tbuckley/cabot-search huggingface dataset:
Late-breaking abstract: Further studies on the mechanism of action of doxofylline
Authors: Thierry Jolas, Clive Page, Luigi Allegra
Journal: European Respiratory Journal (2011)

Xanthines such as theophylline have been used in the treatment of lung diseases since the early 19009s, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. This means that regular plasma levels often have to be obtained and can make the use of theophylline problematic. With the increasing availability of other classes of drugs for the treatment of respiratory diseases, this has limited the use of xanthines, despite their clean clinical benefit in the treatment of patients with asthma and COPD. Doxofylline is a xanthine molecule having both bronchodilator and anti-inflammatory activity, with an improved therapeutic window over conventional xanthines such as theophylline. However, the mechanistic basis of this improved therapeutic window is not understood. The present study has investigated the ability of doxofylline to inhibit human recombinant PDE and HDAC enzymes, and bind to adenosine receptor assays  in vitro  in comparison with theophylline. Theophylline had a significant effect on adenosine receptor binding that was not shared by doxofylline. Our results suggest that doxofylline may have a wider therapeutic window than theophylline due to a lack of adenosine receptor antagonism. Neither drug had any significant inhibitory effect on HDAC enzymes over a wide range.  Additionally, in contrast to doxofylline, theophylline showed a significant effect on PDE3. It has been suggested that the ability of theophylline to inhibit PDE3 may contribute to the unwanted cardiovascular effects observed at higher serum concentrations. The lack of effect of doxofylline on PDE3 may also help explain its improved tolerability profile on the cardiovascular system.
Abstract 47: Awakening After Cardiac Arrest and Post-Resuscitation Hypothermia: Are We Pulling the Plug too Early?
Authors: Keith Lurie, Scott Davis, John Olsen, Dana Oakes, Susie Osaki Holm, Debbie Gillquist, Charles Lick, Demetris Yannopoulos, Barbara Gold
Journal: Circulation (2010)

Introduction: Time to awakening after out-of-hospital cardiac arrest (OHCA) and post-resuscitation therapeutic hypothermia (TH) varies widely. The amount of time clinicians should wait before withd...
Abstract 17275: Induction of Arteriogenesis in Mouse Hindlimb by Human Peripheral Blood B Cells as Determined by Micro-CT Imaging
Authors: Traci Goodchild, Michael Sweet, Jianing Yue, Lisa Godwin, Nicolas Chronos, Mark Poznansky, Jai Pal Singh
Journal: Circulation (2011)

For patients with critical limb ischemia, restoration of blood flow through mechanical or pharmacological revascularization is an important therapeutic goal. Clinical studies have been unsuccessful in enhancement of neovascularization by treatment with angiogenic growth factors. We have shown that bone marrow derived B cells delivered into rat ischemic myocardium preserves cardiac function (Goodchild et al, 2009) and we sought to determine if B cells could be therapeutically beneficial in a mouse model of critical limb ischemia. Since commonly used histological determination of angiogenesis only provides semi-quantitative measure of vessels in limited tissue area without confirming perfusion functionality, this study measured the angiogenic and arteriogenic activities of B cell therapy using high resolution computed tomography. Mice (n=16, Balb/c) had iliac and femoral arteries and veins ligated. Mouse bone marrow B cells (CD19+) isolated by antibody-magnetic bead selection or saline control was injected directly into ischemic muscles. A post-ligation laser Doppler scan was performed to ensure ligation consistency then scanned weekly. On Day 28, mice were euthanized, vasculature flushed, fixed and perfused with contrast agent. Limbs were imaged by micro-CT with reconstruction at 25um. Data represented as vascular segment number and area counted in 500 slices in 3D micro-CT images. At Days 7, 14, 21 and 28, blood flow increased in B cell treated ischemic hindlimbs compared to controls. At Day 28, B cell treatment increased number of vessels in treated-ligated legs compared to unligated legs (8033±439 vs. 5297±710 vessels, respectively; P=0.010) and vessel area (175.9±45.4 vs. 99.0±28.6 mm2, respectively; P=0.012). Vessels ranging from 25-175 and 225-350um were increased in B cell treated-ligated legs compared to unligated legs (P&lt;0.05). Vessel number ratio in treated-ligated legs to unligated legs was higher in B cell treated compared to control treated mice (1.66 vs. 1.05; P=0.025). These data show that unlike angiogenic response to treatment with growth factors, B cells enhanced development of vessels with a wide range of diameters suggesting that B cells may offer therapeutic potential for treatment of ischemic peripheral artery disease.
Abstract MP030: Insufficient Sleep Increases Caloric Intake but not Energy Expenditure
Authors: Andrew D Calvin, Rickey E Carter, James A Levine, Virend K Somers
Journal: Circulation (2012)

Introduction: Identifying and mitigating factors that promote obesity will have a large public health impact. Sleep may be an important regulator of metabolism and energy expenditure. Voluntary sleep restriction is common, with 27% of US adults regularly getting ≤6 h of sleep per day. Epidemiologic evidence suggests a link between short sleep duration and obesity. Human experiments suggest that acute sleep deprivation reduces the anorexigenic hormone leptin, increases the orexigenic factor ghrelin, and promotes caloric intake. Meanwhile, increased energy expenditure during prolonged wakefulness may counterbalance any increased caloric intake associated with a lack of sleep. Hypothesis: We hypothesized that 8 days of modest sleep restriction would reduce leptin, increase ghrelin, promote caloric intake, and increase activity energy expenditure. Methods: We studied 17 healthy individuals age 18–40 y. Subjects completed a protocol consisting of one week of home actigraphy, a 3 night acclimation phase, followed by an 8 night experimental phase in which they were randomized to sleep ad lib or two-thirds of their normal sleep time. Blood was collected at the end of the two periods, food was freely available and caloric intake was calculated daily, and activity energy expenditure was assessed by a comprehensively validated system comprised of inclinometers and accelerometers. Sleep was confirmed using continuous electroencephalography. Mean change from the acclimation period ± standard deviation are presented, with statistical testing by two sample t tests on the changes between acclimation and experimental periods. Results: Subjects included 11 men and 6 women, of whom 8 were randomized to sleep deprivation and 9 served as controls. Sleep duration during the acclimation period averaged 6.5±0.9 h/day but fell to 5.2±0.1 h/d among those randomized to sleep deprivation. The sleep deprivation group consumed +549±583 kcal/d, whereas those randomized to ad lib sleep consumed −143±420 kcal/d (P&lt;0.01). Activity energy expenditure by did not change in either group (+1.2±33.0% vs +8.4±34.0%, P=0.68). Sleep deprivation was associated with a trend towards increased leptin (+8.4±4.7% versus −9.8±13.5%, P=0.12) and decreased ghrelin (−4.9±5.3% vs +4.6±7.0%, P=0.38). Conclusions: Eight days of modest sleep restriction, similar to that encountered in everyday life, was associated with a striking increase in caloric intake with no change in activity energy expenditure. Contrary to expectations, we observed a trend towards increased circulating concentrations of leptin and reduced concentrations of ghrelin, more consistent with a consequence of a positive energy balance than a cause. Our data suggest that chronic sleep restriction may be an important and modifiable behavior promoting obesity.
Abstract 1833: Comprehensive Cardiac Magnetic Resonance Imaging in Family Members of Desmosomal Mutation-Associated Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients Reveals a Possible Early Sign of the Disease
Authors: Darshan Dalal, Harikrishna Tandri, Cynthia James, Crystal Tichnell, Theodore Abraham, Stuart D Russell, Daniel P Judge, David A Bluemke, Hugh Calkins
Journal: Circulation (2007)
Abstract 5798: Nanoparticle-mediated Endothelial Cell-selective Delivery of Pioglitazone Improves Therapeutic Efficacy of Ischemic Neovascularization
Authors: Ryoji Nagahama, Tetsuya Matoba, Kaku Nakano, Kaori Hara, Hiroyuki Tsujimoto, Kenji Sunagawa, Kensuke Egashira
Journal: Circulation (2009)

Background: Recent studies suggest that a peroxisome proliferator activated receptor- γ (PPAR γ ) agonist pioglitazone reduces the incidence of ischemic cardiovascular events. However, it is unknown if pioglitazone induces therapeutic neovascularization after induction of ischemia. Moreover, novel drug delivery system may alleviate potential adverse effects of systemic administration of PPAR γ agonists. We recently reported that intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into vascular endothelial cells of ischemic muscles for 2 weeks post-injection in a murine model of hindlimb ischemia. Hence, we tested the hypothesis that nanoparticle (NP)-mediated endothelial cell selective delivery of pioglitazone is an effective therapy to induce ischemic neovascularization in vivo. Methods and Results: In a murine model of hindlimb ischemia, systemic oral administration of pioglitazone at a dose of 1000 μ g/kg per day, but not other lower doses, enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis 3 weeks after induction of ischemia (Figure A ). In contrast, single intramuscular injection of NP incorporated with pioglitazone at 1 or 10 μ g/kg into ischemic muscles immediately after induction of ischemia significantly enhanced ischemic neovascularization at 3 weeks post-ischemia (Figure B ). Intramuscular injection of PBS, FITC-NP, or pioglitazone only at 1–10 μ g/kg showed no effects on blood perfusion to the ischemic limb. Conclusion: NP-mediated endothelial cell-selective delivery of pioglitazone may effectively induce therapeutic neovascularization. A. Effects of Systemic Oral Administrate of Pioglitazone for 21 days B. Effects of Single Intramuscular Injection of Pioglitazone-NP
Successful use of interventional lung assist device in a patient with near fatal asthma
Authors: Tanner Laura, Murphy Stephen
Journal: European Respiratory Journal (2011)

Interventional lung assist devices (iLA) are pumpless, arterio-venous, extra-corporeal lung support devices with a low resistance gas exchange membrane that allows rapid removal of carbon dioxide (CO2) and moderate oxygenation. Currently they are mainly used in acute respiratory distress syndrome and as a bridge to lung transplantation. We successfully used iLA in an near fatal asthmatic patient with hypercapnic respiratory failure refractory to conventional ventilation.  A male patient aged 55 years presented with a near fatal exacerbation of asthma. He was a current smoker with co-morbidities including obesity, previous poliomyelitis affecting right leg, stroke and ischaemic heart disease. Despite full medical treatment, endobronchial intubation and invasive mechanical ventilation (IMV) plus a range of intravenous and inhaled medications including intravenous terbutaline, ketamine, adrenaline and inhaled adrenaline and isofluorane he developed persistent hypercapnic respiratory failure with PaCO2 > 20. Conventional ventilation strategies were ineffective with poor compliance, high peak airway pressures and prolonged inspiratory times resulting in air trapping and hyperinflation. Therefore an iLA was inserted on day 2. This resulted in enhanced CO2 removal (Pa CO2 21 down to PaCO2 7.6) and allowed protective lung ventilation at lower pressures with less gas trapping and hyperinflation. The iLA was removed on day 12 with spontaneous breathing on day 19. This could represent a useful future strategy for persistent hypercapnic respiratory failure unresponsive to conventional measures in obstructive diseases such as asthma and COPD.
Abstract 15920: A Whole Blood Gene-Expression Based Surrogate Test for Smoking Status
Authors: James A Wingrove, Philip Beineke, Karen Fitch, Hegn Tao, Micahel R Elashoff, Steven Rosenberg, William E Kraus, Robert S Schwartz, Szilard Voros, Eric J Topol, Predict Investigators
Journal: Circulation (2011)

Background Smoking is the leading cause of preventable death, resulting in over 5 million deaths per year worldwide (~ 500,000 occurring in the United States) and has been shown to be detrimental t...
Radiation Sickness
Authors: B. A. Stoll
Journal: BMJ (1962)

In 1042 irradiated patients drug trials were conducted in attempts to assess the relative value of central sedatives (mainly phenothiazines) as compared with pyridoxine and a relatively inert group of drugs. The phenothiazines used were of the older type (chlorpromazine, prochlorperazine, thiopropazate, fluopromazine, pecazine) as well as of the newer type (trifluoperazine, haloperidol). The relatively inert drugs included cyclazine, amphetamine, diphenylhydramine, and lactose. For nausea, the predominant symptom, pyridoxine, the older phenothiazines, and the newer tranquilizer groups are all significantly superior to the inert drugs. The newer tranquilizers are superior to all others, but there is no statistical difference between pyridoxine and the older phenothiazines in the relief of nausea. For vomiting and listlessness, a similar superiority of the newer tranquilizers is shown. In the case of anorexia, however, pyridoxine and the older phenothiazines are superior to the inert group but the newer tranquilizers are relatively less effective. For all drugs used in radiation sickness, anorexia is the most difficult symptom to relieve possibly because its control lies in the appetite center, separate from the vomiting center. Possibly some other factor also enters into its control, such as the loss of taste. Haloperidol and trifluoperazine assessed separately showed no statisticalmore » difference in their relative efficacy in any symptom including anorexia. Radiation of the abdomen and pelvis causes more severe radiation sickness, and inert drugs give, in general, less relief of symptoms arising from radiation of this area than of other parts. All the drugs were less efficacious when radiation is given to the abdomen and pelvis, although not at a significantly statistical level. In comparison of the efficacy of each group for irradiation both above and below the diaphragm, the newer tranquilizers appear significantly superior to all others. For nausea arising in 265 cases of breast irradiation, the new tranquilizers are significantly superior to all others. Anorexia after irradiation may originate in the appetite center or have a different cause such as delayed gastric emptying. Separate origins for vomiting and for anorexia may account for the superior effect noted with the newer tranquilizers on the symptoms of nausea and vomiting and the greatly inferior effect on anorexia. The tranquilizers may act by sedating the vomiting center. Evidence was found for a specific deficiency of pyridoxine in some cases of radiation sickness. Whether this is a direct effect on enzymes, an effect on the bowel, or a result of metabolic changes associated with vomiting is uncertain. Nevertheless pyridoxine may be of value even if other anti-emetic drugs fail to control the symptoms of radiation sickness.« less
Abstract 11464: Socially Disadvantaged City Districts Show a Higher Incidence of Acute ST-Elevation Myocardial Infarctions With Higher 1-Year-Mortality and Elevated Cardiovascular Risk Factors - Results From the Bremen Stemi Registry
Authors: Susanne Seide, Johannes Schmucker, Harm Wienbergen, Andreas Fach, Eduard Fiehn, Kathrin Guenther, Anna Reeske, Rainer Hambrecht
Journal: Circulation (2013)

Background: The influence of social status and occurrence of ST-elevation myocardial infarctions (STEMIs) is widely unknown. Aim of our study was to analyze the association of social status in diff...
Bendamustine In Combination With Rituximab As First-Line Treatment For Indolent Non-Hodgkin Lymphoma: Retrospective Analysis Of An Spanish Registry
Authors: Silvia Solorzano, Carmen Martinez-Chamorro, Carlos Panizo, Cristina Quero, Guillermo Deben, Jose Paz, Ana Batlle, Alfons Serrano, Zayda Muentes, Antonio Gutierrez, Jose Francisco Tomas
Journal: Blood (2013)
Food Allergy
Authors: Gideon Lack
Journal: New England Journal of Medicine (2008)

A 3-year-old boy is admitted to the hospital with hives and wheezing after eating chocolate mousse. At 18 months of age, contact urticaria developed after he put his hand into a cake mix containing egg. He also has a history of chronic rhinitis, nocturnal cough, severe eczema, and a previous hospitalization for recurrent wheezing. How should this child be evaluated and treated?
US drug firms resist over the counter sales.
Authors: Fred Charatan
Journal: BMJ (2001)

An advisory panel of the US Food and Drug Administration (FDA) has voted overwhelmingly that three allergy remedies—loratadine, cetirizine, and fexofenadine—are safe enough to be bought at pharmacies and supermarkets without a doctor's prescription. But the manufacturers of the drugs, marketed in the United States as Claritin, Zyrtec, and Allegra, are resisting the idea.

Wellpoint Health Networks, a large Californian insurer, successfully argued before the FDA panel that all three drugs are safer than many of the other allergy drugs that are already sold over the counter.

Dr John Jenkins, director of the FDA office that evaluates anti-allergy drugs, said: “We have not identified any serious safety concerns with any of these drugs.”

But the makers of the drugs argue that Wellpoint is trying to save money by shifting the cost from insurers to patients. Wellpoint has said that it would save $45m (£32m) a year if the drugs were available over the counter.
Hepatic Artery Embolization for Liver Cancer
Authors: Chusilp Charnsangavej, Sidney Wallace, C. Humberto Carrasco, William Bechtel
Journal: Liver Cancer (1985)

It is well known that the liver has a dual blood supply from the portal vein and hepatic artery. Approximately 75% of blood flow to the liver parenchyma is from the portal vein and 25% is from the hepatic artery; 50% of oxygenation is derived from the portal vein and hepatic artery each. However, most primary and secondary neoplasms of the liver receive the blood supply exclusively (more than 90%) from the hepatic artery [1,2].
Initial Results from a Phase 2 Study of Blinatumomab in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Lia Gore, Franco Locatelli, Gerhard Zugmaier, Christian M. Zwaan, Deepa Bhojwani, Rupert Handgretinger, Peter Bader, Maureen M. O'Brien, Tanya M. Trippett, Benoît Brethon, Carmelo Rizzari, Steven G. DuBois, Paul Gerhardt Schlegel, Phillip Barnette, Chiara Messina, Kuolung Hu, Noemi Mergen, Anja Fischer, James Whitlock, Arend von Stackelberg
Journal: Blood (2014)
Abstract 17982: Krìppel-Like Transcription Factor- 2 Preserves Endothelial Function and Protects Against Pulmonary Hypertension
Authors: Alison A Dungey, Yupu Deng, Jun Yin, Simon Rozowsky, Duncan J Stewart
Journal: Circulation (2011)

RATIONALE: Pulmonary Hypertension (PH) is associated with ongoing endothelial cell (EC) dysfunction. Shear-responsive Krüppel-like Transcription Factor- 2 (KLF2) is thought to maintain EC homeostasis and to enhance NO bioavailability by inducing eNOS transcription and decreasing caveolin-1 expression. Thus, we hypothesized that KLF2 expression would be reduced in experimental PH, and KLF2 overexpression would prevent pulmonary arterial (PA) remodeling and preserve EC function in chronic hypoxia (CH)-induced PH. METHODS: Lung KLF2 mRNA levels were measured at 1, 3, 7, or 21 days in the CH (10% O2) rat model of PH. Selective gene transfer of KLF2 or empty plasmid to lung ECs was achieved by intravenous injection of jetPEI™ with plasmid DNA (150µg) at day 3 of CH. At 21 days of CH, right ventricular systolic pressure (RVSP), RV hypertrophy, and medial area in PAs with external diameters of &lt;30µm and 30-50µm were assessed. Ex vivo lung functional analyses were performed and eNOS expression was assessed 24 hrs after shKLF2 delivery. RESULTS: KLF2 mRNA expression was reduced at 3 days of CH (0.3±0.1;P&lt;0.05; normalized to sham), returning to control levels at 7 and 21 days. Compared with control transfection, KLF2 gene therapy reduced RVSP (69.5 ± 6.5 vs. 46.5 ± 2.6 mmHg; P&lt;0.01; n=11-13) and RV/LV+S weight ratios (0.35 ± 0.02 vs. 0.28 ± 0.01, n=11-13; P&lt;0.05), associated with a 1.3 fold increase in lung eNOS expression (P=0.04), but no change in PA medial area at day 21. Moreover, KLF2 knockdown resulted in increased RVSP in normoxic rats, matched with reduced eNOS expression to 0.60 ± 0.08 fold and a blunted vasodilator response to ACh (-4.68 ± 0.99 vs. -7.17 ± 0.80 ⋔mmHg; P&lt;0.01; n=6), while SNP-induced dilation was unchanged (n=4) compared to transfected controls (RS). CONCLUSIONS: These results suggest that KLF2 is protective in the CH model of PH. The mechanism of protection involved maintenance of eNOS expression and endothelial dilatory function, rather than vascular remodeling.
Abstract 16795: Detection of Brown Adipose Tissue Activation and Mass Using Contrast Ultrasound
Authors: Maeva Clerte, David M Baron, Aidan Flynn, Michael J Raher, Kenneth D Bloch, Michael H Picard, Emmanuel S Buys, Peter Brouckaert, Marielle Scherrer-Crosbie
Journal: Circulation (2011)

Obesity is an increasingly frequent condition and a risk factor for cardiovascular diseases. Brown adipose tissue (BAT), located mostly in the paravertebral and supraclavicular space in humans and between the scapulae in rodents, consumes lipids and glucose to produce heat when it is activated by norepinephrine (NE) or cold. Increasing metabolic activity and/or mass of BAT could open new therapeutic avenues to treat obesity. Currently,18F-fluorodeoxyglucose Positron Emission Tomography is the only imaging technique detecting BAT and its activation in humans. Since increased BAT blood flow is associated with BAT activation, we hypothesized that BAT contrast ultrasound (CU) could estimate the degree of BAT activation and BAT mass, both in mice and humans. To validate the ability of CU to estimate BAT perfusion, the BAT and kidney of C57BL6 wild type mice were imaged with a 14 MHz linear transducer during continuous infusion of DefinityTM microbubble contrast. The time intensity curves of the contrast were quantified and blood flow was estimated by the product of the curve plateau A and slope ß. The BAT/kidney blood flow ratio obtained with CU was compared to that measured with fluorescent microspheres. In another experiment, to validate the ability of CU to estimate BAT mass, the maximal area of perfusion of BAT was compared to the BAT weight, in mice. Finally, the BAT vascular response to activation was assessed in 6 mice before and after infusing 1µg/kg/min NE and in 7 young and lean human volunteers before and after cold exposure (16°C for 2 hours).The BAT/kidney blood flow ratio obtained by CU in mice correlated with microsphere measurements (R2=0.85, p&lt;0.05). The maximal area of BAT measured by CU correlated with BAT weight (R2=0.58, p&lt;0.002). Mice demonstrated a 10-fold increase in BAT perfusion after infusion of NE (Aß 0.6±0.1 vs. 5.5±0.9 dB/s, p&lt;0.05) while kidney perfusion decreased. Similarly, BAT perfusion increased in humans after cold exposure (Aß 0.1±0.0 vs. 1.0±0.4 dB/s,p&lt;0.05). In conclusion, contrast ultrasound imaging can be used to estimate BAT activation and its mass. This noninvasive technique free of ionizing radiation offers a method for serial evaluation and monitoring of therapies designed to activate BAT or augment its mass.