tbuckley/cabot-search huggingface dataset:
Substrate Turnover during Prolonged Exercise in Man
Authors: Gunvor Ahlborg, Philip Felig, Lars Hagenfeldt, Rosa Hendler, John Wahren
Journal: Journal of Clinical Investigation (1974)

Arterial concentrations and substrate exchange across the leg and splanchnic vascular beds were determined for glucose, lactate, pyruvate, glycerol, individual acidic and neutral amino acids, and free fatty acids (FFA) in six subjects at rest and during 4 h of exercise at approximately 30% of maximal oxygen uptake. FFA turnover and regional exchange were evaluated using (14)C-labeled oleic acid. The arterial glucose concentration was constant for the first 40 min of exercise, but fell progressively thereafter to levels 30% below basal. The arterial insulin level decreased continuously, while the arterial glucagon concentration had risen fivefold after 4 h of exercise. Uptake of glucose and FFA by the legs was markedly augmented during exercise, the increase in FFA uptake being a consequence of augmented arterial levels rather than increased fractional extraction. As exercise was continued beyond 40 min, the relative contribution of FFA to total oxygen metabolism rose progressively to 62%. In contrast, the contribution from glucose fell from 40% to 30% between 90 and 240 min. Leg output of alanine increased as exercise progressed. Splanchnic glucose production, which rose 100% above basal levels and remained so throughout exercise, exceeded glucose uptake by the legs for the first 40 min but thereafter failed to keep pace with peripheral glucose utilization. Total estimated splanchnic glucose output was 75 g in 4 h, sufficient to deplete approximately 75% of liver glycogen stores. Splanchnic uptake of gluconeogenic precursors (lactate, pyruvate, glycerol, alanine) had increased 2- to 10-fold after 4 h of exercise, and was sufficient to account for 45% of glucose release at 4 h as compared to 20-25% at rest and at 40 min of exercise. In the case of alanine and lactate, the increase in precursor uptake was a consequence of a rise in splanchnic fractional extraction. It is concluded that during prolonged exercise at a low work intensity (a) blood glucose levels fall because hepatic glucose output fails to keep up with augmented glucose utilization by the exercising legs; (b) a large portion of hepatic glycogen stores is mobilized and an increasing fraction of the splanchnic glucose output is derived from gluconeogenesis; (c) blood-borne substrates in the form of glucose and FFA account for a major part of leg muscle metabolism, the relative contribution from FFA increasing progressively; and (d) augmented secretion of glucagon may play an important role in the metabolic adaptation to prolonged exercise by its stimulatory influence on hepatic glycogenolysis and gluconeogenesis.
Prostaglandin E2 activates Stat3 in neonatal rat ventricular cardiomyocytes: A role in cardiac hypertrophy
Authors: M FRIAS, M REBSAMEN, C GERBERWICHT, U LANG
Journal: Cardiovascular Research (2006)

Journal Article Prostaglandin E2 activates Stat3 in neonatal rat ventricular cardiomyocytes: A role in cardiac hypertrophy Get access Miguel A. Frias, Miguel A. Frias * Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland *Corresponding author. Tel.: +41 22 3729322; fax: +41 22 3729330. Email address: [email protected] Search for other works by this author on: Oxford Academic PubMed Google Scholar Michela C. Rebsamen, Michela C. Rebsamen Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar Christine Gerber-Wicht, Christine Gerber-Wicht Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar Ursula Lang Ursula Lang Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 73, Issue 1, January 2007, Pages 57–65, https://doi.org/10.1016/j.cardiores.2006.09.016 Published: 01 January 2007 Article history Received: 12 June 2006 Revision received: 31 August 2006 Accepted: 21 September 2006 Published: 01 January 2007
Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart.
Authors: G S Friedrichs, K S Kilgore, P J Manley, M R Gralinski, B R Lucchesi
Journal: Circulation Research (1994)

Evidence is presented that heparin pretreatment produces protective effects on myocardial tissue distinct from its anticoagulant activity. The present study examines the ability of heparin sulfate and N-acetyl heparin (a derivative of heparin devoid of anticoagulant effects) to protect the heart from injury associated with global ischemia and reperfusion. Male New Zealand White rabbits were administered either heparin sulfate (n = 7, 300 U/kg i.v.), N-acetyl heparin (n = 6, 1.73 mg/kg i.v.), or vehicle (n = 6). Two hours after treatment, the hearts were removed, perfused on a Langendorff apparatus, and subjected to 30 minutes of global ischemia, followed by 45 minutes of reperfusion. During reperfusion, creatine kinase concentrations in the coronary sinus effluent were greater in hearts from vehicle-treated rabbits compared with hearts from N-acetyl heparin-treated and heparin-treated rabbits. Left ventricular end-diastolic pressure after 45 minutes of reperfusion in the vehicle-treated group was 64 +/- 15 mm Hg compared with 17 +/- 4 and 10 +/- 3 mm Hg in the heparin-pretreated and N-acetyl heparin-pretreated groups, respectively. Heparin, but not N-acetyl heparin, increased the activated partial thromboplastin time, consistent with its known anticoagulant action. Heparin and N-acetyl heparin inhibited complement-mediated erythrocyte lysis in a concentration-dependent manner. The glycosaminoglycans, in contrast to r-hirudin, reduced complement activation-induced injury in the rabbit isolated heart. The results demonstrate that heparin or N-acetyl heparin, administered to the intact rabbit, protects the isolated heart from subsequent myocardial dysfunction secondary to ischemia/reperfusion. The cardioprotective effects of heparin and N-acetyl heparin are independent of an antithrombin mechanism.
Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)
Authors: Masahiro Fukuoka, Yi-Long Wu, Sumitra Thongprasert, Patrapim Sunpaweravong, Swan-Swan Leong, Virote Sriuranpong, Tsu-Yi Chao, Kazuhiko Nakagawa, Da-Tong Chu, Nagahiro Saijo, Emma L. Duffield, Yuri Rukazenkov, Georgina Speake, Haiyi Jiang, Alison A. Armour, Ka-Fai To, James Chih-Hsin Yang, Tony S.K. Mok
Journal: Journal of Clinical Oncology (2011)

The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status.In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS.OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09).EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.
The Rationale and Design of the AASK Cohort Study
Authors: Lawrence J. Appel, John Middleton, Edgar R. Miller, Michael Lipkowitz, Keith Norris, Lawrence Y. Agodoa, George Bakris, Janice G. Douglas, Jeanne Charleston, Jennifer Gassman, Tom Greene, Kenneth Jamerson, John W. Kusek, Julia A. Lewis, Robert A. Phillips, Stephen G. Rostand, Jackson T. Wright
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Hypertensive kidney disease commonly progresses. The primary objective of the AASK (<i>A</i>frican <i>A</i>merican <i>S</i>tudy of <i>K</i>idney Disease and Hypertension) Cohort Study is to determine prospectively the course of kidney function and risk factors for kidney disease progression in African Americans with hypertensive kidney disease who receive recommended anti-hypertensive therapy. The AASK Cohort Study is a prospective, observational study that is an extension of the AASK trial. The AASK trial tested the effects of three medications used as initial anti-hypertensive therapy (ramipril, metoprolol, and amlodipine) and two levels of BP control. Of the 1094 trial participants, approximately 650 to 700 individuals who have not reached ESRD will likely enroll in the Cohort Study. Risk factors to be studied include environmental, genetic, physiologic, and socioeconomic variables. The primary renal outcome is a composite clinical outcome defined by doubling of serum creatinine, ESRD, or death. Medication treatment for hypertension, beginning with the angiotensin converting enzyme inhibitor ramipril, is offered to all participants. In this fashion, the study directly controls two of the major determinants of kidney disease progression: treatment of hypertension and use of renoprotective, anti-hypertensive medication. The minimum duration of follow-up in the Cohort Study is 5 yr (total of 9 to 12 yr, including the period of the AASK trial). Ultimately, data from the AASK Cohort Study should enhance our understanding of the risk factors and processes that determine the progression of kidney disease. Such results might eventually lead to new strategies that delay or prevent ESRD. E-mail: lappel@jhmi.edu
Resolution of acute lung injury and inflammation: a translational mouse model
Authors: Brijesh V. Patel, Michael R. Wilson, Masao Takata
Journal: European Respiratory Journal (2011)

Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution. Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time-points, lung injury was assessed by analysis of blood gases, respiratory mechanics, bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology. Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance and pulmonary inflammation (intra-alveolar leukocyte influx/cytokine levels and histological injury scores). Moreover, mice displayed alveolar–capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble receptor for advanced glycation end-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1 and 3, followed by almost complete recovery over days 5–10. Histology showed evidence of fibrosis on day 10. The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
Statin use in the secondary prevention of coronary heart disease in primary care: cohort study and comparison of inclusion and outcome with patients in randomised trials
Authors: Li Wei, Shah Ebrahim, Christopher Bartlett, Peter D Davey, Frank M Sullivan, Thomas M MacDonald
Journal: BMJ (2005)

To compare the social and demographic profiles of patients who receive statin treatment after myocardial infarction and patients included in randomised trials. To estimate the effect of statin use in community based patients on subsequent all cause mortality and cardiovascular recurrence, contrasting effects with trial patients.Observational cohort study using a record linkage database.Tayside, Scotland (population size and characteristics: about 400,000, mixed urban and rural).4892 patients were discharged from hospital after their first myocardial infarction between January 1993 and December 2001. 2463 (50.3%) were taking statins during an average follow-up of 3.7 years (3.1% in 1993 and 62.9% in 2001).All cause mortality and recurrence of cardiovascular events.319 deaths occurred in the statin treated group (age adjusted rate 4.1 per 100 person years, 95% confidence interval 3.2 to 4.9), and 1200 in the statin untreated group (12.7 per 100 person years, 11.1 to 14.3). More older people and women were represented in the population of patients treated with statins than among those recruited into clinical trials (mean age 67.8 v 59.8; women 39.6% v 16.9%, respectively). The effects of statins in routine clinical practice were consistent with, and similar to, those reported in clinical trials (adjusted hazard ratio for all cause mortality 0.69, 95% confidence interval 0.59 to 0.80; adjusted hazard ratio for cardiovascular recurrence 0.82, 0.71 to 0.95).The community effectiveness of statins in those groups that were not well represented in clinical trials was similar to the efficacy of statins in these trials.
The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart
Authors: Lucie Couture, John A. Nash, Jacques Turgeon
Journal: Pharmacological Reviews (2006)

The passage of drugs across cell membranes dictates their absorption, distribution, metabolism, and excretion. This process is determined by several factors including the molecular weight of the compounds, their shape, degree of ionization, and binding to proteins. Accumulation of xenobiotics into tissues does not depend only on their ability to enter cells, but also on their ability to leave them. For instance, the role of efflux transporters such as ATP-binding cassette (ABC) proteins in the disposition of drugs is now well recognized. Actually, ABC transporters act in synergy with drug-metabolizing enzymes to protect the organism from toxic compounds. The most studied transporter from the ABC transporter superfamily, P-glycoprotein, was found to be overexpressed in tumor cells and associated with an acquired resistance to several anticancer drugs. P-glycoprotein, thought at first to be confined to tumor cells, was subsequently recognized to be expressed in normal tissues such as the liver, kidney, intestine, and heart. Even though information remains rather limited on the functional role of ABC transporters in the myocardium, it is hypothesized that they may modulate efficacy and toxicity of cardioactive agents. This review addresses recent progress on knowledge about the ABC transporters in drug disposition and more precisely their role in drug distribution to the heart.
Visible Age-Related Signs and Risk of Ischemic Heart Disease in the General Population
Authors: Mette Christoffersen, Ruth Frikke-Schmidt, Peter Schnohr, Gorm B. Jensen, Børge G. Nordestgaard, Anne Tybjærg-Hansen
Journal: Circulation (2013)

Background— Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age. Methods and Results— 10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20–1.62) for IHD and 1.57 (1.28–1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline ( P for trend &lt;0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs. Conclusions— Male pattern baldness, earlobe crease, and xanthelasmata—alone or in combination—associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health.
Treatment of childhood obesity by retraining eating behaviour: randomised controlled trial
Authors: A. L Ford, C. Bergh, P. Sodersten, M. A Sabin, S. Hollinghurst, L. P Hunt, J. P H Shield
Journal: BMJ (2009)

<b>Objective</b> To determine whether modifying eating behaviour with use of a feedback device facilitates weight loss in obese adolescents. <b>Design</b> Randomised controlled trial with 12 month intervention. <b>Setting</b> Hospital based obesity clinic. <b>Participants</b> 106 newly referred obese young people aged 9-17. <b>Interventions</b> A computerised device, Mandometer, providing real time feedback to participants during meals to slow down speed of eating and reduce total intake; standard lifestyle modification therapy. <b>Main outcome measures</b> Change in body mass index (BMI) standard deviation score (SDS) over 12 months with assessment 18 months after the start of the intervention. Secondary outcomes were body fat SDS, metabolic status, quality of life evaluation, change in portion size, and eating speed. <b>Results</b> Using the last available data on all participants (n=106), those in the Mandometer group had significantly lower mean BMI SDS at 12 months compared with standard care (baseline adjusted mean difference 0.24, 95% confidence interval 0.11 to 0.36). Similar results were obtained when analyses included only the 91 who attended per protocol (baseline adjusted mean difference 0.27, 0.14 to 0.41; P&lt;0.001), with the difference maintained at 18 months (0.27, 0.11 to 0.43; P=0.001) (n=87). The mean meal size in the Mandometer group fell by 45 g (7 to 84 g). Mean body fat SDS adjusted for baseline levels was significantly lower at 12 months (0.24, 0.10 to 0.39; P=0.001). Those in the Mandometer group also had greater improvement in concentration of high density lipoprotein cholesterol (P=0.043). <b>Conclusions</b> Retraining eating behaviour with a feedback device is a useful adjunct to standard lifestyle modification in treating obesity among adolescents. <b>Trial registration</b> ClinicalTrials.gov NCT00407420.
Germline mutations in RAD51D confer susceptibility to ovarian cancer
Authors: Chey Loveday, Clare Turnbull, Emma Ramsay, Deborah Hughes, Elise Ruark, Jessica R Frankum, Georgina Bowden, Bolot Kalmyrzaev, Margaret Warren-Perry, Katie Snape, Julian W Adlard, Julian Barwell, Jonathan Berg, Angela F Brady, Carole Brewer, Glen Brice, Cyril Chapman, Jackie Cook, Rosemarie Davidson, Alan Donaldson, Fiona Douglas, Lynn Greenhalgh, Alex Henderson, Louise Izatt, Ajith Kumar, Fiona Lalloo, Zosia Miedzybrodzka, Patrick J Morrison, Joan Paterson, Mary Porteous, Mark T Rogers, Susan Shanley, Lisa Walker, Diana Eccles, D Gareth Evans, Anthony Renwick, Sheila Seal, Christopher J Lord, Alan Ashworth, Jorge S Reis-Filho, Antonis C Antoniou, Nazneen Rahman
Journal: Nature Genetics (2011)
Tumor Vascular Proteins As Biomarkers in Ovarian Cancer
Authors: Ronald J. Buckanovich, Dimitra Sasaroli, Anne O'Brien-Jenkins, Jeffrey Botbyl, Rachel Hammond, Dionysios Katsaros, Raphael Sandaltzopoulos, Lance A. Liotta, Phyllis A. Gimotty, George Coukos
Journal: Journal of Clinical Oncology (2007)

Purpose This study aimed to identify novel ovarian cancer biomarkers and potential therapeutic targets through molecular analysis of tumor vascular cells. Methods Immunohistochemistry-guided laser-capture microdissection and genome-wide transcriptional profiling were used to identify genes that were differentially expressed between vascular cells from human epithelial ovarian cancer and healthy ovaries. Tumor vascular markers (TVMs) were validated through quantitative real-time polymerase chain reaction (qRT-PCR) of immunopurified tumor endothelial cells, in situ hybridization, immunohistochemistry, and Western blot analysis. TVM expression in tumors and noncancerous tissues was assessed by qRT-PCR and was profiled using gene expression data. Results We identified a tumor vascular cell profile of ovarian cancer that was distinct from the vascular profile of normal ovary and other tumors. We validated 12 novel ovarian TVMs. These were expressed by immunopurified tumor endothelial cells and localized to tumor vasculature. Select TVMs were found to be specifically expressed in ovarian cancer and were absent in all normal tissues tested, including female reproductive tissues with physiologic angiogenesis. Many ovarian TVMs were expressed by a variety of other solid tumors. Finally, overexpression of any one of three ovarian TVMs by vascular cells was associated with decreased disease-free interval (all P &lt; .005). Conclusion We have identified for the first time the molecular profile of ovarian tumor vasculature. We demonstrate that TVMs may serve as potential biomarkers and molecular targets for ovarian cancer and a variety of other solid tumors.