tbuckley/cabot-search huggingface dataset:
Abstract 3736: The HDL Receptor SR-BI Modulates Platelet Function and Susceptibility to Thrombosis <i>in vivo</i>
Authors: Suzanne J Korporaal, Illiana Meurs, Menno Vergeer, Arnaud Hauer, Reeni B Hildebrand, Domenico Praticò, Jan-Willem N Akkerman, Theo J Van Berkel, Johan Kuiper, Jan Albert Kuivenhoven, Miranda Van Eck
Journal: Circulation (2008)

Objective: Scavenger receptor BI (SR-BI) is a cell surface receptor that promotes the selective uptake of cholesteryl esters from HDL by the liver. In mice, SR-BI deficiency leads to increased plasma HDL cholesterol levels and enhanced susceptibility to atherosclerosis. Recently, a family was identified in which heterozygous carriers of a mutation (P297S) in SR-BI showed elevated HDL cholesterol levels, suggesting that SR-BI is equally important in controlling HDL cholesterol levels in humans. Interestingly, SR-BI is also expressed on platelets, which play a crucial role in atherothrombosis. The aim of this study was to investigate the role of SR-BI in platelet function in both SR-BI knockout (KO) mice and human P297S carriers. Methods &amp; Results: Hematological analysis showed that SR-BI deficiency in mice caused thrombocytopenia (381±69x10 9 SR-BI KO platelets/L vs 878±162x10 9 wildtype (WT) platelets/L, p=0.001). Correspondingly, SR-BI deficiency increased tail bleeding times from 85±8 to 134±16 sec (p=0.02). SR-BI KO platelets were abnormally large (7.1±0.3 fl vs 5.8±0.0 fl for WT platelets, p=0.0004), probably caused by an increased cholesterol content. Platelet count and size of the human P297S carriers were, however, not significantly different from matched controls. The FeCl 3 acute injury model was used to study the effect of SR-BI deficiency in mice on the susceptibility to arterial thrombosis. WT mice developed total arterial occlusion after 24±2 min. In SR-BI KO mice, however, the time to total arterial occlusion was reduced 2-fold to 13±1 min (p=0.02). In line with this finding, SR-BI KO and P297S platelets circulated in an activated state and showed increased adherence to immobilized fibrinogen. The activated state of the platelets in vivo led to desensitization of the receptors for ADP and thromboxane that are essential for positive feedback mechanisms to enhance the platelet response. As a result, ex vivo aggregation of platelets from SR-BI KO mice and P297S carriers was inhibited in response to agonist stimulation as compared to control platelets. Conclusion: SR-BI is not only essential for HDL cholesterol homeostasis and atherosclerosis susceptibility, but also for maintaining normal platelet aggregation and prevention of thrombosis.
Abstract 3441: Paraoxonase-192 Polymorphism Interaction with Low HDL Cholesterol in Coronary Artery Risk
Authors: Andreia M Pereira, Isabel M Mendonca, Ana I Freitas, Ana C Sousa, Susana Gomes, Paula Faria, Sonia Freitas, Ilidio Ornelas, Antonio Brehm, Antonio Cardoso, Roberto Palma dos Reis
Journal: Circulation (2008)

Background: Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidative enzyme in high density lipoproteins (HDL), which protects against lipid per oxidation and Coronary Artery Disease (CAD). PON 1 activity is under genetic control and its molecular basis is a polymorphism in the PON 1 gene that shows two common isoforms: Q (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and R (Arg) with lower ability. Aim: To explore the interaction of the R allele paraoxonase gene and low HDL cholesterol concentrations, in CAD risk emergence. Methods: 818 individuals participated in the study, 298 coronary patients, 55.0±10.3 years, 78.9% male sex, and 520 healthy controls, 47.3±12.6 years, 57.5% male sex, age and sex matched. Low HDL-C was defined as &lt;0.90 mmol/L in men and &lt; 1.11 mmol/L in the women. Comparisons of genotypes between cases and control subjects were performed by a chi-square test. Statistical significance was accepted at p&lt;0.05. Odds ratio as well as their 95% confidence intervals for the RR genotypes and HDL deficient subjects were computed using univariate analysis (2x2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used the epidemiologic tables 4x2 and the synergy measures: the additive model (Rothman’s synergy index) and the multiplicative model (Khoury’s synergy index). We calculated the relative excess risk (RERI) and the attributable proportion (AP) due to interaction (Rothman). Results: The PON 1 RR192 is associated with coronary heart disease [OR=1.61; p=0.043] in whole population. The HDL-deficient subjects 192 RR homozygotes showed an increased risk of CAD (OR=17.38; p&lt; 0.0001) compared to normal HDL 192 RR (OR=1.39; p=0.348) and HDL-deficient subjects not carrying RR genotype (OR=7.79; p&lt;0.0001). The genotype PON 192 RR increases the risk of CAD in the HDL-deficient populations (SI=2.3, SIM=1.6). The attributable proportion due to this interaction (AP) was 0.53, meaning that 53% of CAD was explained by this interaction. Conclusion: These data suggest the existence of a synergistic effect of the RR 192 PON 1 genotype (with lower ability) and HDL-deficient subjects in CAD emergence.
Compression ultrasonography for diagnosing deep vein thrombosis
Authors: D E FitzGerald, A M O'Shaughnessy, J. H Gillard, N. J Screaton, L. H Berman, J. H Reid, D. J Hardwick, S. Wolstenhulme, S. Richards, M. Weston, P. L Harper, L. Watson, R. Bannon, H. Bounameaux, A. Perrier, A. W A Lensing, P. Prandoni
Journal: BMJ (1998)

Editor—We advise caution in adopting the proposed abbreviated examination protocol for detecting deep vein thrombosis in the leg.1,2 Our experience using duplex ultrasonography to study the natural course of deep vein thrombosis leads us to make the following points. 

Firstly, it is incorrect that calf deep vein thrombosis cannot be accurately diagnosed by duplex ultrasonography. Many reports from expert centres refute such an opinion, although we agree that the skill and experience of the sonographer is important. 

Secondly, about 14% of isolated calf deep vein thromboses propagate into the proximal veins. Others have reported an incidence of up to 20% propagation.3

Thirdly, because of the varying attitudes to management of isolated calf deep vein thrombosis some will argue against the need to investigate these veins on the basis that pharmacological treatment is not contemplated. 

Fourthly, isolated superficial femoral deep vein thrombosis without involvement of the popliteal (distal) or common femoral (proximal) venous segments can occur. This presentation may cause few clinical signs and symptoms, and the thrombus only partially occludes the vein with poor adhesion of the clot to the vein wall. The frequency of this presentation makes it mandatory to examine the whole length of the veins in the thigh. The additional time required is minimal, but the information obtained is important. 

Fifthly, the editorial scenario of office based worldwide facilities to diagnose deep vein thrombosis accurately2 requires sufficient technical skill and experience with audit control to assure standards at each of these offices. Reports of therapeutic results could otherwise be confusing. 

The examination protocol recommended by Cogo et al has the attraction of saving time but does so at the expense of ignoring 15-25 cm of vein in the thigh (which might take 2 minutes to examine) and excluding the calf veins, which have a potential to propagate thrombi in 14-20% of cases. Re-investigation after a week detected a further 1% of deep vein thromboses in those venous segments being examined. We believe that one full examination of the veins of the leg would provide more comprehensive information, take less time, and be more cost effective than investing in two examinations over a week evaluating only short selected segments of the venous system.
Abstract 2237: Rapid T1w Molecular Imaging of Atherosclerotic Angiogenesis with Colloidal Iron Oxide Nanoparticle
Authors: Shelton D Caruthers, Angana Senpan, Dipanjan Pan, Todd A Williams, John S Allen, Michael J Scott, Patrick J Gaffney, Samuel A Wickline, Gregory M Lanza
Journal: Circulation (2008)

Introduction : MR molecular imaging and anti-angiogenic treatment with integrin-targeted nanoparticles offer an attractive nanomedicine tool against atherosclerosis. Objective: The objective was to synthesize targeted colloidal iron oxide nanoparticles (CION), which allow high-resolution T1 w images within 2hrs of injection without T2* artifacts or latent blood pool interference. Method: Oleate-coated magnetite nanoparticles were suspended in vegetable oil and emulsified with phospholipid surfactants. With MR (1.5T &amp; 3T), CION (140 –160 nm) were characterized in solution, on fibrin clot phantoms and targeted to angiogenesis in vivo . Blood pool signal was measured over time following IV injection of CION. Result: CION r1 ionic and particulate relaxivities were 1.1±0.1 mmol[Fe] −1 s −1 and 18466±1739 mmol[CION] −1 s −1 at 1.5T and 0.7±0.06 mmol[Fe] −1 s −1 and 10966±1062 mmol[CION] −1 s −1 at 3T. CION targeted to fibrin clots produced marked T1w signal enhancement (SNR=26) versus control clots (SNR=10). T2-weighted images of the bound agent was notable for signal dropout. In atherosclerotic rabbits, the T1 &amp; T2* effects on blood signal ( i.e. , background interference) were resolved in &lt; 1hr. In vivo T1w molecular imaging of the atherosclerotic neovasculature 2h post-injection, was analyzed with a semiautomatic algorithm and demonstrated the potential of T1w neovascular imaging. Conclusion: Targeted CION are a new class of vascular constrained T1w molecular imaging agent with potential for detection and characterization of ruptured plaque and atherosclerotic neovasculature, which overcome the temporal and spatial imaging challenges of previous iron oxide agents.
Dead
Authors: John H Noble
Journal: BMJ (2007)

Servicing the overarching interests of the drug and medical device industry, the United States has apparently successfully intervened in the past (and still tries) with provisions that weaken the protection of human subjects, taking the document farther and farther from the principles and intent of the Nuremberg Code. The World Medical Association, it appears, has been party to medical malpractice in its most wanton manifestation. Fortunately, unlike the Nuremberg Code, most courts of law do not rely on the Declaration of Helsinki for guidance.

The answer to Goodyear et al's question—“Declaring Helsinki—alive or dead?”—seems to be that the Declaration of Helsinki is dead on the basis of no brain waves, no heart beat, and a rapidly bloating, blow fly infested, stinking cadaver.1

Cynically, one must ask “what is the purpose of current efforts to “harmonise” the ethics and legalities of clinical trials in countries with no device regulatory system?” How can one “harmonise” the practice of numerous unethical experiments conducted by researchers with no “internalised ethical values?” How can one “harmonise” wholesale failure to internalise ethical values?” As the ethicist Arthur Caplan said, “In many ways, rats and mice get greater protection as research subjects in the United States than do humans.”2

Efforts to change the Declaration of Helsinki that come from the US should be recognised for what they represent. The United States and the US Federal Drug Administration have abdicated oversight of human subjects research, as indicated by a recent report of the US Department of Health and Human Services inspector general, “. . . federal health officials did not know how many clinical trials were being conducted, audited fewer than 1 percent of the testing sites and, on the rare occasions when inspectors did appear, generally showed up long after the tests had been completed.”2

Sadly, I think that it is time for the rest of the world to look away from the US for moral leadership. Perhaps it is time to turn to the Canadian Ottawa Statement, to which the authors approvingly refer.
Abstract 3638: Abnormalities of Left Ventricular Geometry in Youth with Type 2 Diabetes: A greater effect of obesity than fasting glucose
Authors: Holly M Ippisch, Stephen R Daniels, Elaine M Urbina, Lawrence M Dolan, Baiyang Wang, Thomas R Kimball
Journal: Circulation (2007)

Background: Type 2 diabetes (T2), previously a disease of adult onset, is increasing in prevalence amongst children and young adults. Yet the presence of cardiovascular risks, such as left ventricular hypertrophy (LVH) are largely unknown in this population. Purpose: To determine the frequencies of abnormal left ventricular (LV) mass and geometry in young people with T2. Methods: LV mass (LVM) was assessed by echo, indexed to height in meters 2.7, and compared to healthy Obese (O) and Lean (L) controls of similar age, gender matched, non-diabetics. Statistical analysis was performed with non-parametric tests. Data are presented as mean and standard deviations. Results: A total of 98 T2 (ages 11–23 yrs, 19 ± 4 yrs; 64% female, 36% male; BMI 35 ± 8) were evaluated and compared to O &amp; L controls (BMI 36 ± 7 and 21 ± 3, respectively). Although indexed LVM was higher for T2 compared to L (36 ± 11 vs. 27 ± 6 gm/m2.7, p = &lt;0.0001) it was not different compared to O controls. LV geometry was similarly abnormal in the T2 &amp; O groups, with increased frequency of concentric and eccentric LVH compared to lean controls (Table 1 ). Systolic (SBP) and diastolic (DBP) blood pressure were higher in the T2 vs. O &amp; L (p&lt;0.05). In univariate analysis for T2, indexed LVM correlated with BMI (p&lt;0.0001, R=0.65) but not: BP, gender, race, or fasting plasma glucose. In multiple regression for T2, log index LVM was predicted by BMI (p&lt;0.0001) &amp; gender (p=0.02) (R2=0.46) but not BP, race or fasting plasma glucose. Conclusions: Young people with T2 have higher indexed LVM and abnormal LV geometry compared to lean controls. Obesity, not fasting plasma glucose seems to be a primary factor associated with LVM. These data suggest that obesity is a primary factor in the early cardiac changes in youth with T2. Early weight loss may have a greater beneficial effect on cardiac geometry than glycemic control. Table I: Prevalence of Left Ventricular Geometries
Abstract 4354: Combining Amino-Terminal Pro-B Type Natriuretic Peptide with the Interleukin Receptor Family Member ST2 for Optimal Long-Term Risk Prediction in Acute Dyspnea: Multimarker Results at 4 Years from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study
Authors: Shafiq R Rehman, Roland R van Kimmenade, James L Januzzi
Journal: Circulation (2008)

Background: Acute dyspnea at presentation to the emergency department (ED) is associated with significant mortality risk. Amino-terminal pro-B type natriuretic peptide (NT-proBNP) and interleukin f...
Abstract 915: The Effect of Gender and Race on Outcomes in Patients Undergoing PCI for Proximal Coronary Artery Lesions: A Report from the NHLBI Dynamic Registry of PCI
Authors: Sandy M Green, Faith Selzer, Suresh Mulukutla, Ashley Lee, Lee S Joon, Sherry F Kelsey, Kevin E Kip, Oscar C Marroquin
Journal: Circulation (2008)

Background: Little is known about the effect of gender and race on outcomes in patients after revascularization of proximal coronary lesions (PCL). We investigated their effect on outcomes using the NHLBI Dynamic Registry. Methods: Of the 9962 patients receiving PCI, 3918 (39%) were treated for disease in a proximal coronary artery segment. Left main and PCI for graft lesions were excluded. Primary outcomes were death/MI or need for repeat revascularization at 1 year after the index procedure. Results: 80% of the patients were white (n=3144), 11% black (n=469), 63% male (n=2461), and 37% female (n=1457). Patients with PCL had lower rates of HTN, prior MI, but where older and had more concomitant medical disease. Compared to non-proximal lesions, patients with PCL had higher rate of death (5.4% vs. 4%, p=0.001) and repeat revascularization (16.3% vs. 14.3%, p=0.01). The effect of gender and race were then included in the multivariate model for predicting risk in patients with PCL (Table 1 ). Race did not modify the risk associated with PCL but females had a 32% greater relative risk (p=0.002) of repeat revascularization when compared to men. Conclusions: Treatment of proximal coronary lesions is associated with a more adverse outcomes compared to non-proximal coronary lesions. In this high-risk population, female gender is an independent predictor for the need for repeat revascularization. Table 1: Event rates, unadjusted and adjusted hazard ratios and 95% confidence intervals in patients undergoing proximal vessel PCI
Abstract 17531: Two-Year Clinical Results Comparing Abciximab vs. Eptifibatide in Combination With 600mg vs. 300mg Clopidogrel Loading Dose in Patients With ST-Elevation Myocardial Infarction: Results from the HORIZONS-AMI Trial
Authors: Harsimran S Singh, George Dangas, Roxana Mehran, Giulio Guagliumi, Bernhard Witzenbichler, Ran Kornowski, Cindy L Grines, Bernard J Gersh, Dariusz Dudek, Gregg Stone
Journal: Circulation (2010)

Background:  Platelet GPIIb/IIIa receptor inhibitors (GPI), abciximab (A) and eptifibatide (E), are commonly used in patients with ST-segment elevation myocardial infarction (STEMI) undergoing emergency angiography and percutaneous coronary intervention (PCI). Administration of the ADP receptor inhibitor clopidogrel is also indicated in STEMI. There are no comparative data on the types of GPI agents in combination with high or low (600 mg vs. 300 mg) clopidogrel loading doses.   Methods:  In this sub-study of the HORIZONS-AMI trial, we examined the 2-year clinical outcomes of STEMI patients treated in the heparin plus GPI study arm stratified by the loading dose of clopidogrel. We compared the 4 groups: A+clopidogrel 600 mg (A+C600, n= 612), A+clopidogrel 300 mg (A+C300, n= 346), E+clopidogrel 600 mg (E+C600, n= 565), and E+clopidogrel 300 mg (E+C300, n= 276). Major bleeding, major adverse events (MACE=death, reinfarction, target vessel revascularization (TVR), and stroke), and net adverse clinical events (NACE= MACE and major bleeding) were obtained.   Results:  All four groups had similar baseline ventricular function, conjunctive anti-thrombotic therapies, initial TIMI flow, and lesion severity. Among A+C600, A+C300, E+C600, E+C300, significant differences included hypertension (51%, 58%, 60%, 51%; p=0.007), diabetes (14%, 20%, 18%, 19%; p=0.10), LAD vessel PCI (37%, 46%, 45%, 42%; p=0.003), and closure device use (29%, 15%, 37%, 27%;p=0.001). At 30-day and 2-year follow-up, there were no differences in outcomes by univariate analysis (Table). Multivariate analysis controlling for baseline risks will be presented.   Conclusion:  Patients with STEMI treated with heparin, GPI, and clopidogrel showed similar bleeding risks and clinical efficacy after 2-year follow-up by univariate analysis, regardless of GPI type or clopidogrel loading dose combinations.
Abstract 1486: Activated Vitamin D Regresses Cardiac Hypertrophy and Attenuates Progression to Heart Failure in Dahl Salt-Sensitive Rats
Authors: Bhargavi Yalamarti, Qingen Ke, Natalya Bodyak, Isaac Stillman, Hector Tamez, S. A Karumanchi, Ravi Thadhani, Peter M Kang
Journal: Circulation (2008)
Abstract 11370: Quantification of S-Nitrosation Indicates Thiol Reactivity Can Gauge the Magnitude of Oxidative Stimuli
Authors: Christopher I Murray, Helge Uhrigshardt, Robert N O'Meally, Robert N Cole, Jennifer E Van Eyk
Journal: Circulation (2011)

Oxidative species modify critical cysteine thiols, known as redox-switches, which sense and respond to the cell's fluctuating environment. Depending on the magnitude, these fluctuations can regulat...
Abstract 383: Depletion of Perivascular Macrophages of the Blood-Brain Barrier Reduces Sympathetic Drive in Rats after Myocardial Infarction
Authors: Yang Yu, Zhi-hua Zhang, Shun-guang Wei, Jordi Serrats, Robert M Weiss, Robert B Felder
Journal: Circulation (2008)

Pro-inflammatory cytokines induce cyclooxygenase-2 (COX-2) activity and synthesis of prostaglandin E2 (PGE 2 ) in perivascular macrophages of hypothalamic paraventricular nucleus (PVN). Cytokine-induced PGE 2 synthesis in the brain contributes to increased sympathetic nerve activity following myocardial infarction (MI). Perivascular macrophages can be selectively depleted by clodronate liposomes. Depletion of perivascular macrophages of the blood-brain barrier will reduce COX-2 expression and cytokine-induced sympathetic nerve activity in rats after MI. Clodronate liposomes (CLOD), control liposomes (LIPO) or vehicle (VEH, artificial CSF) were injected (1 μl/min over 40 minutes) into lateral ventricle in rats within 24 hours of MI, or normal rats. One week after injection, perivascular macrophages were completely destroyed and COX-2 immunoreactivity was eliminated in PVN of all CLOD-treated rats but not in LIPO or VEH-treated rats. Activated microglia were unaffected by CLOD. Compared with sham-operated rats (n=10), VEH-treated MI rats (n=11) had increased COX-2 (0.09±0.01* vs 0.05±0.01, normalized to GAPDH, *P&lt;0.05), interleukin-1β (IL-1β, 0.48±0.06* vs 0.21±0.03) and tumor necrosis factor - α (TNF-α, 0.50±0.09* vs 0.22±0.08) mRNA in PVN, IL-1β (23±2* vs 15±1, pg/ml), TNF-α (5±1* vs 2±0, pg/ml), norepinephrine (1146±143* vs 450±66, pg/ml) levels in plasma, PGE 2 (1152±109* vs 480±84, pg/ml) in CSF and Fra-like-positive neurons (40±3* vs 21±2) in PVN. CLOD treatment of MI rats (n=11) normalized COX-2 mRNA in PVN and reduced CSF PGE 2 (by 30%#, #P&lt;0.05 vs VEH), plasma norepinephrine (by 34%#) and Fra-like positive PVN neurons (by 29%#), but had no effects on IL-1β and TNF-αin PVN or plasma. In normal rats, CLOD treatment (n=9) reduced (P&lt;0.05, vs VEH) sympatho-excitatory responses (renal sympathetic nerve activity, blood pressure and heart rate) induced by intracarotid artery injection of TNF-α (0.5 μg/kg). No effects were found in LIPO-treated MI or normal rats. Pro-inflammatory cytokines stimulate sympathetic excitation after MI by inducing COX-2 activity and PGE 2 production in perivascular macrophages of the blood-brain barrier.