management group compared with the control group (22.7% <i>v</i> 21.9%, P=0.86). <b>Conclusions:</b> Intensive case management does not reduce the prevalence of violence in psychotic patients in comparison with standard care. <h3>What is already known on this topic</h3> Psychosis and violence are known to be associated Community psychiatric interventions aimed at reducing the risk of violence have not been evaluated <h3>What this study adds</h3> Increasing the intensity of contact between patients and case managers does not reduce the prevalence of violent behaviour in patients with psychosis Younger age, learning difficulties, and a history of violence, drug misuse, and victimisation predict violent behaviour in psychotic patients
Association of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease
Authors: Ramin Farzaneh-Far
Journal: JAMA (2010)

Context Increased dietary intake of marine omega-3 fatty acids is associated with prolonged survival in patients with coronary heart disease.However, the mechanisms underlying this protective effect are poorly understood.Objective To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age.Design, Setting, and Participants Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years). Main Outcome MeasuresWe measured leukocyte telomere length at baseline and again after 5 years of follow-up.Multivariable linear and logistic regression models were used to investigate the association of baseline levels of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) with subsequent change in telomere length.Results Individuals in the lowest quartile of DHAϩEPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17),whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08;PϽ.001 for linear trend across quartiles).Levels of DHAϩEPA were associated with less telomere shortening before (unadjusted ␤ coefficient ϫ 10 -3 = 0.06; 95% CI, 0.02-0.10)and after (adjusted ␤ coefficient ϫ 10 -3 =0.05; 95% CI, 0.01-0.08)sequential adjustment for established risk factors and potential confounders.Each 1-SD increase in DHAϩEPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98). ConclusionAmong this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.
Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia
Authors: A C Logan, B Zhang, B Narasimhan, V Carlton, J Zheng, M Moorhead, M R Krampf, C D Jones, A N Waqar, M Faham, J L Zehnder, D B Miklos
Journal: Leukemia (2013)

Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifies immunoglobulin heavy chain (IGH) loci using consensus V and J segment primers followed by high-throughput sequencing (HTS), enabling quantification with a detection limit of one CLL cell per million mononuclear cells. Using this IGH–HTS approach, we analyzed MRD patterns in over 400 samples from 40 CLL patients who underwent reduced-intensity allo-HCT. Nine patients relapsed within 12 months post-HCT. Of the 31 patients in remission at 12 months post-HCT, disease-free survival was 86% in patients with MRD <10−4 and 20% in those with MRD ⩾10−4 (relapse hazard ratio (HR) 9.0; 95% confidence interval (CI) 2.5–32; P<0.0001), with median follow-up of 36 months. Additionally, MRD predicted relapse at other time points, including 9, 18 and 24 months post-HCT. MRD doubling time <12 months with disease burden ⩾10−5 was associated with relapse within 12 months of MRD assessment in 50% of patients, and within 24 months in 90% of patients. This IGH–HTS method may facilitate routine MRD quantification in clinical trials.
Guidelines of care for acne vulgaris management
Authors: John S. Strauss, Daniel P. Krowchuk, James J. Leyden, Anne W. Lucky, Alan R. Shalita, Elaine C. Siegfried, Diane M. Thiboutot, Abby S. Van Voorhees, Karl A. Beutner, Carol K. Sieck, Reva Bhushan
Journal: Journal of the American Academy of Dermatology (2007)
Non-cemented hip prostheses
Authors: B M Wroblewski
Journal: BMJ (1985)

naire), stress (mood adjective checklist), and depression (daily symptom record)).Thus, of the 28 variables reported on, only five (17 9%) were found to be significantly improved by progesterone during the first month of treatment (table II) and four (14 3%) overall during the four months of the study (table III).Secondly, and similarly, the apparently impres- sive graph of the total menstrual distress question- naire scores during the four months of treatment, by omitting any index of the range of the results, belies the fact that the difference between placebo and progesterone as judged by that particular value was actually statistically insignificant.This is clearly evident from the results quoted in tables II and III, which form the basis for the graph.Thirdly, for most symptoms of the premenstrual syndrome, including three of the four most commonly reported complaints quoted by the authors in table I, this controlled study has shown that progesterone is neither clinically nor statistic- ally superior to placebo.
Measurement of effective alveolar carbon dioxide tension during spontaneous breathing in normal subjects and patients with chronic airways obstruction.
Authors: J Jordanoglou, N Koulouris, D Kyroussis, P Rapakoulias, P Vassalos, J Madianos
Journal: Thorax (1995)

BACKGROUND--The measurement of effective alveolar carbon dioxide tension (PA-CO2eff) is still a matter of debate. It has, however, become common practice to use arterial instead of alveolar CO2 tension for computing alveolar oxygen tension (PAO2) and physiological dead space, not only in normal subjects but also in patients. The purpose of this study was to estimate alveolar CO2 tension during spontaneous breathing with a new bedside technique which is simple and non-invasive, and to compare these values with arterial CO2 tension measured in normal subjects and patients with chronic airways obstruction. METHODS--The subjects breathed quietly through the equipment assembly (mouthpiece, monitoring ring, Fleisch transducer head) connected to a pneumotachograph and a fast response infrared CO2 analyser. The method is a computerised calculation of the volume weighted effective alveolar CO2 tension obtained from the simultaneously recorded expiratory flow and CO2 concentration versus time curves. An arterial blood sample was taken to measure PaCO2 for comparison during the study. RESULTS--The results showed a mean difference (PACO2eff-PaCO2) of -0.205 kPa in 20 normal subjects and -0.460 kPa in 46 patients. The 95% confidence interval of the bias was -0.029 to -0.379 kPa in normal subjects and -0.213 to -0.707 kPa in patients. The limits of agreement between PACO2eff and PaCO2 were 0.526 to -0.935 in normal subjects and 1.170 to -2.088 in patients. CONCLUSIONS--The volume weighted effective alveolar PCO2 in normal subjects and patients with chronic airways obstruction is lower than the arterial PCO2 and is recommended as a better estimate in the classical equations for estimating dead space and intrapulmonary shunt.
Independent and combined actions of interleukin-1β, tumor necrosis factor α, and glucagon on amino acid metabolism in the isolated perfused rat liver
Authors: J.P. De Bandt[, S.K. Lim, F. Plassart, C.Coudray Lucas, C. Rey, R. Poupon, J. Giboudeau, L. Cynober
Journal: Metabolism (1994)
Five-year follow-up of Algerian victims of the “Ardystil syndrome”
Authors: F Ould Kadi, T Abdesslam, B Nemery
Journal: European Respiratory Journal (1999)

In the February 1998 issue of the European Respiratory Journal, ROMERO et al. [1] reported on an outbreak of organizing pneumonia in textile printing workers in Spain.In an accompanying editorial [2], it was mentioned that this occupational disaster had also affected workers in Algeria [3].It was also pointed out that this form of organizing pneumonia was unusual in that a substantial proportion of affected subjects died (six in Spain and one in Algeria) or appeared to have developed lung fibrosis [1,4].Although the disease could not be documented so well in Algeria, we do have 5-yr follow-up data on three (B±D) out of the four surviving patients who presented initially [3].The fourth subject (E) who was also the least affected, married and could not be contacted.All three patients still complain of asthenia and dyspnoea (grade 2 in subject B, grade 1 in the other two), chest pain and dry cough (permanent in subject B), and they have crepitations at auscultation.Figure 1 presents the chest radiographs of subject C at presentation (1993), and in 1994 and July l997.In patients B and C, the alveolar±interstitial lesions progressively cleared, but in 1997, increased bronchial and interstitial shadows could be noted; in subject B, the distribution of the lesions appeared to be quite asymmetrical, while subject C developed a more prominent pulmonary artery arc.In subject D who had only limited radiological abnormalities at presentation, the chest radiograph remained normal.With regard to ventilatory function, table 1 shows that in subjects B and C who had very poor spirometric values in 1993 and 1994, there was a substantial improvement, but mild restrictive impairment (low forced vital capacity (FVC) with increased forced expiratory volume in one second (FEV1)/FVC ratio) was still present in 1998.In subject D ventilatory function was mildly obstructive in 1993, and FVC, but not FEV1, decreased slightly with time.None of the patients received any specific treatment.We conclude from these follow-up observations in a limited number of victims of the Ardystil syndrome that the spontaneous evolution of the disease over the course of 5 yrs is favourable, with radiological and functional improvement, but without a complete return to normality and with evidence of fibrotic lung disease.Unfortunately a more complete evaluation of these patients using state-ofthe-art functional, radiological and other means is not possible at present.
Potential Impact of Genetic Testing on Cancer Prevention Trials, Using Breast Cancer as an Example
Authors: S. G. Baker, L. S. Freedman
Journal: JNCI Journal of the National Cancer Institute (1995)

Using breast cancer as an example, we explored the potential impact that a highly predictive genetic test could have on the design and analysis of cancer prevention trials. We discuss three situations in this article: 1) trials that are in progress when the genetic test first becomes available as a research tool but is not available for general use, 2) trials in progress when the genetic test becomes generally available to the public, and 3) trials that begin after the test becomes generally available. We have concluded that the availability of a highly predictive genetic test will provide impediments to prevention trials in the form of increased noncompliance and also will provide opportunities in the form of new trials that include only persons at very high risk of developing cancer. Such trial designs could, under favorable circumstances, substantially reduce the size, duration, and cost of cancer prevention trials. The availability of a highly predictive genetic test will make the discovery of effective interventions even more urgent, and the randomized trial will still provide the most reliable method of evaluating prevention strategies.
Triptolide Attenuates Pulmonary Arterial Hypertension and Neointimal Formation in Rats
Authors: JOHN L. FAUL, TOSHIHIKO NISHIMURA, GERALD J. BERRY, GAIL V. BENSON, RONALD G. PEARL, PETER N. KAO
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

This paper reports the effect of triptolide (a diterpenoid triepoxide) on the development of monocrotaline (MCT)-induced pulmonary hypertension in pneumonectomized rats. Male Sprague– Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Rats received therapy from Day 5 to 35 with triptolide (0.25 mg/kg intraperitoneally, every other day, n = 10), or vehicle (0.1 ml of ethanol/cremophor intraperitoneally, every other day, n = 10). By Day 35, triptolide-treated rats demonstrated lower mean pulmonary arterial pressure (mPAP) than vehicle-treated rats (mPAP 21 ± 3 versus 42 ± 5 mm Hg, p < 0.001). Triptolide-treated rats also had significantly less right ventricular hypertrophy (RVH) and pulmonary arterial neointimal formation. In a rescue experiment, rats initiated therapy on Day 21. At Day 35, vehicle-treated rats (n = 4) had higher mPAP (40 ± 9 mm Hg), greater RVH, and more severe pulmonary arterial neointimal formation than rats that received triptolide (0.25 mg/kg every other day, n = 7, mPAP 30 ± 4 mm Hg) and rats that received triptolide (0.2 mg/kg daily, n = 7, mPAP 25 ± 5 mm Hg, p < 0.01). In pneumonectomized rats that receive MCT, triptolide attenuates the development of pulmonary hypertension and RVH, and promotes regression of pulmonary arterial neointimal formation.
Activated N-Ras signaling regulates arterial-venous specification in zebrafish
Authors: Chun-Guang Ren, Lei Wang, Xiao-E Jia, Yi-Jie Liu, Zhi-Wei Dong, Yi Jin, Yi Chen, Min Deng, Yong Zhou, Yi Zhou, Rui-Bao Ren, Wei-Jun Pan, Ting-Xi Liu
Journal: Journal of Hematology & Oncology (2013)

The aberrant activation of Ras signaling is associated with human diseases including hematological malignancies and vascular disorders. So far the pathological roles of activated Ras signaling in hematopoiesis and vasculogenesis are largely unknown. A conditional Cre/loxP transgenic strategy was used to mediate the specific expression of a constitutively active form of human N-Ras in zebrafish endothelial and hematopoietic cells driven by the zebrafish lmo2 promoter. The expression of hematopoietic and endothelial marker genes was analyzed both via whole mount in situ hybridization (WISH) assay and real-time quantitative PCR (qPCR). The embryonic vascular morphogenesis was characterized both by living imaging and immunofluorescence on the sections with a confocal microscopy, and the number of endothelial cells in the embryos was quantified by flow cytometry. The functional analyses of the blood circulation were carried out by fluorescence microangiography assay and morpholino injection. In the activated N-Ras transgenic embryos, the primitive hematopoiesis appeared normal, however, the definitive hematopoiesis of these embryos was completely absent. Further analysis of endothelial cell markers confirmed that transcription of arterial marker ephrinB2 was significantly decreased and expression of venous marker flt4 excessively increased, indicating the activated N-Ras signaling promotes the venous development at the expense of arteriogenesis during zebrafish embryogenesis. The activated N-Ras-expressing embryos showed atrophic axial arteries and expansive axial veins, leading to no definitive hematopoietic stem cell formation, the blood circulation failure and subsequently embryonic lethality. Our studies revealed for the first time that activated N-Ras signaling during the endothelial differentiation in vertebrates can disrupt the balance of arterial-venous specification, thus providing new insights into the pathogenesis of the congenital human vascular disease and tumorigenic angiogenesis.
Genetic Determinants of Response to Clopidogrel and Cardiovascular Events
Authors: Tabassome Simon, Céline Verstuyft, Murielle Mary-Krause, Lina Quteineh, Elodie Drouet, Nicolas Méneveau, P. Gabriel Steg, Jean Ferrières, Nicolas Danchin, Laurent Becquemont
Journal: New England Journal of Medicine (2008)

Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown.We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up.Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51).Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials.gov number, NCT00673036.)
Transbronchial biopsy as a tool to evaluate small-airways disease in asthma. Pros
Authors: L-P. Boulet
Journal: European Respiratory Journal (2002)

Asthma is an inflammatory disease and although the existence of small airways disease has been described, a few decades ago, in asthma and chronic obstructive pulmonary disease (COPD), the possibility that small airway inflammation/remodelling is involved in the pathophysiology and clinical manifestations of these conditions has recently been re-emphasised 1–3. Previous observations had shown small airways changes in asthma. Using surgically resected lung specimen of patients with asthma, Hamid et al. 1 observed an airway inflammatory process not only in large but also small airways, activated eosinophils being more numerous in peripheral airways. Small-airways disease has also been found in fatal asthma 4. The inner-wall area of distal airways was found to be increased in patients who died of asthma or other causes; structural changes such as smooth-muscle thickening were observed in peripheral airways. There was an increased interest in exploring small-airways inflammation, with the development of new medications such as hydrofluoroalkanes-propelled beclomethasone (QVARTM, 3M Pharmaceuticals, St-Paul, MN, USA). This …
Gastroesophageal Reflux Induced by Exercise in Healthy Volunteers
Authors: C S Clark, B B Kraus, J Sinclair, D O Castell
Journal: JAMA (1989)

The effects of different types of exercise on gastroesophageal reflux were evaluated during fasting and postprandially in 12 asymptomatic volunteers (7 men and 5 women; mean age, 28 years) using an ambulatory intraesophageal pH monitor. The 1-hour exercise period included stationary bicycling (aerobic exercise with little agitation of the body), running (aerobic exercise with a high degree of agitation of the body), and a weight routine (nonaerobic exercise). Each exercise was performed for 15 minutes with 5 minutes of rest between exercises. The weight routine consisted of five different exercises (sit-ups, bench press, sitting arm press, prone leg curls, and sitting leg press) chosen to compare upper-body vs lower-body exercise and supine vs upright position. Each exercise hour was preceded by a 1-hour baseline period on 2 days (fasting and postprandial). The results indicate that vigorous exercise can induce gastroesophageal reflux in normal subjects. Running induced the most reflux, and aerobic exercises with less bodily agitation (bicycle) produced less reflux and may offer an alternate form of exercise for patients with reflux. The weight routine induced gastroesophageal reflux in some subjects, although no particular exercise was associated with more reflux. Postprandial exercise showed a similar pattern of induced gastroesophageal reflux, although of greater amount. (<i>JAMA</i>. 1989;261:3599-3601)